pf-06463922 and Lung-Neoplasms

This study aimed to compare the relative efficacy of lorlatinib, an anaplastic lymphoma kinase-tyrosine kinase inhibitor, with chemotherapy, for patients with second-line or later advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. The endpoints of interest were overall survival (OS) and progression-free survival (PFS).. Evidence for lorlatinib was informed by the single-arm phase I/II trial B7461001. A systematic literature review (SLR) was performed to identify OS and PFS data for chemotherapy. Unanchored matching-adjusted indirect comparisons (MAICs) between lorlatinib and chemotherapy (pemetrexed/docetaxel, platinum-based, or systemic therapy) were performed.. The SLR identified 3 relevant studies reporting PFS. Lorlatinib was associated with a significant decrease in the hazard of progression versus the 2 types of chemotherapy assessed. For PFS, the MAIC of lorlatinib versus the combined treatment arm of docetaxel or pemetrexed resulted in an adjusted hazard ratio (HR) of 0.22 (95% confidence interval [CI] 0.15-0.31). When lorlatinib was compared with platinum-based chemotherapy through an MAIC, the adjusted HR for PFS was 0.40 (95% CI 0.29-0.55). An exploratory comparison was performed for OS with evidence for systemic therapy (assumed equivalent to chemotherapy) not identified in the SLR. Lorlatinib provided a significant decrease in hazard of death (OS) versus systemic therapy, with HRs ranging from 0.12 (95% CI 0.05-0.27) to 0.43 (95% CI 0.27-0.60).. Lorlatinib demonstrated a significant improvement in PFS compared with chemotherapy, although limitations in the analyses were identified. The evidence informing OS comparisons was highly limited but suggested benefit of lorlatinib compared with systemic therapy.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Docetaxel; Humans; Lactams, Macrocyclic; Lung Neoplasms; Pemetrexed; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (. This review summarizes the mechanism of action, efficacy, and safety of lorlatinib in. Lorlatinib has shown good efficacy and safety in

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases

This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non-small cell lung cancer (NSCLC).. A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Abstracts related to lung cancer presented at important international conferences were also reviewed. Randomized clinical trials that qualified the inclusion criteria were subjected to Bayesian network meta-analysis and systematically reviewed.. The authors included a total of nine studies including 2441 patients and seven first-line treatments (ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed-based chemotherapy). Overall, lorlatinib appeared to confer the best progression-free survival (PFS) (probability of being the best [Prbest], 90%; surface under the cumulative ranking curve [SUCRA], 98%), and the same conclusion was obtained on paired comparisons (lorlatinib vs. ceritinib [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.20-0.47); lorlatinib vs. chemotherapy [HR, 0.17; 95% CI, 0.12-0.23]; crizotinib vs. lorlatinib [HR, 3.6; 95% CI, 2.4-5.2]; and brigatinib vs. lorlatinib [HR, 1.7; 95% CI, 1.0-2.8]). Alectinib conferred the best overall survival (OS) and safety profile. In the Asian population, ensartinib conferred the best PFS (Prbest 50%, SUCRA 87%), and for patients with brain metastases at baseline, lorlatinib showed the best PFS (Prbest 70%, SUCRA 93%).. For first-line treatment of patients with ALK-positive NSCLC, lorlatinib was associated with the best PFS and objective response rate, but poorer safety profile, whereas alectinib demonstrated the best OS and safety profile. In Asians, ensartinib conferred the best PFS benefit, and in the brain baseline metastasis population, lorlatinib conferred the best PFS benefit.. Among the many molecularly targeted drugs currently used to treat anaplastic lymphoma kinase mutation-positive non-small cell lung cancer, lorlatinib may be one of the most effective targeted drugs. Lung cancer has long been at the top of cancer rankings in terms of incidence and mortality. Today, the treatment of lung cancer has moved into the era of precision therapy. In this article, we use a statistical approach to compare the efficacy and safety of targeted drugs that have been used in the first-line treatment of anaplastic lymphoma kinase mutations to improve the reference for clinicians to make treatment decisions in the real world.

Topics: Anaplastic Lymphoma Kinase; Bayes Theorem; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors

Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Central Nervous System Neoplasms; Humans; Lactams, Macrocyclic; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors

We aimed to investigate the cost effectiveness of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), used first-line in Sweden to treat patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). In January 2022, the European Medicines Agency (EMA) extended its approval of lorlatinib to include adult patients with ALK+ NSCLC not previously treated with an ALK inhibitor. Extended first-line approval was based on results from CROWN, a phase III randomized trial that enlisted 296 patients randomized 1:1 to receive lorlatinib or crizotinib. Our analysis compared lorlatinib against the first-generation ALK-TKI crizotinib, and second-generation ALK TKIs alectinib and brigatinib.. A partitioned survival model with four health states [pre-progression, non-intracranial (non-central nervous system [CNS]) progression, CNS progression, and death] was constructed. The progressed disease state (which is typically modelled in cost-effectiveness analyses of oncology treatments) was explicitly separated into non-CNS and CNS progression as brain metastases, which are common in NSCLC, and can have a large impact on patient prognosis and health-related quality of life. Treatment effectiveness estimates in the lorlatinib and crizotinib arms of the model were derived from CROWN data, while indirect relative effectiveness estimates for alectinib and brigatinib were informed using network meta-analysis (NMA). Utility data were derived from the CROWN study in the base case, and cost-effectiveness results were compared when applying UK and Swedish value sets. Costs were obtained from Swedish national data. Deterministic and probabilistic sensitivity analyses were conducted to test model robustness.. Fully incremental analysis identified crizotinib as the least costly and least effective treatment. Brigatinib was extendedly dominated by alectinib and, subsequently, alectinib was extendedly dominated by lorlatinib. Lorlatinib was associated with an incremental cost-effectiveness ratio (ICER) of Swedish Krona (SEK) 613,032 per quality-adjusted life-year (QALY) gained compared with crizotinib. Probabilistic results were generally consistent with deterministic results, and one-way sensitivity identified NMA HRs, alectinib and brigatinib treatment duration, and the CNS-progressed utility multiplier as key model drivers.. The ICER of SEK613,032 for lorlatinib versus crizotinib falls below the typical willingness-to-pay threshold per QALY gained for high-severity diseases in Sweden (approximately SEK1,000,000). Furthermore, as brigatinib and alectinib were extendedly dominated in the incremental analysis, the results of our study indicate that lorlatinib may be considered a cost-effective treatment option for first-line patients with ALK+ NSCLC in Sweden when compared with crizotinib, alectinib, and brigatinib. Longer-term follow-up data for endpoints informing treatment effectiveness for all first-line treatments would help to reduce uncertainty in the findings.

Topics: Adult; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Quality of Life; Randomized Controlled Trials as Topic; Sweden

Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors

This summary shows the updated results of an ongoing research study called CROWN that was published in. After 3 years of being observed, people who took lorlatinib were more likely to be alive without their cancer getting worse than people who took crizotinib. At 3 years, 64% of people who took lorlatinib were alive without their cancer getting worse compared with 19% of people who took crizotinib. The cancer was less likely to have spread within or to the brain in people who took lorlatinib than in people who took crizotinib. After 3 years of being observed, 61% of people were still taking lorlatinib and 8% of people were still taking crizotinib. People who took lorlatinib had more severe side effects than people who took crizotinib. However, these side effects were manageable. The most common side effects with lorlatinib were high levels of cholesterol or high levels of triglycerides (a type of fat) in the blood. Life-threatening side effects were seen in 13% of people who took lorlatinib and 8% in crizotinib. Two people who took lorlatinib died because of side effects from lorlatinib.. The updated results from the CROWN study showed that a larger percentage of people who took lorlatinib continued to benefit from their treatment after being observed for 3 years compared with those who took crizotinib.

Topics: Aminopyridines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors

To date, no direct comparisons have compared the effectiveness of all ALK inhibitors (ALKis) against ALK-positive non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the efficacy and safety of ALKis in ALK-positive NSCLC.. The effectiveness of ALKis was evaluated by assessing progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and PFS with baseline brain metastasis (BM). The serious adverse events (SAEs: Grade ≥ 3) and adverse events (AEs) leading to discontinuation were pooled to evaluate safety. We conducted an indirect treatment comparison between all ALKis by using a Bayesian model.. Twelve eligible trials including seven treatments were identified. All of the ALKis improved PFS and ORR relative to chemotherapy. Consistent with alectinib, brigatinib, lorlatinib, and ensartinib showed significant differences versus crizotinib and ceritinib. Lorlatinib seemed to prolong PFS compared with alectinib (0.64, 0.37 to 1.07), brigatinib (0.56, 0.3 to 1.05), and ensartinib (0.53, 0.28 to 1.02). No significant difference was found among them in OS except for alectinib versus crizotinib. Moreover, alectinib was significantly more effective than crizotinib (1.54, 1.02 to 2.5) in achieving the best ORR. Subgroup analyses based on BM indicated that PFS was dramatically lengthened by lorlatinib. Compared with other ALKis, alectinib notably reduced the rate of SAEs. There was no striking difference between discontinuation for AEs, except for ceritinib versus crizotinib. The ranking of validity showed that lorlatinib had the longest PFS (98.32%) and PFS with BM (85.84%) and the highest ORR (77.01%). The rank of probabilities showed that alectinib had the potentially best safety in terms of SAEs (97.85%), and ceritinib had less discontinuation (95.45%).. Alectinib was the first choice for patients with ALK-positive NSCLC and even for those with BM, whereas lorlatinib was the second choice. Long-term follow-up and prospective studies are warranted to compare ALKis and to verify our conclusions directly.

Topics: Anaplastic Lymphoma Kinase; Bayes Theorem; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making.. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework.. Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included. A network meta-analysis of all-grade AEs, fatal AEs, and treatment discontinuation due to AEs revealed no significant differences among the six ALK-TKIs. The rates of grade 3-4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%). The toxicity spectra of ALK-TKIs were different. The most frequent AEs associated with crizotinib were gastrointestinal reactions, visual disorders, neutropenia, edema, fatigue, and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, while those in the alectinib group were anemia and constipation. Diarrhea, hepatotoxicity, and increased serum creatinine were most common with ceritinib. The most frequent AEs in the brigatinib group were gastrointestinal reactions, hypertension, cough, headache, and elevated ALT or AST levels. The most significant toxicities of ensartinib were skin disorders, including pruritus and rash. Changes in lipid levels were the most frequent AEs associated with lorlatinib; weight gain, cognitive effects, and mood effects were lorlatinib-specific AEs.. The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3-4 AEs and the combined incidence.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Tyrosine Kinase Inhibitors

ALK tyrosine kinase inhibitors (TKIs) have revolutionized the treatment and largely improved the survival outcomes of patients with NSCLC harboring. A virtual webinar was held on July 2023 to discuss the state of the art and future perspectives in the treatment of. Alectinib and brigatinib are the preferred front-line treatment options in Italy, pending approval of the front-line medicine lorlatinib, which would be considered among the choices. Due to a local regulatory limitation of second-line lorlatinib, which is not allowed after front-line brigatinib, alectinib is commonly the preferred front-line choice to follow a sequence of alectinib, followed by lorlatinib, followed by platinum plus pemetrexed chemotherapy. Age and performance status were not considered per se as clinical features influencing treatment choice. However, treatment compliance is deemed a relevant factor in decision making with regard to the number of pills to be administered. In general, given the availability of alternative choices, the spectrum of patients' comorbidities and polypharmacotherapy interactions should be taken into account in treatment selection according to the toxicity profile of each compound. In addition, several issues were debated with regard to improving treatment outcomes, including testing, brain metastases, and management of an oligoprogressive disease.. The treatment scenario of ALK-positive disease is dynamically evolving. Furthermore, not all FDA- and EMA-approved compounds are approved in Italy with the same indications. This influences therapeutic opportunities and increases the need for greater clinical expertise to help and guide treatment selection.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Tyrosine Kinase Inhibitors

The therapeutic arsenal for advanced ALK positive non-small cell lung cancer has been enriched by specific treatments targeting this molecular abnormality, with five molecules available, including lorlatinib, approved since July 2020. This treatment can have side effects common to other tyrosine kinase inhibitors, as well as other less common disorders affecting the central nervous system such as impaired cognitive function, speech or mood. The prevalence of neuro-psychiatric effects under treatment with lorlatinib reported in studies is nearly 40 % with a mild to moderate intensity in most cases. Given the potential impact on patients' quality of life and even on compliance with treatment, it is essential to include their detection during consultations. The main problem is still to have simple screening tools adapted to clinical practice. A multidisciplinary expert panel (pulmonologist, medical oncologist, psychiatrist, neurologist, pharmacist, nurse) therefore met to propose, based on data from the literature and their clinical experience, elements of management in order to detect these cognitive disorders at an early stage and optimize treatment tolerance. The subjects discussed concern screening and assessment tools, the management of side effects, and their prevention. The use of the practical elements proposed by the group could help optimize the identification and management of central nervous system disorders occurring on lorlatinib.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Central Nervous System Diseases; Drug-Related Side Effects and Adverse Reactions; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Quality of Life

Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, has been approved as a treatment for ALK-positive lung cancer. This review provides information regarding the pharmacology and clinical features of lorlatinib, including its efficacy and associated adverse events. Pivotal clinical trials are discussed along with the current status of lorlatinib as a treatment for ALK-positive lung cancer and future therapeutic challenges.. Lorlatinib has been approved as a new standard treatment for lung cancer with gene alteration known as ALK fusion. This review provides information regarding the characteristics of lorlatinib, including its efficacy and the unexpected medical problems that occur during treatment. Today, treatment of ALK-positive lung cancer is more complicated because of the active development of drugs like lorlatinib. This review demonstrates the logic of including lorlatinib as part of the treatment plan and sheds light on the future of treatment for ALK-positive lung cancer.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles

To conduct a network meta-analysis of randomised controlled trials to determine the optimal clinical choice of first-line therapy for patients with ALK receptor tyrosine kinase (. Clinical trials in patients with histologically confirmed. Nine trials with 2,407 patients were included for analyses. Lorlatinib was better than brigatinib for progression-free survival (PFS) (hazard ratio 0.79, 95% confidence interval 0.63, 0.98). In subgroup analyses, lorlatinib exhibited the highest probability of best PFS ranking in patients with or without baseline brain metastases (38% and 80%, respectively); brigatinib had the highest probability of best PFS ranking among Asian patients (47%). Alectinib offered the highest survival advantage (57% probability), while lorlatinib was likely to be the best treatment for an objective response (41% probability). Alectinib displayed the highest probability of being ranked lowest for grade ≥3 adverse events (86%).. Lorlatinib was associated with the best PFS overall, and was suitable for patients with or without brain metastases. Brigatinib was associated with the best PFS in Asian patients.

Topics: Anaplastic Lymphoma Kinase; Bayes Theorem; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Gene Rearrangement; Humans; Lactams, Macrocyclic; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic

Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57,

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Network Meta-Analysis; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC.. We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases.. A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%).. Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gene Rearrangement; Humans; Lactams; Lung Neoplasms; Network Meta-Analysis; Organophosphorus Compounds; Piperazines; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Treatment Outcome

Major issues in anaplastic lymphoma kinase-positive non-small cell lung carcinoma are acquired resistance against anaplastic lymphoma kinase inhibitors and control of central nervous system metastasis. The development of these inhibitors has changed therapeutic strategy in patients with advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Brigatinib and lorlatinib were designed to penetrate the blood-brain barrier and to inhibit resistant mutations against anaplastic lymphoma kinase inhibitors. We review the clinical data supporting treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma with brigatinib and lorlatinib. Brigatinib has shown promising antitumour activity, including substantial activity against central nervous system metastases, in crizotinib-treated (ALTA trial) patients and crizotinib-naïve (ALTA-1L trial) patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. In addition, brigatinib improved progression-free survival compared with crizotinib in anaplastic lymphoma kinase inhibitor-naïve patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Lorlatinib has demonstrated clinical antitumour activity against both intracranial and extracranial lesions in patients with anaplastic lymphoma kinase- or c-ros oncogene 1 (ROS1)-positive non-small cell lung carcinoma. Ongoing trials and further studies of these agents' biological and clinical properties would provide insight into the optimal therapeutic strategy for administering them to achieve the best survival benefit.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Organophosphorus Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

We report the case of a woman who developed hyperlipidemia on lorlatinib therapy found to have minimal change disease. We review therapies for cancer known to alter the lipid profile, in addition to reviewing secondary hyperlipidemia workup. We also propose a mechanism for lorlatinib-induced hyperlipidemia.. A 63 year old woman with non-small cell lung adenocarcinoma on lorlatinib therapy develops marked hyperlipidemia.. This is a case of hyperlipidemia in a patient on lorlatinib. The case highlights that therapies for lung cancer and other malignancies have the potential to alter the lipid profile. We propose minimal change disease as a possible mechanism for lorlatinib-induced dyslipidemia. Additionally, we discuss the crucial aspects of secondary hyperlipidemia workup.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Female; Humans; Hyperlipidemias; Lactams; Lung Neoplasms; Middle Aged; Pyrazoles

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrazoles

Rearrangements of the ALK gene are found in approximately 5% of non-small-cell lung cancer. It is of particular importance to test for this rearrangement in patients with metastatic lung adenocarcinoma because these tumors are highly sensitive to therapy with ALK-targeted inhibitors. Lorlatinib is a reversible potent third generation tyrosine kinase inhibitor that is highly selective and targets ALK and ROS1. It was developed to target resistant ALK mutants including the most common G1202R. Lorlatinib has excellent central nervous system (CNS) penetration and its efficacy has also been demonstrated even in patients with intracranial metastases after progression on second generation ALK inhibitors. Potential toxicities include neurocognitive effects and hyperlipidemia. "A User's Guide to Lorlatinib" reviews the mechanism of action, pharmacology and clinical trial data. Also covering the management of adverse events, this "guide" has been prepared to be a practical reference tool to both clinicians and basic researchers.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Approximately 3-7% of advanced non-small cell lung cancers (NSCLC) are driven by an anaplastic lymphoma kinase (. Herein, the authors review the mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of lorlatinib and provide their future perspectives on this drug.. Lorlatinib is a potent

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles; Treatment Outcome

Approximately 3-5% of patients with non-small cell lung cancer （NSCLC）belonged to anaplastic lymphoma kinase (ALK)-positive NSCLC. The treatment drugs of ALK-positive NSCLC mainly included crizotinib, ceritinib, alectinib, and brigatinib. Although these drugs had some effects, most of them were usually easy to develop drug resistance. Lorlatinib is a new inhibitor of ALK for treating ALK-positive NSCLC,the effect is obvious, and not easy to develop resistance. Areas covered: The main mechanism of action, pharmacokinetics, clinical efficacy and safety of lorlatinib were introduced in this paper. Expert commentary: Lorlatinib is a new, reversible, ATP-competitive small molecule inhibitor of ALK and c-ros oncogene 1 (ROS1). It can inhibit tumor cell growth in ALK- and ROS1-overexpressing tumor cells. Clinical trial indicated that lorlatinib had obvious therapeutic effect for patients with ALK-positive NSCLC. Lorlatinib could also pass through the blood-brain barrier, which had a good effect on patients with brain metastasis. Adverse events of lorlatinib were mostly mild and moderate in severity, and patients were easily tolerated. Most common adverse events were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles

Anaplastic lymphoma kinase (ALK) rearrangements were first implicated as driving mutations in non-small cell lung cancer in 2007. Since then, a number of novel, small-molecule inhibitors directed against the ALK receptor have demonstrated superiority over standard chemotherapies in the treatment of ALK rearrangement-positive lung cancer. Of considerable importance when considering such therapies is the ability of each to overcome mutations conferring acquired resistance, as well as penetrate the central nervous system (CNS), the most common site of metastasis and traditionally the most difficult to breach. Herein is a review of the efficacy, indications, and degree of CNS penetration for the ALK-targeting agents crizotinib, ceretinib, alectinib, brigatinib, and lorlatinib, as well as a summary of ongoing clinical trials comparing these drugs.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Organophosphorus Compounds; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Small Molecule Libraries

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Humans; Lactams; Lactams, Macrocyclic; Lung; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases

Detection of molecular aberrations driving the biology and the clinical behavior of advanced non-small cell lung cancer (NSCLC) allows the adoption of specific therapeutic strategies dramatically impacting disease courses. Among these, ROS1 rearrangements are present in 1-2% of lung adenocarcinomas. Thanks to similarities between ALK and ROS1 oncogenes, lessons inferred from ALK can be applied to ROS1-positive NSCLC; nevertheless, disparities exist between diseases mastered by these two fusion genes. In the absence of more common genetic alterations detected in NSCLC (e.g. EGFR and KRAS mutations, ALK gene fusions), seeking for ROS1 rearrangements is crucial. Dedicated molecular diagnostics should be standardized, hopefully relying upon practical and efficient algorithms, comprehending immunohistochemistry and fluorescence in situ hybridisation. The major clinical impact exerted by crizotinib represents the main reason for which not even a sole ROS1-positive tumor should be undetected. The recent approval of the inhibitor by both American and European health agencies would hopefully boost the widespread testing for ROS1, eventually increasing the absolute number of positive cases, potential further source of information regarding molecular and clinical resistance. In vitro and clinical evidence have already been generated concerning crizotinib resistance and strategies to maintain patients under specific driver-inhibition are being successfully developed. Gathering data concerning diagnostics, preclinical evidence, clinical practice and ongoing studies, the present review depicts the current scenario of ROS1 inhibition in NSCLC.

Topics: Aminopyridines; Anilides; Antineoplastic Agents; Benzamides; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Indazoles; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Molecular Diagnostic Techniques; Oncogene Fusion; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Pyrimidines; Sulfones

The discovery of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved-ceritinib and alectinib-and others that are in development-brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor-pre-treated and -naïve NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK+ NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK-mutation-driven tumors.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Crizotinib as the first-generation ALK inhibitor has shown significant activity in ALK-mutated non-small cell lung cancer (NSCLC). Second- and third-generation ALK inhibitors are entering clinical applications for ALK+ NSCLC. In addition, a third-generation ALK inhibitor, lorlatinib (PF-06463922), was reported to resensitize NSCLC to crizotinib. This review provided a summary of clinical development of alectinib, ceritinib, brigatinib (AP26113), and lorlatinib.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Kaplan-Meier Estimate; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies. In addition, early clinical data demonstrated that 3

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Piperidines; Precision Medicine; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity through its rearrangement in non-small cell lung cancer (NSCLC), and patients (pts) with ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib, and ceritinib, than with chemotherapy. Despite the excellent efficacy of ALK inhibitors, resistance to these drugs is inevitably encountered in most ALK-rearranged pts. Cases of resistance are subtyped into three groups, i.e., systemic, oligo, and central nervous system (CNS) types, with the CNS being used to be considered a sanctuary. With regard to the management of CNS lesions in pts with ALK+ NSCLC, a growing body of evidence has gradually demonstrated the intracranial (IC) efficacy of ALK inhibitor (ALKi) in ALK+ NSCLC pts with brain metastases (BMs). Although the efficacy of crizotinib for the CNS lesions remains controversial, a recent retrospective investigation of ALK+ pts with BM enrolled in PROFILE 1005 and PROFILE 1007 demonstrated that crizotinib is associated with a high disease control rate for BM. However, BM comprises the most common site of progressive disease in pts with or without baseline BMs, which is a serious problem for crizotinib. Furthermore, alectinib can be used to achieve strong and long-lasting inhibitory effects on BM. In addition to alectinib, the IC efficacy of other next-generation ALK inhibitors, such as ceritinib, AP26113 and PF-06463922, has been demonstrated. In this article, we review the latest evidence regarding the BM and IC efficacy of ALK inhibitors in pts with ALK+ NSCLC.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

After a median follow-up of 18·3 months, the third-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, lorlatinib, improved progression-free survival in patients with treatment-naive, ALK-positive non-small-cell lung cancer in the phase 3 CROWN study. Here we report updated efficacy data, including intracranial activity, from an unplanned analysis after 3 years of follow-up.. CROWN is an ongoing, international, randomised, open-label phase 3 trial done in 104 centres in 23 countries worldwide. Eligible participants were aged 18 years and older or aged 20 years and older (depending on local regulations) with advanced, ALK-positive non-small-cell lung cancer, had received no previous systemic treatment for metastatic disease, had at least one extracranial measurable target lesion (according to the Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1), and had an Eastern Cooperative Oncology Group performance status score of 0-2. Patients were randomly assigned (1:1) to oral lorlatinib 100 mg daily or oral crizotinib 250 mg twice daily in 28-day cycles. Randomisation was stratified by the presence or absence of brain metastasis, and by ethnicity. Since the primary endpoint of the study had been met at the planned interim analysis, no further formal analysis of progression-free survival was planned, per protocol. The current unplanned analysis was done to further characterise tumour-related endpoints with a longer follow-up and is presented descriptively. For the planned study, the primary endpoint was progression-free survival assessed by blinded independent central review. Secondary endpoints included progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, duration of response, intracranial duration of response, and safety. Efficacy endpoints were also assessed by the presence or absence of baseline brain metastases. This study is registered with ClinicalTrials.gov, NCT03052608.. Between May 11, 2017, and Feb 28, 2019, 425 patients were screened for eligibility, of whom 296 were enrolled and randomly assigned to the lorlatinib (n=149) or crizotinib (n=147) group. At data cutoff for this unplanned analysis (Sept 20, 2021), median duration of follow-up for progression-free survival was 36·7 months (IQR 31·3-41·9) for lorlatinib and 29·3 months (10·8-35·0) for crizotinib. Median progression-free survival by blinded independent central review was not reached (95% CI not reached-not reached) for lorlatinib and was 9·3 months (7·6-11·1) for crizotinib (hazard ratio [HR] 0·27 [95% CI 0·18-0·39]). 3-year progression-free survival was 64% (95% CI 55-71) in the lorlatinib group and 19% (12-27) in the crizotinib group. Progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, and duration of response were improved with lorlatinib versus crizotinib. In patients with baseline brain metastases (n=37 lorlatinib; n=39 crizotinib), the HR for time to intracranial progression for lorlatinib versus crizotinib was 0·10 (95% CI 0·04-0·27); in patients without baseline brain metastases (n=112 lorlatinib; n=108 crizotinib), the HR was 0·02 (95% CI 0·002-0·14). In patients without brain metastases, one (1%) in the lorlatinib group and 25 (23%) in the crizotinib group had intracranial progression. Grade 3-4 adverse events occurred in 113 (76%) of 149 patients (most commonly due to altered lipid levels) with lorlatinib and in 81 (57%) of 142 patients with crizotinib. Adverse events led to treatment discontinuation in 11 (7%) patients in the lorlatinib group and 14 (10%) patients in the crizotinib group. There were no new safety signals.. These updated, long-term data from CROWN show the durable benefit of lorlatinib over crizotinib in patients with treatment-naive, ALK-positive non-small-cell lung cancer and support the use of first-line lorlatinib in patients with and without baseline brain metastases.. Pfizer.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors

Brain metastases are especially common in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), with a cumulative incidence of over 50% and associated with a poor prognosis, high symptom burden, and decreased quality of life. Lorlatinib is a brain-penetrant, third-generation ALK tyrosine kinase inhibitor (TKI), which has a high potency against resistance mutations seen with earlier generation ALK TKIs. In 2018, lorlatinib was granted accelerated approval in second- and third-line treatment for use in patients with ALK-positive metastatic NSCLC on the basis of phase 1/2 study results. This initial approval was expanded for first-line treatment of patients with ALK-positive metastatic NSCLC on the basis of the interim analysis of the phase 3 CROWN study showing longer progression-free survival, time to intracranial progression, duration of response, and objective response rate compared with crizotinib. This manuscript is a transcript of our podcast, in which we discuss the clinical significance of controlling the onset of brain metastases, considerations in selecting a first-line therapy option, efficacy and safety observed in patients with and without brain metastases, and rationales for using lorlatinib upfront versus reserving for a later line in therapy.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Quality of Life

Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with anaplastic lymphoma kinase- (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of lorlatinib.. Participants were assigned to mild, moderate, and severe renal impairment groups and to a matching normal renal function group based on absolute estimated glomerular filtration rate (eGFR, based on the Modification of Diet in Renal Disease equation and adjusted for body surface area [BSA]) and were evaluated for pharmacokinetics and safety.. A total of 29 participants (5 with severe renal impairment; 8 each with moderate and mild impairment and normal renal function) were enrolled and received a single dose of lorlatinib 100 mg. One of the participants with severe renal impairment had end-stage renal disease with a baseline absolute eGFR of 10.3 mL/min. No serious adverse events (AEs) were reported. Eighteen AEs, all mild or moderate in severity, were reported by 12 participants (5, 2, 4, and 1 in the normal, mild, moderate, and severe groups, respectively). Area under the plasma concentration-time profile from time zero extrapolated to infinity (AUC. Lorlatinib 100 mg was well tolerated. As participants with mild and moderate renal impairment did not experience clinically meaningful increases in lorlatinib exposure, no lorlatinib dose adjustment is recommended in these populations. Patients with severe renal impairment are recommended to reduce the starting dose of lorlatinib from 100 mg QD to 75 mg QD.. NCT03542305 (available May 31, 2018 on clinicaltrials.gov).

Topics: Adult; Aminopyridines; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Pyrazoles; Renal Insufficiency

Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC.. Retrospective analyses in the ongoing phase 2 trial (NCT01970865) investigated the clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with previous crizotinib treatment as the only ALK TKI were group A (n = 28); those with at least one previous second-generation ALK TKIs were group B (n = 74). LBPD was defined as greater than 3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with the best overall response of complete or partial response or stable disease were included.. There were no major differences in baseline characteristics between groups. The median duration of treatment for patients who continued LBPD was 32.4 months (group A) and 16.4 months (group B) versus 12.5 months (group A) and 7.7 months (group B) for patients who did not continue LBPD. The median overall survival in group A was not reached (NR) in patients who continued LBPD versus 24.4 months (95% confidence interval [CI]: 12.1-NR); group B's median was 26.5 months (95% CI: 18.7-35.5) in patients who continued LBPD versus 14.7 months (95% CI: 9.3-38.5) in patients who did not continue LBPD. The median overall survival postprogression for groups A and B was NR (95% CI: 21.4-NR) and 14.6 months (95% CI: 11.2-19.2) in patients who continued LBPD and 8.0 months (95% CI: 1.5-NR) versus 5.3 months (95% CI: 2.8-14.3) in patients who did not continue LBPD.. Continuing LBPD is a viable treatment strategy for select patients with ALK-positive NSCLC who progressed on lorlatinib.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Lorlatinib was found to have activity in ALK-positive NSCLC in a global phase 1 and 2 study. We report an ongoing phase 2 study in Chinese patients with ALK-positive advanced or metastatic NSCLC.. Open-label, dual-cohort study (NCT03909971); patients had progressive disease after ALK tyrosine kinase inhibitor treatment (cohort 1: previous crizotinib; cohort 2: one ALK tyrosine kinase inhibitor other than crizotinib [±prior crizotinib]), more than or equal to one unirradiated extracranial target lesion, and Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received oral lorlatinib 100 mg once daily in continuous 21-day cycles. Primary end point: objective response in cohort 1 by independent central radiology (ICR) according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were based on patients receiving more than or equal to one dose.. At data cutoff (August 10, 2020), 109 patients were enrolled (cohort 1: n = 67; cohort 2: n = 42). A total of 47 patients in cohort 1 (70.1%, 95% confidence interval [CI]: 57.7-80.7, p < 0.0001; primary end point) and 20 patients in cohort 2 (47.6%, 95% CI: 32.0-63.6, secondary end point) achieved objective response by ICR. Median progression-free survival was not reached in cohort 1 and was 5.6 months in cohort 2. In patients with brain lesions at baseline, 29 of 36 patients in cohort 1 (80.6%, 95% CI: 64.0-91.8) and 10 of 21 patients in cohort 2 (47.6%, 95% CI: 25.7-70.2) achieved objective intracranial response by ICR. Hypercholesterolemia (92.7%) and hypertriglyceridemia (90.8%) (cluster terms) were common treatment-related adverse events (TRAEs). Nine patients (8.3%) had serious TRAEs; one permanently discontinued from treatment because of TRAEs.. Lorlatinib was found to have a robust and durable response and high intracranial objective response in previously treated Chinese patients with ALK-positive NSCLC.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Crizotinib; Humans; Lactams; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Taiwan

The CNS is a recurrent site of progression in anaplastic lymphoma kinase (ALK)-rearranged (ALK+) lung cancer. Lorlatinib is a third-generation ALK inhibitor developed to penetrate the CNS and overcome. Patients with ALK+ lung cancer who had intracranial progression on ≥ 1 ALK inhibitor without measurable extracranial disease received lorlatinib 100 mg once daily. The primary end point was intracranial disease control rate at 12 weeks per modified RECIST v1.1. Secondary end points included intracranial progression-free survival, intracranial objective response rate, and safety/tolerability.. Twenty-three patients were enrolled between November 2016 and January 2019. Fifteen (65%) patients had irradiated CNS metastases, with a median of 20.2 months between radiation and lorlatinib. Control of intracranial disease was observed in 21 (95%) evaluable patients at 12 weeks. The intracranial objective response rate was 59% with six complete and seven partial responses. The median intracranial progression-free survival was 24.6 months (95% CI, 20.2 to not reached). With a median follow-up of 16.8 months, nine patients developed disease progression, including four patients with CNS progression. The most common treatment-related adverse events were hypercholesterolemia (96%), hypertriglyceridemia (87%), edema (65%), cognitive effects (52%), and mood effects (43%). Three patients discontinued treatment because of toxicity, including two patients with fatal respiratory events.. Lorlatinib induced durable intracranial disease control in patients with CNS-only relapse on second-generation ALK inhibitors, suggesting that tumors with CNS-limited progression on brain-penetrant ALK tyrosine kinase inhibitors remain ALK-dependent.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrazoles

Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced. Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted.. PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78%. First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Quality of Life

To analyze the efficacy and safety of lorlatinib in Asian and non-Asian patients with pretreated anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) from a phase 1/2 study.. In this ongoing phase 2 part of the trial, patients with ALK- or ROS1-positive, advanced NSCLC enrolled into six expansion cohorts (EXP1-6), based on ALK and ROS1 status and previous therapy, and received lorlatinib 100 mg once daily. The primary endpoint was objective tumor response and intracranial response. Post hoc analyses of activity were conducted in Asian and non-Asian (based on race) ALK-positive patients who received either previous crizotinib with or without chemotherapy (EXP2-3A) or at least one second-generation ALK tyrosine kinase inhibitor with any number of chemotherapy regimens (EXP3B-5). Analysis of safety (adverse events [AEs]) was in the phase 1 and 2 study population who started lorlatinib 100 mg once daily.. 17 Asian patients were enrolled in EXP2-3A and 53 in EXP3B-5; 33 non-Asian patients were enrolled in EXP2-3A and 73 in EXP3B-5. Objective response rates in the Asian and non-Asian subgroups were 82.4% (95% confidence interval [CI]: 56.6-96.2) and 63.6% (95% CI: 45.1-79.6) in EXP2-3A, and 47.2% (95% CI: 33.3-61.4) and 30.1% (95% CI: 19.9-42.0) in EXP3B-5, and median progression-free survival was 13.6 and 12.5 months (EXP2-3A) and 6.9 and 5.5 months (EXP3B-5). Lorlatinib exhibited antitumor activity across ALK resistance mutations, while no differences according to the EML4-ALK variant could be detected. The most common treatment-related AEs were hypercholesterolemia, hypertriglyceridemia, edema, and peripheral neuropathy in both Asian and non-Asian subgroups.. Lorlatinib showed substantial overall and intracranial activity in pretreated patients with ALK-positive NSCLC in both Asian and non-Asian patients. AE profiles were similar between Asian and non-Asian patients.. gov NCT01970865.

Topics: Aminopyridines; Asian People; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Quality of life (QoL) for patients with non-small cell lung cancer (NSCLC) is negatively impacted by their disease and treatment side effects. We present detailed patient-reported outcome (PRO) data from the phase 3 CROWN study, which compared lorlatinib with crizotinib in patients with previously untreated ALK-positive advanced NSCLC.. PROs were assessed using the European Organisation for Research and Treatment of Cancer QoL Questionnaire with Lung Cancer module. A longitudinal, random-intercept, random-slope, mixed-effect model assessed score changes from baseline up to (not including) end of treatment. Mean changes of absolute scores from baseline at each cycle were calculated and presented up to cycle 18 (≥ 10-point change considered clinically meaningful).. In both lorlatinib (n = 148) and crizotinib (n = 140) arms, there were longitudinal improvements across multiple functioning and symptom scores during treatment compared with pre-treatment. Numerical improvements for most longitudinal functioning scores (physical, role, emotional, social) favored lorlatinib; cognitive functioning favored crizotinib. Numerical improvements favored lorlatinib for several symptoms (fatigue, nausea and vomiting, insomnia, appetite loss, constipation, diarrhea [clinically meaningful improvement], and cough); peripheral neuropathy favored crizotinib. Subgroup analyses showed PROs did not differ by presence/absence of baseline brain metastases.. Patients receiving first-line lorlatinib or crizotinib showed improvements and delayed deterioration in QoL, functioning, and several symptoms. Alongside the previously reported significantly longer progression-free survival and higher intracranial response rates for lorlatinib versus crizotinib, these data further support the use of lorlatinib over crizotinib in patients with advanced ALK-positive NSCLC with/without baseline brain metastases and provide evidence of several QoL improvements with lorlatinib when used in the first-line setting.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Patient Reported Outcome Measures; Protein Kinase Inhibitors; Quality of Life

Lorlatinib, a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinase, is indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) following progression on crizotinib and at least one other ALK inhibitor, or alectinib/ceritinib as the first ALK inhibitor therapy for metastatic disease. The population pharmacokinetics (PopPK) of lorlatinib was conducted by nonlinear mixed effects modeling of data from 330 patients with ALK-positive or ROS1-positive NSCLC and 95 healthy participants from six phase I studies in healthy volunteers; demographic, metabolizer phenotype, and patient prognostic factors were evaluated as covariates. Lorlatinib plasma PK was well-characterized by a two-compartment model with sequential zero-order and first-order absorption and a time-varying induction of clearance. Single dose clearance was estimated to be 9.04 L/h. Assuming that the metabolic auto-induction of lorlatinib reaches saturation in ~ 5 half-lives, clearance was estimated to approach a maximum of 14.5 L/h at steady-state after a period of ~ 7.25 days. The volume of distribution of the central compartment was estimated to be 121 L and the first-order absorption rate constant was estimated to be 3.1 h

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Female; Healthy Volunteers; Hepatic Insufficiency; Humans; Lactams; Lung Neoplasms; Male; Middle Aged; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proton Pump Inhibitors; Pyrazoles; Renal Insufficiency; Serum Albumin

Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs.. In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.. Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5).. Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases

Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the second-line treatment of patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. Lorlatinib is metabolized by cytochrome P450 (CYP) 3A and contraindicated with strong CYP3A inducers because of significant transaminase elevation. This phase I, open-label, two-period study evaluated the impact of a moderate CYP3A inducer, modafinil, on the safety and pharmacokinetics of lorlatinib.. Healthy participants received single-dose oral lorlatinib (50 mg [n = 2], 75 mg [n = 2], or 100 mg [n = 2 + 10 in an expanded cohort]) in Period 1 followed by modafinil 400 mg/day (days 1-19) and single-dose lorlatinib (day 15, same dose as previous) both orally in Period 2. Blood samples were collected for 120 h after each dose of lorlatinib.. Of 16 participants, ten completed the study; six participants, all in the expanded 100-mg cohort, discontinued because of adverse events during the modafinil lead-in dosing period. Single doses of lorlatinib 50-100 mg were well tolerated when administered alone and in the presence of steady-state modafinil. Of the ten participants who completed the study, all had transaminase values within normal limits during the combination of lorlatinib with modafinil. The ratios of the adjusted geometric means (90% confidence interval) for lorlatinib area under the plasma concentration-time profile extrapolated to infinity and maximum plasma concentration were 76.69% (70.15-83.83%) and 77.78% (65.92-91.77), respectively, when lorlatinib 100 mg was co-administered with steady-state modafinil compared with lorlatinib administration alone.. Lorlatinib 100 mg may be safely co-administered with moderate CYP3A inducers.. ClinicalTrials.gov NCT03961997; registered 23 May, 2019.

Topics: Aminopyridines; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Drug Interactions; Healthy Volunteers; Humans; Lactams; Lung Neoplasms; Modafinil; Pyrazoles

Lorlatinib demonstrated efficacy (including intracranial activity) in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in a phase I/II study (NCT01970865).. This analysis describes the pharmacokinetics (PK) of lorlatinib following single and multiple dosing.. This ongoing, multicenter, open-label, single-arm, phase I/II trial enrolled patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive advanced NSCLC. In phase I, patients received escalating doses of lorlatinib (10-200 mg orally once daily) and twice-daily doses of 35, 75, and 100 mg in continuous 21-day cycles. In phase II, lorlatinib was administered at a starting dose of 100 mg once daily in continuous 21-day cycles. Parameters investigated included the potential for lorlatinib to inhibit/induce cytochrome P450 (CYP) 3A; the absorption/metabolism of lorlatinib and its major metabolite PF-06895751; and differences in these parameters between Asian and non-Asian patients.. Data were available for 54 patients from phase I and 275 patients from phase II. Lorlatinib plasma exposure increased dose proportionally after single doses of 10-200 mg, and slightly less than dose proportionally after multiple doses. Lorlatinib clearance increased following multiple dosing compared with single dosing, indicating autoinduction. The area under the concentration-time curve from time zero to time τ (the dosing interval; AUC. Lorlatinib is highly brain penetrant and exhibits autoinduction after multiple dosing. There appears to be no inherent differences in lorlatinib PK between healthy subjects and cancer patients, or between Asian and non-Asian patients. ClinicalTrials.gov NCT01970865.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Lorlatinib is a small molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinases and is approved for the treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). In the phase I/II study (NCT01970865), potential exposure-response (E-R) relationships between lorlatinib and selected safety and efficacy end points were evaluated in patients with NSCLC. E-R relationships were assessed for safety end points with incidence > 10% in all treated patients (n = 328). In total, 4 safety end points were assessed: hypercholesterolemia grade ≥ 3, hypertriglyceridemia grade ≥ 3, weight gain grade ≥ 2, and treatment-emergent adverse events (TEAEs) grade ≥ 3. Using logistic regression, significant relationships were identified between lorlatinib plasma exposure and risk of hypercholesterolemia grade ≥ 3 (odds ratio (OR) 5.256) and risk of TEAE grade ≥ 3 (OR 3.214). The covariates baseline cholesterol and time on study prior to the event (TE) were associated with the probability of hypercholesterolemia grade ≥ 3. Baseline cholesterol and TE were found to have a statistically significant correlation with TEAE grade ≥ 3. Exposure-efficacy relationships were assessed for objective response rate (ORR; n = 197) and intracranial objective response rate (IC-ORR; n = 132). Lorlatinib plasma exposure was not identified as a statistically significant factor related to either efficacy end point. The only significant E-R relationships identified for efficacy were between baseline alkaline phosphatase and baseline amylase with IC-ORR (ORs 0.363 and 1.015, respectively). These findings support the lorlatinib indicated dose and dose modification guidelines regarding the management of lorlatinib-related AEs.

Topics: Adult; Aged; Aminopyridines; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypercholesterolemia; Lactams; Lung Neoplasms; Male; Middle Aged; Pyrazoles; Risk Assessment; Treatment Outcome

Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC) previously treated with a second-generation ALK inhibitor or with first- and second-generation ALK inhibitors. We examined the cost-effectiveness of second- or third-line+ (2L+ or 3L+) lorlatinib in Sweden, versus chemotherapy.. A partitioned survival model with three health states (progression free, progressed, or death) was used. Lorlatinib relative efficacy versus chemotherapy was derived using unanchored matching adjusted indirect treatment comparisons from a phase 2 clinical trial. Utility data were derived from the same trial and published studies. Costs (year 2019) were obtained from Swedish national data. Costs and benefits were discounted at 3% per annum using a societal perspective (base case). Model robustness was evaluated with deterministic and probabilistic sensitivity analyses.. For 2L+, the average discounted total quality-adjusted life year (QALY) gain was 1.29 years. Total incremental costs were Swedish krona (SEK) 731,791, resulting in an incremental cost-effectiveness ratio (ICER) of SEK 566,278 per QALY gained. Non-discounted survival gain amounted to 1.94 years. For 3L+, the average discounted total QALY gain was 1.25 years. Total incremental costs were SEK 754,801, resulting in an ICER of SEK 603,934 per QALY gained. Non-discounted survival gain was 1.88 years. Sensitivity analyses were consistent.. ICERs ranged from SEK 421,000 to SEK 384,066 less than the boundary for a cost-effective treatment for a high-severity disease in Sweden (SEK 988,000), suggesting 2L+ or 3L+ lorlatinib is a cost-effective treatment for ALK-positive NSCLC versus chemotherapy.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Humans; Lactams; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Quality-Adjusted Life Years; Sweden

Lorlatinib is approved worldwide as treatment for anaplastic lymphoma kinase-positive and c-ros oncogene 1-positive non-small cell lung cancer. The objectives of this phase 1, open-label crossover study (NCT02569554) in healthy adult participants were to determine (1) the effects of the proton pump inhibitor (PPI) rabeprazole on lorlatinib pharmacokinetics (PK), (2) the effects of a high-fat meal on lorlatinib PK, and (3) the relative bioavailability of an oral solution to tablet formulation of lorlatinib under fasted conditions. Participants were followed on-study for ≥50 days after the first dose of lorlatinib. Participants received treatments over 4 periods, with a washout of ≥10 days between consecutive lorlatinib doses. Twenty-seven participants were enrolled and received lorlatinib, and all were assessed for PK and safety. Results showed no effect of multiple doses of rabeprazole on the total plasma exposure of a single oral dose of lorlatinib 100-mg tablets. The results also indicated that a high-fat meal had no effect on lorlatinib PK after a single 100-mg oral dose. In addition, the relative bioavailability of lorlatinib oral solution compared with lorlatinib tablets was complete (approximately 108%). The safety profile of lorlatinib was consistent with that reported in previous studies, and most treatment-related adverse events were mild to moderate. These data indicate that lorlatinib can be administered with drugs that modify gastric acid, including PPIs, without restriction. These results also confirm that lorlatinib can be administered regardless of food intake.

Topics: Adult; Aminopyridines; Carcinoma, Non-Small-Cell Lung; Cross-Over Studies; Drug Interactions; Female; Food; Food-Drug Interactions; Healthy Volunteers; Humans; Lactams; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Proton Pump Inhibitors; Pyrazoles; Rabeprazole; Young Adult

Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib.. This phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1-12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib.. When a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUC. The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers.. ClinicalTrials.gov identifier, NCT02804399.

Topics: Adult; Aminopyridines; Antineoplastic Agents; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Cross-Over Studies; Drug Interactions; Female; Healthy Volunteers; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Pyrazoles; Rifampin; Young Adult

Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood-brain barrier.. We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs.. In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ≥ 1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach.. Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2-3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n = 37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metastases [43% vs. 9% (n = 22)]. In patients who received ≥ 1 prior second-generation ALK TKI [EXP3B-5 (n = 139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n = 94) and 55% vs. 12% (n = 45), respectively).. Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. CLINICALTRIALS.. NCT01970865.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Incidence; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Pyrazoles

Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with. We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced. The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively.. In an interim analysis of results among patients with previously untreated advanced

Topics: Adult; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Hyperlipidemias; Intention to Treat Analysis; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Mutation; Pyrazoles; Survival Analysis

Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ALK and ROS1 with preclinical activity against most known resistance mutations in ALK and ROS1. We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive non-small-cell lung cancer (NSCLC).. In this open-label, single-arm, phase 1-2 trial, we enrolled patients (aged ≥18 years) with histologically or cytologically confirmed advanced ROS1-positive NSCLC, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 2 or less (≤1 for phase 1 only) from 28 hospitals in 12 countries worldwide. Lorlatinib 100 mg once daily (escalating doses of 10 mg once daily to 100 mg twice daily in phase 1 only) was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was overall and intracranial tumour response, assessed by independent central review. Activity endpoints were assessed in patients who received at least one dose of lorlatinib. This study is ongoing and is registered with ClinicalTrials.gov, NCT01970865.. Between Jan 22, 2014, and Oct 2, 2016, we assessed 364 patients, of whom 69 with ROS1-positive NSCLC were enrolled. 21 (30%) of 69 patients were TKI-naive, 40 (58%) had previously received crizotinib as their only TKI, and eight (12%) had previously received one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. The estimated median duration of follow-up for response was 21·1 months (IQR 15·2-30·3). 13 (62%; 95% CI 38-82) of 21 TKI-naive patients and 14 (35%; 21-52) of 40 patients previously treated with crizotinib as their only TKI had an objective response. Intracranial responses were achieved in seven (64%; 95% CI 31-89) of 11 TKI-naive patients and 12 (50%; 29-71) of 24 previous crizotinib-only patients. The most common grade 3-4 treatment-related adverse events were hypertriglyceridaemia (13 [19%] of 69 patients) and hypercholesterolaemia (ten [14%]). Serious treatment-related adverse events occurred in five (7%) of 69 patients. No treatment-related deaths were reported.. Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent.. Pfizer.

Topics: Adolescent; Adult; Aminopyridines; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Response Evaluation Criteria in Solid Tumors; Survival Rate; Young Adult

Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non-small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that. Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for. Approximately one quarter of patients had. In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Clinical Decision-Making; Disease Progression; DNA Mutational Analysis; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Patient Selection; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Risk Factors; Time Factors

Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.. In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1-5 only), and safety data for all treated patients (EXP1-6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865.. Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5-97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were achieved in 93 (47·0%; 39·9-54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5-73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1-80·8) of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32·1%; 15·9-52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4-97·2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five (55·6%; 21·2-86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3-67·5) of 49 patients in EXP4-5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported.. Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy.. Pfizer.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Female; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Time Factors; Tumor Burden

Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC.. In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865.. Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31-63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23-63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21-79).. In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608).. Pfizer.

Topics: Adult; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Gene Rearrangement; Humans; Internationality; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Maximum Tolerated Dose; Middle Aged; Patient Selection; Prognosis; Prospective Studies; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases; Risk Assessment; Survival Analysis; Treatment Outcome

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Binding Sites; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lactams; Lactams, Macrocyclic; Liver Failure; Liver Neoplasms; Lung Neoplasms; Middle Aged; Molecular Structure; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far.. A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations.. Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations.. Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983-91. ©2016 AACR.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Topics: Brain Neoplasms; Crizotinib; Humans; Lung Neoplasms; Receptor Protein-Tyrosine Kinases

Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) with a broad coverage against ALK mutations, has demonstrated dramatic effects in patients with ALK-rearranged lung cancer. The mechanisms of acquired resistance to lorlatinib by secondary ALK compound mutations have recently been reported; however, resistance mechanisms other than secondary mutations remain unclear. Here, we investigated the molecular mechanisms of the acquired resistance in ALK-rearranged lung cancer cells in vitro. We established two different lorlatinib-resistant ALK-rearranged lung cancer cell lines (H3122LR and A925LLR) via long-term administration of lorlatinib. These resistant cells did not harbor the secondary ALK mutations and showed cross-resistance to the other kinds of ALK-TKIs (crizotinib or alectinib) compared with the parental cells; however, these resistant cells overexpressed the phosphorylated human epidermal growth factor receptor 3 (HER3) protein and the ligand of HER3 (neuregulin 1; NRG1). Pharmacological inhibition of HER3 with pan-HER inhibitors or genetic knockdown of HER3 with siRNA resensitized H3122LR and A925LLR cells to lorlatinib in vitro, indicating that H3122LR and A925LLR acquired resistance by NRG1/HER3 activation. These findings demonstrated that targeting NRG1/HER3 is a potential novel therapeutic option for lorlatinib-resistant ALK-rearranged lung cancer.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Neuregulin-1; Protein Kinase Inhibitors

The safety profile of lorlatinib includes neurocognitive adverse events (NAEs). Baseline factors associated with developing NAEs remain poorly characterized.. Records from patients who received lorlatinib through prospective studies at Massachusetts General Hospital (MGH, n = 124) or the phase 1/2 B7461001 (NCT01970865; n = 248) study were reviewed to identify potential associations between comorbidities, baseline medications, and NAEs.. Most patients experienced a NAE (MGH: 60%, B7461001: 49%). Cognitive effects occurred in 40% and 29% of patients in the MGH and B7461001 cohorts, respectively. Brain metastases (p = 0.008), brain radiation (p = 0.033), psychiatric illness (p = 0.008), psychiatric medications (p < 0.001), antiepileptics (p < 0.001), and stimulants (p = 0.026) were associated with developing cognitive effects in B7461001. Mood effects occurred in 36% and 23% of patients in the MGH and B7461001 cohorts, respectively. In the MGH cohort, psychiatric illness (p = 0.02) and stimulants (p = 0.01) were associated with developing mood effects whereas brain surgery (p = 0.020), psychiatric medications (p < 0.001), benzodiazepines (p = 0.002), and sedatives (p = 0.034) were associated with developing mood effects in B7461001. Psychotic effects were infrequent (MGH: 3%, B7461001: 9%) and were associated with brain surgery in the MGH cohort (p = 0.001) and age in B7461001 (p = 0.014). Speech effects were observed in 23% and 11% of patients in the MGH and B7461001 cohorts, respectively. Brain radiation (p = 0.012) and antiepileptics (p < 0.001) were associated with speech effects in B7461001. Dose reductions were implemented for 52% and 18% of patients with NAEs in MGH and B7461001 cohorts, respectively, with mitigating effect.. Neurocognitive effects from lorlatinib are common. Lorlatinib-related NAEs may be influenced by multiple factors, including brain metastases, brain radiation, psychiatric illness, and use of neurotropic medications.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Anticonvulsants; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Humans; Lactams, Macrocyclic; Lung Neoplasms; Prospective Studies; Protein Kinase Inhibitors

This real-world analysis describes treatment patterns, sequencing and clinical effectiveness, toxicities, and health utility outcomes in advanced-stage, incurable ALK-positive NSCLC patients across five different ALK-TKIs.. Clinicodemographic, treatment, and toxicity data were collected retrospectively in patients with advanced-stage ALK-positive NSCLC at Princess Margaret Cancer Centre. Patient-reported symptoms, toxicities, and health utilities were collected prospectively.. Of 148 ALK-positive NSCLC patients seen July 2009-May 2021, median age was 58.9 years; 84 (57%) were female; 112 (76%) never-smokers; 54 (47%) Asian and 40 (35%) white; 139 (94%) received at least one ALK-TKI: crizotinib (n = 74; 54%) and alectinib (n = 61; 44%) were administered mainly as first-line ALK-TKI, ceritinib, brigatinib and lorlatinib were administered primarily after previous ALK-TKI failure. Median overall survival (OS) was 54.0 months; 31 (21%) patients died within two years of advanced-stage diagnosis. Treatment modifications were observed in 35 (47%) patients with crizotinib, 19 (61%) with ceritinib, 41 (39%) with alectinib, 9 (41%) with brigatinib and 8 (30%) with lorlatinib. Prevalence of dose modifications and self-reported toxicities were higher with early versus later generation ALK-TKIs (P<.05). The presence of early treatment modification was not negatively associated with progression-free survival (PFS) and OS analyses.. Serial ALK-TKI sequencing approaches are viable therapeutic options that can extend quality of life and quantity-of-life, though a fifth of patients died within two years. No best single sequencing approach could be determined. Clinically relevant toxicities occurred across all ALK-TKIs. Treatment modifications due to toxicity may not necessarily compromise outcomes, allowing multiple approaches to deal with ALK-TKI toxicities.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Quality of Life; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Tyrosine kinase inhibitors (TKIs) that target the ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene have shown dramatic therapeutic effects in patients with ROS1-rearranged non-small-cell lung cancer (NSCLC). Nevertheless, advanced ROS1-rearranged NSCLC is rarely cured as a portion of the tumor cells can survive the initial stages of ROS1-TKI treatment, even after maximum tumor shrinkage. Therefore, understanding the mechanisms underlying initial cell survival during ROS1-TKI treatment is necessary to prevent cell survival and achieve a cure for ROS1-rearranged NSCLC. In this study, we clarified the initial survival mechanisms during treatment with lorlatinib, a ROS1 TKI. First, we established a patient-derived ezrin gene-ROS1-rearranged NSCLC cell line (KTOR71). Then, following proteomic analysis, we focused on yes-associated protein 1 (YAP1), which is a major mediator of the Hippo pathway, as a candidate factor involved in cell survival during early lorlatinib treatment. Yes-associated protein 1 was activated by short-term lorlatinib treatment both in vitro and in vivo. Genetic inhibition of YAP1 using siRNA, or pharmacological inhibition of YAP1 function by the YAP1-inhibitor verteporfin, enhanced the sensitivity of KTOR71 cells to lorlatinib. In addition, the prosurvival effect of YAP1 was exerted through the reactivation of AKT. Finally, combined therapy with verteporfin and lorlatinib was found to achieve significantly sustained tumor remission compared with lorlatinib monotherapy in vivo. These results suggest that YAP1 could mediate initial cell resistance to lorlatinib in KTOR71 cells. Thus, combined therapy targeting both YAP1 and ROS1 could potentially improve the outcome of ROS1-rearranged NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Survival; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proteomics; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Verteporfin; YAP-Signaling Proteins

Topics: Aminopyridines; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Lorlatinib is an active treatment for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) pretreated with ALK-tyrosine kinase inhibitors (-TKIs). However, there is paucity of data on the activity of platinum/pemetrexed chemotherapy administered at the time of progression on lorlatinib. In addition, it is uncertain whether continuation of lorlatinib beyond progression (LBP) would provide any additional clinical benefit. Here, we describe two cases experiencing an exceptional response to platinum/pemetrexed chemotherapy plus LBP and make an attempt to identify which patients' characteristics and biologic profiles of the tumor could predict benefit from such an approach. In this report, presence of controlled brain metastases, rapidly progressing extracranial disease, and presence of ALK-dependent mechanisms of resistance were associated with benefit from platinum/pemetrexed chemotherapy plus lorlatinib beyond progression.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams, Macrocyclic; Lung Neoplasms; Pemetrexed; Platinum; Protein Kinase Inhibitors

Topics: Aminopyridines; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors

ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway.. We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX).. Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth.. In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Humans; Lactams, Macrocyclic; Lung Neoplasms; Mice; Neuroblastoma; Protein Kinase Inhibitors

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases

Alectinib, an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is the recommended first-line treatment for ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Lorlatinib was approved as a subsequent therapeutic option after progression while receiving ALK TKI treatment. However, data on the use of lorlatinib in the second- or third-line setting after alectinib failure are limited in Japanese patients. This retrospective real-world observational study investigated the clinical effectiveness of lorlatinib in second- or later-line settings after alectinib failure in Japanese patients. Clinical and demographic data collected in the Japan Medical Data Vision (MDV) database between December 2015 and March 2021 were used. Patients diagnosed with lung cancer who received lorlatinib following alectinib failure after the November 2018 marketing approval of lorlatinib in Japan were included. Of 1954 patients treated with alectinib, 221 were identified from the MDV database as receiving lorlatinib after November 2018. The median age of these patients was 62 years. Second-line lorlatinib treatment was reported for 154 patients (70%); third- or later-line lorlatinib treatment was reported for 67 patients (30%). The median duration of treatment (DOT) for all lorlatinib-treated patients was 161 days (95% confidence interval [CI], 126-248), and 83 patients (37.6%) continued treatment after data cut-off (March 31, 2021). Median DOTs of 147 days (95% CI, 113-242) and 244 days (95% CI, 109 to not reached) were reported with second-line and third- or later-line treatment, respectively. Consistent with clinical trial data, this real-world observational study supports data suggesting the effectiveness of lorlatinib after alectinib failure in Japanese patients.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; East Asian People; Humans; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Retrospective Studies

Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body's proteins, it leads to various autoimmune disorders. Additionally, when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; B-Lymphocytes; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Tyrosine Kinase Inhibitors

Infant-type hemispheric glioma, a new subtype of pediatric high-grade glioma, arises in the cerebral hemispheres. Despite better survival outcomes, the treatment of infant-type hemispheric glioma is still facing challenges. Here, we reported a case of QKI-ALK fusion, infant-type hemispheric glioma with lung metastasis who achieved a complete clinical response after lorlatinib treatment. This typical case demonstrated the importance of appropriate molecularly targeted treatments in ALK-fused tumors, and lorlatinib may serve as an effective complement to conventional chemotherapy and radiotherapy in primary glioma harboring ALK fusions and its metastasis.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Child; Glioma; Humans; Infant; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors

Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective for treatment of

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Retrospective Studies

Recently, cases of cardiovascular toxicities, such as pericarditis, caused by anaplastic lymphoma kinase (ALK) inhibitors have been reported; however, whether these adverse events are common among all ALK inhibitors remains unclear.. This study aimed to clarify the cardiovascular toxicity profile of ALK inhibitors using an adverse event spontaneous report database.. We analyzed data from VigiBase, the WHO global database of individual safety reports, from its inception in 1968 to December 2021. We calculated the reporting odds ratio to evaluate the association between ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) and 21 cardiovascular adverse events. Time to onset of pericarditis from ALK inhibitor administration was analyzed.. Of the 27,994,584 reports, 19,911 involved treatment with ALK inhibitors. Among the 21 cardiovascular toxicities, only pericarditis signals were detected with all five ALK inhibitors (crizotinib [reporting odds ratios (ROR), 4.7; 95% CI 3.63-6.15], ceritinib [ROR, 12.9; 95% CI 9.37-17.79], alectinib [ROR, 4.8; 95% CI 3.15-7.42], brigatinib [ROR, 3.5; 95% CI 1.33-9.46], and lorlatinib [ROR, 6.4; 95% CI 3.60-11.22]). For torsade de pointes/QT prolongation, signals were detected with crizotinib (ROR, 5.0; 95% CI 3.72-6.77) and ceritinib (ROR, 4.2; 95% CI 2.17-8.05), whereas for hypertension, they were identified only with brigatinib (ROR, 3.9; 95% CI 2.88-5.20), and for heart failure, they were detected with alectinib (ROR, 2.2; 95% CI 1.60-2.90), crizotinib (ROR, 2.1; 95% CI 1.72-2.48), and lorlatinib (ROR, 2.0; 95% CI 1.27-3.23). Regarding time-to-onset analysis from drug administration to adverse event reporting, for pericarditis, it ranged from 52.5 days for alectinib to 166.5 days for crizotinib.. Systematic evaluation of ALK inhibitor-associated adverse events revealed differences in the cardiotoxicity profiles among ALK inhibitors. Understanding the differences in the cardiovascular toxicity profile of each ALK inhibitor will contribute to safe drug therapy when switching between ALK inhibitors.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Pericarditis; Pharmacovigilance; Protein Kinase Inhibitors; World Health Organization

Topics: Aminopyridines; Humans; Hypercholesterolemia; Lactams, Macrocyclic; Lung Neoplasms; PCSK9 Inhibitors; Proprotein Convertase 9; Protein Kinase Inhibitors

Activating point mutations in Anaplastic Lymphoma Kinase (ALK) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib resistance.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Drug Resistance, Neoplasm; Humans; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Neuroblastoma; Protein Kinase Inhibitors

To dynamically monitor the changes of genomic characteristics during lorlatinib treatment and analyze the resistance profile of lorlatinib in ALK-positive advanced Chinese patients with non-small cell lung cancer (NSCLC) with first- and second-generation ALK inhibitor resistance.. Ten eligible patients who were from a phase 2 study in China and admitted to the Fifth Medical Center of PLA General Hospital were analyzed. Blood samples were collected for next-generation sequencing (NGS) to characterize genetic variation at baseline, during treatment, and after disease progression.. Among the 10 patients treated with lorlatinib, objective response rate (ORR) was 50%. The median progression-free survival (PFS) was 13.3 months, and median overall survival (OS) was 15.6 months. At baseline, the mutation frequency of ALK in circulating tumor DNA (ctDNA) was higher in the group who received two lines of previous anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), and a similar trend was observed for TP53. After one follow-up cycle, the decreased variant allele frequency (VAF) had a trend to be predictive for responses. In six patients in which blood samples had been taken after lorlatinib resistance, ALK compound mutations were found in three patients (50%), which were G1202R/L1196M, L1196M/D1203N, and G1202R/F1174C. The DNMT3A N403Tfs*4, ERCC3 E259D, and GNAS p.A436_P459del variants were only detected after progression in two of the other three patients without ALK compound mutations.. The dynamic changes of genomic characteristics during lorlatinib treatment revealed the mutation landscape of Chinese patients with NSCLC after ALK-TKI resistance, indicated that the resistance profile of lorlatinib were heterogeneous, which laid the foundation for subsequent treatment to overcome lorlatinib resistance.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Drug Resistance, Neoplasm; Humans; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608).. Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association.. Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49-2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67-3.30).. In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.

Topics: Anaplastic Lymphoma Kinase; Biomarkers; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors

We spotlight the promising preliminary findings reported by Goldsmith et al. of a phase 1 first-in-child study showcasing the safety and efficacy of lorlatinib against treatment-refractory or relapsed ALK-driven neuroblastoma.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams, Macrocyclic; Lung Neoplasms; Neoplasm Recurrence, Local; Neuroblastoma; Protein Kinase Inhibitors

Topics: Aminopyridines; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Psychotic Disorders

Lorlatinib is the only targeted therapy approved in Canada to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) whose tumor has progressed despite treatment with second-generation ALK tyrosine kinase inhibitor (TKI), a patient population with high unmet need and lack of publicly reimbursed targeted treatments in Canada. We prospectively examined the real-world effectiveness and impact of lorlatinib on quality-of-life in 59 lorlatinib-treated patients, characterized as: median age of 62.0 years; 47.5% were female; 32.2% had central nervous system metastases; 50.8% had 2+ prior ALK TKI lines; and alectinib was the most common ALK TKI (72.9%) administered before lorlatinib, including 44.1% who received first-line alectinib. With a median follow-up of 15.3 months (IQR: 6.2-19.2), median time-to-treatment discontinuation of lorlatinib was 15.3 months (95% CI: 7.9-not reached), with 54.2% (95% CI: 40.8-65.9%) of patients without treatment discontinuation at 12 months. At baseline, the mean health utility score (HUS) was 0.744 (SD: 0.200). At 3 months, patients receiving lorlatinib demonstrated a 0.069 (95% CI: 0.020-0.118;

Topics: Anaplastic Lymphoma Kinase; Canada; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quality of Life

Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling.. ALK fusions and ALK with or without TP53 mutations were assessed by next-generation sequencing. End points included objective response rate (ORR), duration of response, and progression-free survival (PFS) by blinded independent central review on the basis of EML4::ALK variants and ALK with or without TP53 or other mutation status.. ALK fusions were detected in the ctDNA of 62 patients in the lorlatinib arm and 64 patients in the crizotinib arm. ORRs were numerically higher with lorlatinib versus crizotinib for EML4::ALK variant 1 (v1; 80.0% versus 50.0%) and variant 2 (v2; 85.7% versus 50.0%) but were similar between the arms for variant 3 (v3; 72.2% versus 73.9%). Median PFS in the lorlatinib arm was not reached for EML4::ALK v1 and v2 and was 33.3 months for v3; in the crizotinib arm, median PFS was 7.4 months, not reached, and 5.5 months, respectively. ORRs and PFS were improved with lorlatinib versus crizotinib regardless of TP53 mutation status and in patients harboring preexisting bypass pathway resistance alterations. In the lorlatinib arm, PFS was lower in patients who had a co-occurring TP53 mutation. Results from ctDNA analysis were similar to those observed with tumor tissue samples.. Patients with untreated ALK-positive advanced NSCLC derived greater clinical benefits, with higher ORRs and potentially longer PFS, when treated with lorlatinib compared with crizotinib, independent of EML4::ALK variant or ALK mutations, TP53 mutations, or bypass resistance alterations.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Tumor Suppressor Protein p53

Adult-onset neuroblastoma (AON) differs significantly in biology and clinical behavior from childhood-onset disease. AON poses therapeutic challenges since tolerance of intensive multimodality therapies that are standard of care for pediatric neuroblastoma (NB) is poor. AON is enriched for somatic mutations including anaplastic lymphoma kinase (. A single-center retrospective review of adults with NB receiving ALKi (2012-2022) was performed. Response was evaluated using International Neuroblastoma Response Criteria.. ALKis, particularly lorlatinib, are effective treatment options for AON. However, AEs necessitating dose reduction are common.

Topics: Adolescent; Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Neuroblastoma; Protein Kinase Inhibitors; Young Adult

BACKGROUND Chemotherapy has been the conventional treatment method for advanced non-small-cell lung cancer (NSCLC). Nevertheless, the identification and comprehension of oncogenic driver alterations have paved the way for targeted therapies, significantly enhancing patient outcomes. The management of locally advanced NSCLC that is positive for ALK presents a challenge due to the lack of reported randomized controlled trials. The efficacy of neoadjuvant and adjuvant targeted therapy in this context remains uncertain. CASE REPORT A 54-year-old man was diagnosed with stage IIIB (pT1N3M0) upper right lung adenocarcinoma carrying the EML4-ALK fusion gene. Clinically, the patient had multiple enlarged lymph nodes in the right hilum and mediastinum, with the largest measuring approximately 28×19 mm by CT scan and we found that the L4 lymph node was invaded by metastasis. Then, the patient received 1 cycle of chemotherapy with paclitaxel in combination with nedaplatin and subsequently received maintenance treatment involving lorlatinib. Two months later, clinical evaluations revealed progressive reduction of the lesions, especially the reduced size of the mediastinal lymph nodes. Therefore, the patient underwent thoracoscopic partial lobectomy and lymphadenectomy and achieved pathological complete response (pCR). After 3 months, a follow-up CT scan was similar to the first postoperative CT scan and no tumor was found. CONCLUSIONS This case demonstrates the potential advantage of lorlatinib as a neoadjuvant therapy in advanced ALK-positive NSCLC. It emphasizes the importance of identifying new therapeutic targets by next-generation sequencing (NGS) and implementing precise treatment strategies in clinical practice.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Protein Kinase Inhibitors

Video: Lorlatinib podcast video.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles

The SARS-COV-2 (COVID-19) pandemic is challenging the management of cancer patients. In this article, we present two patients diagnosed with anaplastic lymphoma kinase (ALK) + non-small cell lung adenocarcinoma (NSCL CA), infected with COVID-19, who had a previous multi-line therapy with Brigatinib and Lorlatinib, and received Favipiravir for their current infection.. A 58-year-old man and a 65-year-old woman were diagnosed as ALK ( + ) NSCL CA. Both patients received tyrosine kinase inhibitors (TKI) for lung cancer when diagnosed with COVID-19. No adverse effects were observed with the concurrent use of Favipiravir, an antiviral drug currently used for COVID-19 and TKI.. Considering the pharmacokinetic effects of favipiravir and the ALK inhibitor TKI's used on our cases (Brigatinib-Lorlatinib), the concurrent use of these drugs was safe and prevented the delay in the primary treatment of the malignancy of our patients.. To our knowledge, these are the only reported cases diagnosed as ALK ( + ) NSCL CA who received favipiravir because of COVID-19 while using TKI, and both patients recovered completely without any side effects.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; COVID-19 Drug Treatment; Female; Humans; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; SARS-CoV-2

ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) is a rare lung cancer with limited treatment options. Phase I-II studies with ROS1-tyrosine kinase inhibitors (TKIs) included small numbers of patients and real-world data are lacking. We investigate the efficacy and safety of lorlatinib, a third-generation TKI targeting ALK and ROS1, in patients with ROS1+ NSCLC treated through an expanded access program.. Consecutive patients with advanced ROS1+ NSCLC treated with lorlatinib between October 2015 and June 2019 were included. Data were collected from medical records. The primary endpoint was progression-free survival.. Out of the 80 patients included, 47(59%) were female, 49(62%) never smokers (less than 100 cigarettes over the lifetime), and 68(85%) had stage IV NSCLC at diagnosis. Most frequent histology was adenocarcinoma (95%) and median age was 58.2 years. At the time of lorlatinib initiation, 51(64%) patients had brain metastases and 55(81%) were PS 0-1. Lorlatinib was administered as second/third/fourth/fifth+ line in 29%/28%/18%/26% of patients. All patients previously received at least one ROS1 TKI, and 55(69%) previously received chemotherapy. Median follow-up from lorlatinib initiation was 22.2 months. Median progression-free survival and overall survival from lorlatinib initiation were 7.1 months [95% confidence interval (CI) 5.0-9.9 months] and 19.6 months (95% CI 12.3-27.5 months). Median duration of treatment with lorlatinib was 7.4 months (95% CI 6.5-13.1 months). Overall response and disease control rates were 45% and 82%, respectively. The central nervous system response rate was 72%. Treatment was stopped due to toxicity in 10 patients (13%). The safety profile was consistent with previously published data.. Lorlatinib is a major treatment option for advanced refractory ROS1+ NSCLC in treatment strategy.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) represents a rare subset of lung cancer, with specific presentation, and multiple treatment options, including selective tyrosine kinase inhibitors (TKIs). Real-world evidence is insufficient regarding the actual real-life treatment sequences in the late line setting, and available clinical trials may not reflect real-world situation. Here, we took advantage of the French Expanded Access Program (EAP) of lorlatinib, a third-generation TKI targeting ALK and ROS1, to assess treatment sequencing, and lorlatinib efficacy and safety, in patients with ALK+ NSCLC.. All consecutive patients with advanced ALK+ NSCLC treated between October 2015 and June 2019 with lorlatinib as part of EAP were included. Data were collected and reviewed from medical records by independent research staff of the French Thoracic Cancer Intergroup. The primary endpoint was progression-free survival (PFS).. Of the 208 patients included, 117 (56%) were female, 142 (69%) were never smokers, and 180 (87%) had stage IV NSCLC at diagnosis. The most frequent histology was adenocarcinoma (94%), and the median age was 60.9 years. At the time of lorlatinib initiation, 160 (77%) patients had brain metastases, and 125 (72%) were performance status 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 4%/17%/30%/49% of patients. A total of 162 (78%) patients had previously been treated with chemotherapy, 194 (93%) with a first-generation ALK-TKI, 195 (94%) with a second-generation ALK-TKI. The median follow-up from lorlatinib initiation was 23.3 months. The median PFS, median overall survival (OS) from lorlatinib initiation and median OS from advanced NSCLC diagnosis were 9.9 months (95% confidence interval [CI] 6-12.3 months), 32.9 months (95% CI 18.7 months to not reached) and 97.3 months (95% CI 75.7-152.8 months), respectively. The median duration of treatment with lorlatinib was 11.8 months (95% CI 8.5-18.8 months). Overall response and disease control rate were 49% and 86%, respectively. Central nervous system objective response rate was 56%. Treatment was stopped due to toxicity in 28 patients (14%). The safety profile of lorlatinib was consistent with previously published data.. Real-world evidence indicates that lorlatinib offers a significant clinical benefit and high intracerebral antitumour activity in heavily pretreated patients with ALK+ NSCLC.. NCT03727477.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Pyrazoles

Treatment options for heavily treated anaplastic lymphona kinase (ALK )-positive nonsmall cell lung cancer (NSCLC) patients, who typically bear-resistant mechanisms to ALK tyrosine kinase inhibitors (TKIs), are usually limited to chemotherapy, which elicits limited clinical benefit and may incur severe toxicity. It is clinically relevant to explore other revenues for these patients. poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib are currently approved to treat BReast CAncer gene 1/2 ( BRCA1/2 )-mutated patients in a few tumor types. There have been a trial and two case reports of an olaparib-containing regimen in treating epidermal growth factor receptor (EGFR)-positive or driver-negative NSCLC. We report a case of a 27-year-old female nonsmoker diagnosed with ALK -rearranged metastatic lung adenocarcinoma. She was treated with alectinib and acquired ALK p.I1171N and p.V1180L mutations. Germline BRCA2 p.F2801fs was also identified. After sequential lines of ceritinib and chemotherapy, lorlatinib was chosen as the fourth-line therapy and maintained control for 6 months. Shortly after progression, the patient was admitted to the ICU due to critically severe stenosis caused by a tracheal mass and soon relieved by embolization and stenting. Afterward lorlatinib plus olaparib was started and elicited a rapid response within 1 month. The progression-free survival was 6 months as of the latest follow-up, with the best response of partial response. To the best of our knowledge, this case is the first to provide clinical evidence of antitumor activity of olaparib plus ALK TKI in ALK -positive, g BRCA -mutated metastatic NSCLC. Together with previous reports in EGFR -positive or driver-negative patients, our finding warrants further studies on PARP inhibition in BRCA1/2 -mutated NSCLC.

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Anaplastic Lymphoma Kinase; BRCA2 Protein; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Tracheal Stenosis

Lorlatinib is a third-generation, brain-penetrant anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with robust intracranial activity in patients with ALK- or ROS1-positive non-small cell lung cancer (NSCLC). Data from the ongoing open-label, single-arm, multicenter, phase-1/2 study of lorlatinib in patients with metastatic ALK- or ROS1-positive NSCLC were used to further investigate the potential brain penetration of lorlatinib. Patients received escalating lorlatinib doses (10-200 mg once daily or 35-100 mg twice daily) or the approved dosing (100 mg daily). Plasma was collected from all patients, and cerebrospinal fluid (CSF) was collected at baseline and during the study from 5 patients with suspected or confirmed leptomeningeal carcinomatosis or carcinomatous meningitis. For those 5 patients, lorlatinib concentrations ranged from 2.64 to 125 ng/mL in the CSF and from 12.7 to 457 ng/mL in the plasma; free plasma concentrations ranged from 4.318 to 155.385 ng/mL. The CSF/free plasma ratio was 0.77 (R

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

A 44-year-old woman with ALK-positive advanced adenocarcinoma of the lung was treated with crizotinib, and the lung lesions disappeared. The patient was treated with alectinib and chemotherapy, but brain metastases worsened; therefore, we performed an ALK resistance gene mutation test using plasma samples. Since no ALK resistance gene mutations were detected, we speculated that ALK inhibitors failed to achieve therapeutic effects due to poor transport to the central nervous system. Therefore, we switched to lorlatinib, and found a reduction in brain metastases. In ALK-positive advanced lung cancer, plasma-based resistance gene testing may be useful for treatment decisions.

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lactams; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Drug Approval; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases

Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrazoles

To provide evidence-based recommendations updating the 2021 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) with driver alterations.. ASCO updated recommendations on the basis of an ongoing systematic review of randomized control trials from 2020 to 2021.. This guideline update reflects changes in evidence since the previous update. Two studies provide the evidence base. Outcomes of interest include efficacy and safety.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams; Lung Neoplasms; Organophosphorus Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Although lorlatinib, the third generation of echinoderm microtubule protein 4-anaplastic lymphoma kinase (EML4-ALK) tyrosine kinase inhibitor (TKI), overcame the previous generation ALK-TKIs' drug resistance problems, but the mechanism of lorlatinib resistance remained unclear. Furthermore, optimal chemotherapy for lorlatinib-resistant non-small cell lung cancer (NSCLC) patients was still unknown.. A lorlatinib-resistant NSCLC cell line SNU-2535LR was generated by gradually increasing dose of lorlatinib to crizotinib-resistant cell line SNU-2535 in vitro. To study the resistance mechanism of SNU-2535LR cells, we applied CCK-8 assay to detect the sensitivity of crizotinib and the reverse effect of APR-246, a p53 activator, on lorlatinib-induced resistance and different chemotherapy drugs to SNU-2535LR cells. We also detected the expressions of EML4-ALK-related proteins of SNU-2535LR cells via western blot.Please confirm that author names have been identified correctly and are presented in the right order.Dear Editor:     I have carefully confirmed that the author names have been identified correctly and are presented in right order.Thank you very much!                                                                     Your sincerely BoXie RESULTS: The sensitivity of SNU-2535LR cells to lorlatinib was decreased significantly than that of SNU-2535 cells. EML4-ALK fusion was decreased both at protein level and DNA level in SNU-2535LR cells. More interesting, the crizotinib-resistant mutation ALK p.G1269A disappeared, while new TP53 mutation emerged in SNU-2535LR cells. APR-246 can reverse the lorlatinib resistance in SNU-2535LR cells, with a reversal index of 4.768. Compared with SNU-2535 cells, the sensitivity of SNU-2535LR cells to gemcitabine, docetaxel and paclitaxel was significantly increased (P < 0.05), but decreased to cisplatin (P < 0.05).. This study demonstrated that the combination of p53 protein agonist and lorlatinib may provide a new therapeutic strategy for NSCLC patients with lorlatinib resistance and TP53 mutation. Furthermore, the results also provide guidance for selecting optimal chemo-regimens for NSCLC patients after ALK-TKIs failure.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line; Cisplatin; Crizotinib; Docetaxel; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Microtubule Proteins; Mutation; Paclitaxel; Protein Kinase Inhibitors; Pyrazoles; Tumor Suppressor Protein p53

Anaplastic lymphoma kinase tyrosine kinase inhibitors are standard therapeutic agents prescribed for anaplastic lymphoma kinase-positive non-small cell lung cancer, and treatment with these agents has been shown to contribute to long-term survival in patients. However, there is no consensus regarding the course of treatment after the onset of anaplastic lymphoma kinase tyrosine kinase inhibitors related drug-induced interstitial lung disease. Here, we present a case of successful lorlatinib treatment after the onset of drug-induced interstitial lung disease caused by alectinib.. A 57-year-old Japanese man was diagnosed with stage IVB non-small cell lung cancer by bronchoscopy, but gene mutation testing could not be performed because of the small amount of specimen. After diagnosis, first-line therapy with cisplatin/pemetrexed was initiated, but the patient developed renal dysfunction. Bronchoscopy was performed again to guide further treatment, and the non-small cell lung cancer was found to be anaplastic lymphoma kinase positive. Alectinib was started after the onset of progressive disease, but it resulted in drug-induced interstitial lung disease, necessitating alternative treatments. He subsequently received nanoparticle albumin bound paclitaxel, which was halted in view of the renal dysfunction. Thereafter, lorlatinib was administered, which was continued without drug-induced interstitial lung disease relapse.. Since alectinib can occasionally cause drug-induced interstitial lung disease, as in the present case, lorlatinib may be an option to continue treatment in patients without other treatment alternatives.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Kidney Diseases; Lactams; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles

Anaplastic lymphoma kinase (ALK) fusions represent the second most common oncogenic driver mutation in non-small cell lung cancer (NSCLC). As the new class of 3rd generation of ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown robust potency and brain-penetrant clinical activity against a wide spectrum of multiple resistance mutations within the ALK domain detected during crizotinib and 2nd generation ALK TKI treatment. Lorlatinib is generally well-tolerated with unique adverse drug reaction/adverse event, including hyperlipidemia and central nervous system effects, which are mostly mild to moderate severity and manageable through dosage modifications and/or standard medical intervention. For advanced NSCLC with ALK positivity, patients should be evaluated for baseline characteristics and pre-existing medication, informed of the potential toxicities, and periodically monitored to balance benefits and risks. Moreover, a multidisciplinary group of experts is essential to establish a comprehensive diagnostic and therapeutic strategy.
.. 【中文题目：洛拉替尼特殊不良反应管理中国专家共识】 【中文摘要：间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）中第二常见的肿瘤驱动基因。作为新型的第三代ALK酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI），洛拉替尼对多种ALK激酶域突变具有广谱且高效的临床活性，并具有强大的穿透血脑屏障效力。洛拉替尼的总体耐受性良好，其独特的不良反应或不良事件包括高脂血症与中枢神经系统反应等，多为轻至中度，通常经剂量调整和/或标准医疗干预即可管理。对于ALK阳性晚期NSCLC，开始洛拉替尼治疗前应充分评估患者基线特征与既往用药状况，预先告知患者可能经历的用药相关不良反应，并定期监测以实现药物临床获益的最大化。同时，多学科专家团队对于建立全面的诊断和治疗策略是至关重要的。
】 【中文关键词：间变性淋巴瘤激酶；肺肿瘤；洛拉替尼；不良反应】.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; China; Consensus; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases

Topics: Aminopyridines; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles

The third-generation anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI) lorlatinib has a unique side effect profile that includes hypercholesteremia and hypertriglyceridemia in >80% of lung cancer patients. Here, we tested the hypothesis that lorlatinib might directly promote the accumulation of cholesterol and/or triglycerides in human hepatic cells. We investigated the capacity of the hepatoprotectant silibinin to modify the lipid-modifying activity of lorlatinib. To predict clinically relevant drug−drug interactions if silibinin were used to clinically manage lorlatinib-induced hyperlipidemic effects in hepatic cells, we also explored the capacity of silibinin to interact with and block CYP3A4 activity using in silico computational descriptions and in vitro biochemical assays. A semi-targeted ultrahigh pressure liquid chromatography accurate mass quadrupole time-of-flight mass spectrometry with electrospray ionization (UHPLC-ESI-QTOF-MS/MS)-based lipidomic approach revealed that short-term treatment of hepatic cells with lorlatinib promotes the accumulation of numerous molecular species of cholesteryl esters and triglycerides. Silibinin treatment significantly protected the steady-state lipidome of hepatocytes against the hyperlipidemic actions of lorlatinib. Lipid staining confirmed the ability of lorlatinib to promote neutral lipid overload in hepatocytes upon long-term exposure, which was prevented by co-treatment with silibinin. Computational analyses and cell-free biochemical assays predicted a weak to moderate inhibitory activity of clinically relevant concentrations of silibinin against CYP3A4 when compared with recommended (rosuvastatin) and non-recommended (simvastatin) statins for lorlatinib-associated dyslipidemia. The elevated plasma cholesterol and triglyceride levels in lorlatinib-treated lung cancer patients might involve primary alterations in the hepatic accumulation of lipid intermediates. Silibinin could be clinically explored to reduce the undesirable hyperlipidemic activity of lorlatinib in lung cancer patients.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 CYP3A; Hepatocytes; Humans; Lactams; Lactams, Macrocyclic; Lipids; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Silybin; Tandem Mass Spectrometry; Triglycerides

Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)/receptor tyrosine kinase inhibitor (ROS1), demonstrated efficacy in ROS1 positive (ROS1+) non-small cell lung cancer (NSCLC), although approval is currently limited to the treatment of ALK+ patients. However, lorlatinib-induced resistance mechanisms, and its efficacy against the resistance mutation G2032R in ROS1, respectively, have not yet been fully understood. Furthermore, concomitant tumor suppressor gene p53 (TP53) mutations occur in driver alteration positive NSCLC, but their prognostic contribution in the context of ROS1 inhibition remains unclear. Here we report a ROS1+ NSCLC patient who developed an on target G2032R resistance mutation during second-line lorlatinib treatment, indicating the lack of activity of lorlatinib against ROS1 G2032R. The resistance mutation was detected in plasma-derived ctDNA, signifying the clinical utility of liquid biopsies.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Liquid Biopsy; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Tumor Suppressor Protein p53

Six anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including one domestic (ensartinib) and five imported ALK-TKIs (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib), have been recommended as first-line treatments for advanced ALK-positive NSCLC in China. This study sought to examine the cost-effectiveness of these six novel therapies in Chinese patients.. We constructed a Markov model to compare the cost-effectiveness of the six ALK-TKIs as a first-line treatment for patients with advanced ALK-positive NSCLC from the perspective of the Chinese healthcare system. Transition probabilities were estimated by synthesizing data from the PROFILE 1,029 trial and a network meta-analysis. Health state utilities and costs were sourced from published literature, publicly available national databases, and local general hospitals. The robustness of model was assessed. Compared with crizotinib, ensartinib achieved additional 0.12 quality-adjusted life-year (QALY) with marginal costs of $3,249, resulting in an incremental cost-effectiveness ratio (ICER) of $27,553/ QALY. When compared with ceritinib and brigatinib, ensartinib achieved additional 0.06 and 0.03 QALYs with substantially reduced costs. When compared with lorlatinib and alectinib, ensartinib was associated with a lower QALY and decreased total costs; the ICERs for lorlatinib and alectinib were $934,101/ QALY and $164,888/ QALY, respectively.. For Chinese patients with advanced ALK-positive NSCLC, ensartinib was a cost-effective option compared with crizotinib, and was a dominant alternative to ceritinib and brigatinib. Although lorlatinib and alectinib were associated with prolonged survival compared with ensartinib, they were less cost-effective than ensartinib due to the overwhelming total costs.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Cost-Benefit Analysis; Crizotinib; Humans; Lactams; Lung Neoplasms; Network Meta-Analysis; Organophosphorus Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyrimidines; Sulfones

This is a summary of a research study (known as a clinical trial) called CROWN. The study tested two medicines called lorlatinib and crizotinib in participants with untreated non-small cell lung cancer that had spread to other parts of their body. All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib, they were checked regularly to see if their tumors had grown or spread to other parts of their body (known as tumor progression) and to monitor any side effects. After 1 year of treatment, the participants who took lorlatinib were twice as likely to be alive with no tumor growth as the participants who took crizotinib. More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%). This was also true of the participants whose cancer had spread to their brain. The most common side effects in participants who took lorlatinib were increases in the amount of cholesterol and triglycerides (a type of fat) in their blood, swelling, weight gain, nerve damage, unclear thoughts, and diarrhea. Among the participants who took crizotinib, the most common side effects were diarrhea, feeling like you want to throw up, sight problems, swelling, vomiting, changes in liver function, and feeling tired. Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment. ClinicalTrials.gov NCT number: NCT03052608.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams; Language; Lung Neoplasms; Pyrazoles

Although anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib.. A 55-year-old woman with no history of smoking presented to our hospital with a swelling on the left neck. Clinical imaging and histopathological examination revealed a tumor of adenocarcinoma histology in the left upper lung with no CNS metastasis.. The patient was diagnosed with ALK-positive lung adenocarcinoma (cT3N3M1b: stage IVA).. She received the second-generation ALK inhibitors, alectinib and brigatinib, in the first and second-line settings, respectively. However, she developed meningeal carcinomatosis. Hence, treatment with lorlatinib was initiated in the third-line setting.. The symptoms associated with meningeal carcinomatosis, such as disturbance of consciousness and diplopia, improved dramatically. At 8 months from the initiation of lorlatinib, the patient remained well without disease progression.. Lorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lactams; Lung Neoplasms; Meningeal Carcinomatosis; Middle Aged; Organophosphorus Compounds; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyrimidines

Topics: Adenocarcinoma of Lung; Aminopyridines; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 15; Humans; Lactams; Lung Neoplasms; Mice; Mice, Nude; Microtubule-Associated Proteins; Neoplasm Proteins; Oncogene Proteins, Fusion; Pyrazoles; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays

Lorlatinib is an oral anaplastic lymphoma kinase (ALK) and C-ros oncogene (ROS1) tyrosine kinase inhibitor with excellent central nervous system (CNS) penetrability. It is currently approved for use as second line therapy for those with ALK positive non-small cell lung cancer (NSCLC). Given its CNS penetrating effects, lorlatinib has shown to cause CNS adverse events such as seizures, hallucinations, and changes in cognitive function. To our knowledge proteinuria has not been previously described with this medication.. We report a case lorlatinib induced proteinuria in a patient receiving lorlatinib as second line treatment for ROS1 rearranged NSCLC.. Our case demonstrates objective evidence for proteinuria induced by lorlatinib, which may also be dose dependent.

Topics: Aged; Aminopyridines; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Proteinuria; Pyrazoles

Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial-mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis.

Topics: Aminopyridines; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Survival; Down-Regulation; Epithelial-Mesenchymal Transition; Humans; Lactams; Lung Neoplasms; Matrix Metalloproteinases; Piperidines; Pyrazoles; Tumor Cells, Cultured

Topics: Aminopyridines; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles; Receptor Protein-Tyrosine Kinases

The CROWN study suggests that lorlatinib is effective in patients newly diagnosed with advanced

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles

Acquired mutations in anaplastic lymphoma kinase (

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Humans; Lactams; Lung Neoplasms; Male; Mutation; Pyrazoles

Should lorlatinib be the standard first-line treatment in advanced ALK-rearranged lung cancer? In the New England Journal of Medicine, Shaw et al. present interim analysis results from CROWN, a randomized, phase 3 study comparing lorlatinib with crizotinib as initial therapy in patients with advanced ALK-rearranged NSCLC.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles

Patients with

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Immune Checkpoint Inhibitors; Lactams; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Nivolumab; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyrimidines; Sulfones; Time Factors; Treatment Outcome; Tumor Microenvironment

ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

Topics: Aminopyridines; Aniline Compounds; Animals; Apoptosis; Benzamides; Carbazoles; Cell Line; Cell Survival; Crizotinib; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Immunoblotting; Indazoles; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mice, Inbred BALB C; Molecular Dynamics Simulation; Neoplasm Recurrence, Local; Piperidines; Proto-Oncogene Proteins; Pyrazines; Pyrazoles; Receptor Protein-Tyrosine Kinases

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Gene Deletion; Humans; Lactams; Lung Neoplasms; Positron Emission Tomography Computed Tomography; Pyrazoles

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Carbazoles; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Muscle, Skeletal; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyrazoles

Lorlatinib is a potent small-molecule anaplastic lymphoma kinase inhibitor approved for the treatment of patients with nonsmall cell lung cancer. In a drug-drug interaction study in healthy human participants, liver enzyme elevations were observed when a single 100 mg dose of lorlatinib was administered after multiple doses of rifampin, a strong cytochrome P450 (CYP) 3A inducer and a pregnane X receptor (PXR) agonist. A series of in vitro and in vivo studies were conducted to evaluate potential mechanisms for the observed clinical toxicity. To investigate the involvement of CYP3A and/or PXR in the observed liver toxicity, studies were conducted in cynomolgus monkeys administered lorlatinib alone or with coadministration of multiple doses of known CYP3A inducers that are predominantly PXR agonists (rifampin, St. John's wort) or predominantly constitutive androstane receptor agonists (carbamazepine, phenytoin) and a net CYP3A inhibitory PXR agonist (ritonavir). Results from the investigative studies identified cynomolgus monkeys as a pharmacologically relevant nonclinical model, which recapitulated the elevated liver function test results observed in humans. Furthermore, liver toxicity was only observed in this model when lorlatinib was coadministered with strong CYP3A inducers, and the effects were not restricted to, or exclusively dependent upon, a PXR activation mechanism. These results generated mechanistic insights on the liver enzyme elevations observed in the clinical drug-drug interaction study and provided guidance on appropriate product safety label for lorlatinib.

Topics: Aminopyridines; Animals; Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Humans; Lactams; Lactams, Macrocyclic; Liver; Lung Neoplasms; Macaca fascicularis; Pyrazoles

The echinoderm microtubule associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) were fractured and fused to become EML4-ALK. Most of these EML4-ALK-positive non-small cell lung cancer patients respond well to the ALK inhibitor. Many patients can benefit from drug target therapy for a long time, and some patients can achieve long-term survival of more than 7 years under the optimized treatment mode. This patient has lung adenocarcinoma positive for EML4-ALK fusion gene, but the treatment outcome is obviously different from that of other patients with lung cancer positive for EML4-ALK fusion gene. After the first to third generations of ALK inhibitor targeted therapy and chemotherapy, the disease progresses rapidly, the drug resistance time is short, the survival time is short, and the benefit is limited. The patient received targeted therapy of Crizotinib, Ceritinib and Lorlatinib successively from July 15, 2019, followed by two chemotherapy courses of Bevacizumab combined with Pemetrexed and Carboplatin. The patient died on September 10, 2020, with a survival of 15 months. At the same time, the treatment showed common adverse reactions of ALK inhibitors. This paper analyzed the therapeutic effect and treatment dilemma of this patient, and provided an exploration direction for the treatment of patients with EML4-ALK fusion gene positive lung cancer.
.. 【中文题目：经3种ALK抑制剂及化疗治疗的
1例非小细胞肺癌病例报道】 【中文摘要：棘皮动物微管相关蛋白4（echinoderm microlubule-associated protein-like 4, EML4）和间变淋巴瘤激酶基因（anaplastic lymphoma kinase, ALK）可发生断裂后融合为EML4-ALK基因。对于EML4-ALK阳性非小细胞肺癌（non-small cell lung cancer, NSCLC），一代至三代的ALK抑制剂的使用已显示出显著疗效，很多患者可以从药物治疗中实现长期获益，部分患者在优化的治疗模式下可取得超过7年的长期生存。本例患者为EML4-ALK融合基因阳性肺腺癌，治疗结局却明显不同于其他EML4-ALK融合基因阳性肺癌患者，经过一代至三代ALK抑制剂靶向治疗和化学治疗疾病进展快，耐药时间短，生存期短，获益有限。患者2019年7月15日开始先后口服克唑替尼、色瑞替尼、劳拉替尼靶向治疗，行贝伐珠单抗联合培美曲塞、卡铂化疗2个疗程，于2020年9月10日患者死亡，生存期15个月。同时治疗中表现出ALK抑制剂的常见不良反应。本文分析本例患者的治疗疗效及治疗困境，为EML4-ALK融合基因阳性肺癌患者治疗提供探索方向。
】 【中文关键词：EML4-ALK融合基因；AIK抑制剂；肺肿瘤】.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Crizotinib; Female; Humans; Lactams; Lung Neoplasms; Microtubule-Associated Proteins; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Serine Endopeptidases; Sulfones

Rearrangements in the anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) genes characterise two distinct molecular subsets of non-small cell lung cancer (NSCLC) tumours. Lorlatinib is a third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) shown to have systemic and intracranial activity in treatment-naive patients and in those who progressed on first- and second-generation TKIs. Despite being generally well tolerated, lorlatinib has a unique and challenging safety profile that includes hyperlipidaemia and central and peripheral nervous system adverse events (AEs). This article summarises a set of strategies designed to monitor and manage lorlatinib-related AEs that were agreed upon by a multidisciplinary panel of specialists in a meeting held in July 2020. Among the recommendations hereby described, special emphasis was placed on communication: prescribing physicians should inform patients and their families/caregivers about the likelihood and nature of lorlatinib AEs, encouraging them to report any symptoms, while at the same time reassuring them that most events are manageable and resolve spontaneously and have little to no interference with cancer treatment. Importantly, all patients should undergo a set of baseline assessments, including biochemical analysis, evaluation of cardiovascular risk, electrocardiogram (ECG), neurological evaluation and contrast-enhanced magnetic resonance imaging of the brain, which should be repeated regularly during lorlatinib treatment. Supportive medications to treat or relieve lorlatinib AEs were also discussed, as were the conditions requiring specialist consultations and/or adjustments in lorlatinib therapy. The overall goal of this article is to serve as a practical guide for oncologists to systematically and effectively approach lorlatinib AEs.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Portugal; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pharmaceutical Preparations; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases

We describe a case of an anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third-generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Lung Neoplasms; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Uterine Neoplasms

Anaplastic lymphoma kinase (ALK) translocation is a rare driver mutation in lung cancer. This study was aimed to report on the efficacy of lorlatinib in real-world practice and to evaluate the impact of prior ALK inhibitor treatments. We retrospectively evaluated patients with ALK-positive non-small cell lung cancer (NSCLC) treated with lorlatinib regarding its efficacy, the impact of prior ALK inhibitor treatments and the adverse events, in particular dyslipidemia. A total of 22 ALK-positive patients were analyzed. All patients had received at least one second-generation ALK inhibitor(s), while 12 patients had a history of crizotinib treatment. For lorlatinib, the objective response rate was 35.7%, and disease control rate was 64.3%. Their progression-free survival (PFS) was 6.2 months. With prior therapies, patients receiving only second-generation ALK inhibitor(s) treatment showed PFS longer than those with both crizotinib and second-generation ALK inhibitor(s) treatments (15.2 vs. 6.2 months). Moreover, patients who showed benefits from prior ALK inhibitor(s) also had a PFS longer than those who did not (6.5 vs. 3.5 months). Regarding adverse events, 94.7% of patients had dyslipidemia and 21.1% of them were in grade 3 or 4. None of these patients discontinued the treatment due to dyslipidemia. No acute complication occurred with dyslipidemia. The real-world efficacy of lorlatinib and adverse events were similar to those reported in clinical trials. Interestingly, the history and responses of prior ALK inhibitor treatments may influence the efficacy of subsequent lorlatinib treatment.

Topics: Adult; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lactams; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Progression-Free Survival; Pyrazoles; Retrospective Studies

The prognosis of pancreatic cancer has improved only modestly in recent years. This is partly due to the lack of development in precision oncology including immune oncology in this entity. Rearrangements of the proto-oncogene tyrosine protein kinase ROS1 gene represent driver alterations found especially in lung cancer. Tyrosine kinase inhibitors (TKI) with activity against ROS1 including lorlatinib substantially improved the outcome of this patient population. Anecdotal evidence reports treatment of pancreatic cancer harboring ROS1 fusions with ROS1 TKI, but data concerning treatment of patients with ROS1 point mutations are lacking.. This case describes a pancreatic cancer patient harboring a ROS1 point mutation that occurred without an underlying ROS1 rearrangement and thus not in the resistance situation. The heavily pretreated patient showed a strong decrease of the tumor biomarkers (CA19-9 and CEA) and radiologically a durable stable disease to the targeted treatment with lorlatinib, thereby achieving a progression-free survival of 12 months.. Our data are the first to show a clinical benefit from targeted treatment with ROS1 TKI in a cancer patient with a thus far undescribed ROS1 point mutation without a concomitant ROS1 rearrangement. Furthermore, they indicate that ROS1 could be an oncogenic driver in pancreatic cancer. This subgroup could be eligible for targeted treatments, which may contribute to the urgently needed improvement in patient outcome.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Mutation; Pancreatic Neoplasms; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pyrazoles

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear.. This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed.. Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%.. The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Crizotinib; DNA Mutational Analysis; Drug Resistance, Neoplasm; Female; High-Throughput Nucleotide Sequencing; Humans; Lactams; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Mutation; Piperidines; Predictive Value of Tests; Prospective Studies; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Sulfones; Taiwan; Treatment Outcome

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in the on-target treatment group than that in the off-target group (13.0 vs 1.2 months). In conclusion, resistance to ALK-TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Asian People; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recombinant Proteins; Sulfones

ROS-1-positive non-small cell lung cancers (NSCLCs) are rare (approximately 1% of all NSCLCs) and require a first-line treatment by crizotinib. Crizotinib resistance is frequent within the first 12 months of treatment. Lorlatinib is a novel tyrosine kinase inhibitor of ROS-1 recently indicated for metastatic or locally advanced crizotinib-resistant NSCLC. We report the use of lorlatinib as second-line with a complete tumoral response after only 3 months of treatment. This case shows the major role of F-FDG PET/CT in treatment evaluation and monitoring targeted therapy in metastatic NSCLC.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Crizotinib; Fluorodeoxyglucose F18; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Pyrazoles; Radiopharmaceuticals

Targeted small molecule EGFR Tyrosine Kinase Inhibitors (TKI's) and the Anaplastic Lymphoma Kinase (ALK) inhibitors have been promising tools for advanced non-small-cell lung cancers (NSCLCs). However, tumours tend to develop subsequent mutations, rendering them drug-resistant. Hence, alternative pathways of therapy need to be explored.. Gefitinib, erlotinib and afatinib, once considered as alternatives to platinum-based cytotoxic chemotherapy, have been rendered ineffective in patients with NSCLCs harbouring T790M mutation. Osimertinib is effective in T790M-mutant cancers, but not against those exhibiting the subsequent C797S mutation. ALK gene alterations have rendered tumours insensitive to crizotinib. However, lorlatinib and brigatinib are effective in tumours showing ALK+ mutations. Drugs acting through alternative pathways like the PD-1 pathway, BRAF, VEGFR, EGFR antibodies and NTRK inhibition have been showing promising results.. Osimertinib, brigatinib and allosteric C797S EGFR inhibitors like AI1045, BRAF inhibitors like LXH254 under trials and entrictinib, a recently approved NTRK inhibitor, have all shown improved progression-free survival compared with earlier generations of small molecule inhibitors for NSCLCs.

Topics: Aminopyridines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Molecular Targeted Therapy; Organophosphorus Compounds; Pyrazoles; Pyrimidines

ROS1-rearranged non-small cell lung cancer (NSCLC) has demonstrated promising response to lorlatinib; however, no targeted therapy is available after failure of lorlatinib and information on acquired resistance mechanisms mediating lorlatinib resistance among ROS1-rearranged NSCLC patients is limited. We report a ROS1-rearranged NSCLC patient who responded to immunochemotherapy after acquisition of ROS1 G2032K-mediated lorlatinib resistance.. Next-generation sequencing (NGS) was performed on supraclavicular lymph nodes (SLN) and blood samples obtained from the 53-year old male patient with advanced CD74-ROS1-rearranged NSCLC. In vitro experiments with patient-derived SLN tumor cells and in silico homology modeling were performed to investigate mechanisms of G2032K-mediated inhibitor resistance.. NGS analysis revealed the detection of an acquired ROS1 G2032 K after failure from lorlatinib. Homology modeling revealed the conformational change in the inhibitor binding site induced by the ROS1 G2032 K that disrupted lorlatinib binding. In vitro experiments using patient-derived cells bearing concurrent CD74-ROS1-rearrangement and ROS1 G2032 K demonstrated half-maximal inhibitory concentration IC50 of 730.2 nM for lorlatinib, 812.1 nM for entrectinib, and 1546 nM for crizotinib, indicating resistance to these inhibitors. With PD-L1 expression of TPS 30 %, nab-paclitaxel plus pembrolizumab was administered as fifth-line treatment and achieved partial response, with sustained response ongoing for 7 months as of January 31, 2020.. ROS1 G2032 K is a novel mutation that mediates resistance to lorlatinib. With the lack of targeted therapeutic options after lorlatinib resistance, checkpoint inhibitor plus chemotherapy may be considered as a treatment option in patients with ROS1-rearranged NSCLC.

Topics: Adenocarcinoma of Lung; Albumins; Aminopyridines; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Mutation, Missense; Paclitaxel; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

To evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily.. PRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM).. 255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %).. Lorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted.

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Patient Reported Outcome Measures; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Quality of Life; Surveys and Questionnaires

Lorlatinib, a next-generation central nervous system-penetrant ALK/ROS1 tyrosine kinase inhibitor (TKI), is approved to treat TKI-refractory ALK-positive (ALK+) NSCLC based on results from a phase 2 study.. A real-world analysis was performed on ALK+ or ROS1-positive (ROS1+) patients with NSCLC enrolled in lorlatinib early or expanded access programs in Hong Kong, Singapore, South Korea, Taiwan, Thailand, and the United States.. A total of 95 patients with NSCLC (76 ALK+ and 19 ROS1+) were analyzed. Among ALK+ patients treated with less than two previous TKIs, two or more previous TKIs, and three or more previous TKIs, the objective response rates (ORR) and median progression-free survival (mPFS) were 42% (95% confidence interval [CI]: 26-59; n = 38) and not reached (NR) (95% CI: 4.5-NR; n = 45), 35% (95% CI: 22-49; n = 55) and 11.2 months (95% CI: 4.5-NR; n = 66), and 18% (95% CI: 4-43; n = 17) and 6.5 months (95% CI: 3.5-11.6; n = 21), respectively. The ORRs and mPFSs were 13% (95% CI: 0-53; n = 8) and 9.2 months (95% CI: 3.3-NR; n = 9) for patients treated with one second-generation ALK TKI as the only ALK TKI received. For ROS1+ patients, ORRs and mPFSs were 41% (95% CI: 18-67; n = 17) and 11.9 months (95% CI: 6.4-NR; n = 19). The intracranial ORRs were 35% (95% CI: 22-49) and 55% (95% CI: 23-83) for 52 ALK+ and 11 ROS1+ patients. mPFS was 9.3 months (95% CI: 1.0-NR; n = 13) for patients with leptomeningeal carcinomatosis. No new safety signals were noted.. Lorlatinib exhibited meaningful activity in TKI-refractory ALK+ or ROS1+ patients with NSCLC enrolled in early or expanded access programs.

Topics: Aminopyridines; Hong Kong; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases; Republic of Korea; Taiwan

The FAM179A gene has recently been screened as a new fusion partner fusing to the anaplastic lymphoma kinase gene (ALK) in plasma cell-free DNA (cfDNA) of patients with non-small-cell lung cancer (NSCLC). However, the response of patients with NSCLC harboring the FAM179A-ALK fusion to ALK inhibitors remains unknown. In this study we report a novel FAM179A-ALK rearrangement variant (F1, A19) identified by next-generation sequencing in an NSCLC patient with multiple brain metastases (M1c). This patient responded sensitively to lorlatinib as evaluated by brain MRI and chest CT, followed up using plasma cfDNA. The conclusion is that we found a novel FAM179A-ALK rearrangement variant (F1, A19) and provided evidence of its sensitivity to ALK inhibitors.

Topics: Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles

Topics: Aminopyridines; Benzamides; Central Nervous System; Humans; Indazoles; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Neoplasm Recurrence, Local; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Lorlatinib is a third-generation tyrosine-kinases inhibitor (TKI) targeting ALK/ROS1 fusions. The FDA has approved lorlatinib for TKI-pretreated ALK(+) NSCLC, while its approval for ROS1(+) is still pending. Here we present the largest real-world data of NSCLC patients harboring ALK/ROS1 rearrangements treated with lorlatinib.. 123 patients were enrolled retrospectively (data cut-off 1/1/2019). Lorlatinib was administered through an early access program for patients with no other available therapy. Outcome and response were defined by each investigator upon RECIST 1.1 criteria.. 106 ALK(+) and 17 ROS1(+) patients recruited from 8 different countries. The ALK(+) cohort included 50 % males, 73 % never-smokers and 68 % with brain metastases. Extracranial (EC) and intracranial (IC) response rates (RR) were 60 % and 62 %, with disease control rates (DCR) of 91 % and 88 % respectively. Mean duration of therapy (DoT) was 23.9 ± 1.6 months and median overall survival (mOS) was 89.1 ± 19.6 months. ROS1 cohort enrolled 53 % males, 65 % never-smokers and 65 % had brain metastases. EC and IC RR were 62 % and 67 % with DCR of 92 % and 78 % respectively. Median DoT was 18.1 ± 2.5 months and mOS of 90.3 ± 24.4 months. OS and DoT in both cohorts were not significantly correlated with line of therapy nor other parameters. The most common adverse events of any grade were peripheral edema (48 %), hyperlipidemia (47 %), weight gain (25 %) and fatigue (30 %). CNS adverse events such as cognitive effect of grade 1-2 were reported in 18 % of patients.. Lorlatinib shows outstanding EC/IC efficacy in ALK/ROS1(+) NSCLC. The observed mOS of 89 ± 19 months in ALK(+) NSCLC supports previous reports, while mOS from of 90 ± 24 months is unprecedented for ROS1(+) NSCLC.

Topics: Aminopyridines; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Topics: Adenocarcinoma of Lung; Albumins; Aminopyridines; Antibodies, Monoclonal, Humanized; Humans; Immune Checkpoint Inhibitors; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation, Missense; Paclitaxel; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases. Biopsy confirmed IMT with TPM4-ALK fusion. He was treated with prednisolone without clinical benefit. He received the Trk/ROS1/ALK inhibitor entrectinib in a clinical trial but his disease progressed in less than 3 months. Ifosfamide and etoposide in addition to radiotherapy to the brain and chest were administered. Transient improvement in the radiotherapy-treated areas was observed but his disease progressed shortly afterwards on all sites including the development of new adrenal metastasis. Compassionate use of the third-generation ALK inhibitor lorlatinib resulted in excellent partial response on all disease sites after 2 months, followed by a further 6 months of disease stabilisation. Repeat imaging showed slight increase in size of the cerebral metastasis but stable disease elsewhere, for which he was given stereotactic radiotherapy. His disease progressed 3 months later and lorlatinib was substituted with another ALK inhibitor brigatinib but he deteriorated and died shortly afterwards. Our patient tolerated lorlatinib well for 11 months with minimal toxicities, although he developed unilateral right-sided lung consolidation that was probably related to a combination of infection, radiotherapy and lorlatinib, which needed treatment with antibiotics and corticosteroids. This case demonstrates a role of lorlatinib in the treatment of TPM4-ALK-rearranged IMT despite failure of entrectinib.

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Benzamides; Gene Fusion; Granuloma, Plasma Cell; Humans; Indazoles; Inflammation; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrazoles; Treatment Failure; Tropomyosin

Topics: Adenocarcinoma of Lung; Albumins; Aminopyridines; Antibodies, Monoclonal, Humanized; Humans; Immune Checkpoint Inhibitors; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation, Missense; Paclitaxel; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Topics: Acrylamides; Afatinib; Aminopyridines; Anaplastic Lymphoma Kinase; Aniline Compounds; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; B7-H1 Antigen; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; ErbB Receptors; Gefitinib; Hope; Humans; Lactams; Lung; Lung Neoplasms; Piperidines; Programmed Cell Death 1 Receptor; Pyrazoles; Quinazolinones; Survival Analysis

ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.

Topics: Aminopyridines; Benzamides; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Crizotinib; Drug Development; Drug Resistance, Neoplasm; Humans; Indazoles; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Membrane Glycoproteins; Mutation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Receptor, trkB

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Drug Development; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Topics: Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Organophosphorus Compounds; Pneumonia; Prognosis; Pyrazoles; Pyrimidines

Topics: Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Organophosphorus Compounds; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

The administration of target inhibitors is paramount to grant the longest survival in patients with ALK-positive non-small cell lung cancer (NSCLC). The eventual resistance to tyrosine kinase inhibitors (TKI) is monitored clinically and radiologically for prompt molecule shift to further generation TKI, if available. However, the early radiological detection of progression pattern (e.g. nodule onset) should be regarded with caution because overlaps exist with non-tumor cell proliferation and/or accumulation. Here we report the case of a stage IV ALK-rearranged NSCLC patient exposed to serial crizotinib, brigatinib, ceritinib, and lorlatinib (this latter brought to complete brain and leptomeningeal disease response), in a period of more than five years. During lorlatinib, the appearance of solid pulmonary nodules was obviously interpreted as disease progression. However, surgical biopsies of the pulmonary nodules revealed features of sarcoid-like granulomatous lymphadenitis, namely without tumor cell. This invasive approach, besides documenting for the first time a sarcoid-like reaction to ALK inhibitors, allowed to revert the radiological diagnosis and maintain lorlatinib, for the best patient outcome. The pragmatic relevance of these findings suggests a careful attitude towards the interpretation of radiologic patterns of disease progression in patients under TKI.

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Diagnosis, Differential; Disease Progression; Female; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Prognosis; Pyrazoles; Sarcoidosis

Topics: Aminopyridines; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Crizotinib; Drug Approval; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Neoplasm Metastasis; Organophosphorus Compounds; Pyrazoles; Pyrimidines; Recurrence; Treatment Outcome

Alectinib has shown a greater efficacy to ALK-rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming resistance has not been established yet.. We established lorlatinib-resistant cells harboring ALK-I1171N or -G1202R compound mutations by performing ENU mutagenesis screening or using an in vivo mouse model. We performed drug screening to overcome the lorlatinib-resistant ALK-compound mutations. To evaluate these resistances in silico, we developed a modified computational molecular dynamic simulation (MP-CAFEE).. We discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. FUND: This work was mainly supported by MEXT/JSPS KAKENHI Grants and AMED Grants.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Dynamics Simulation; Mutation, Missense; Protein Binding; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Software; Sulfones

Non-small-cell lung cancer (NSCLC) patients harboring ALK or ROS1 rearrangements invariably acquire resistance to the first- and second-generation tyrosine kinase inhibitors (TKIs), most notably ALK G1202R and ROS1 G2032R. Lorlatinib, a novel third-generation TKI, produced remarkable results from the first-in-man phase 1 trial: an overall response rate of 46% and 50% for previously treated ALK- and ROS1-positive patients, respectively. However, the efficacy of lorlatinib has not been widely validated in Asian patients.. Patients with advanced NSCLC with ALK or ROS1 rearrangements who initiated lorlatinib therapy between November 2016 and July 2018 were retrospectively analyzed.. Twelve consecutive patients were included. The median age was 55 years (range, 36-76 years). Ten (83%) had ALK-positive NSCLC and 2 (17%) had ROS1-positive NSCLC. All patients had a history of first- or second-generation ALK TKI receipt. Two ALK-positive patients and one ROS1-positive patient had the G1202R and G2032R mutations, respectively. The overall response rate was 64% and the disease control rate was 91%. Of the 3 ALK-positive patients with intracranial target lesions, 1 (33%) had a complete response and 2 (67%) a partial response, producing an intracranial objective response of 100%. The median progression-free survival was 6.5 months (range, 1.0-16.5 months). The most common adverse event was hypercholesterolemia (83%), and no adverse event-related dose reductions or treatment discontinuations were reported.. This study is the first to report that lorlatinib is an important novel therapeutic option for Asian patients who have advanced NSCLC harboring ALK/ROS1 mutations whose disease progressed during treatment with first- and second-generation TKIs.

Topics: Adult; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Republic of Korea; Retrospective Studies

Lung cancer causes the highest number of cancer-related deaths worldwide. Resistance to therapy is a major clinical issue contributing to the poor prognosis of lung cancer. In recent years, targeted therapy has become a concept where subgroups of non-small cell lung cancer (NSCLC) with genetically altered receptor tyrosine kinases are targeted by tyrosine kinase inhibitors (TKIs). One such subgroup harbors a gene fusion of echinoderm microtubule-associated protein-like 4 (EML4) with anaplastic lymphoma kinase (ALK). Although most NSCLC patients with EML4-ALK fusions initially respond to ALK TKI-therapy they eventually develop resistance. While ALK kinase domain mutations contribute to ALK TKI-refractoriness, they are only present in a fraction of all ALK TKI-resistant tumors. In this study we sought to explore a possible involvement of microRNAs (miRNAs) in conferring resistance to ALK TKIs in ALK TKI-refractory NSCLC cell lines. We subjected our ALK TKI-refractory cancer cells along with parental cancer cells to systematic miRNA expression arrays. Furthermore, ALK TKI-refractory cancer cells were exposed to a synthetic miRNA inhibitory Locked Nucleic Acid (LNA)-library in the presence of ALK TKIs Crizotinib or Lorlatinib. The outcome of the combined approaches uncovered miR-100-5p to confer resistance to Crizotinib and Lorlatinib in EML4-ALK NSCLC cells and to be a potential therapeutic target in drug resistance.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; MicroRNAs; Microtubule-Associated Proteins; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Serine Endopeptidases

Lorlatinib is a novel third-generation tyrosine kinase inhibitor (TKI) which targets anaplastic lymphoma kinase (ALK) as well as receptor tyrosine kinase c-ros oncogene 1 (ROS1). A critical limitation of conventional ALK/ROS TKIs is their association with acquired resistance mutations (particularly ALK G1202R and ROS1 G2032R) in the ALK or ROS1 gene, although these are not the only resistance mechanisms. Another limitation of this class of drugs is their inadequate efficacy against central nervous system metastasis, likely attributable to the blood-brain barrier (BBB). Therefore, lorlatinib was developed to overcome these limitations by being more potent, selective and permeable to the BBB than previous-generation ALK/ROS1 TKIs and subsequently received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) in April 2017. In September 2018, Japan became the first country where lorlatinib received approval for treating patients with ALK-rearranged non-small cell lung cancer. Eventually, the FDA approved lorlatinib (Lorbrena; Pfizer) in November 2018. Lorlatinib use is expected to increase in importance, owing to its promising efficacy in clinical trials.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad-spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second-generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid-lowering agent. Prescription of supportive therapy should also consider the potential for drug-drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK-positive metastatic non-small cell lung cancer previously treated with a second-generation ALK TKI. IMPLICATIONS FOR PRACTICE: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer. Lorlatinib is a potent, brain-penetrant, third-generation, macrocyclic ALK/ROS1 TKI, with broad-spectrum potency against most known resistance mutations that can develop during treatment with existing first- and second-generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.

Topics: Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Mutation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Severity of Illness Index; Treatment Outcome

Topics: Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinogenesis; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Liquid Biopsy; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Oncogene Proteins, Fusion; Organophosphorus Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors have been developed for the treatment of EML4-ALK-rearranged non-small-cell lung cancer, with the newer generation agents brigatinib, alectinib and lorlatinib showing pronounced central nervous system activities. Intracranial efficacy is an important feature for these agents, as metastatic lesions frequently occur in the central nervous system in the ALK-positive setting. Here, we report on an updated case of a patient who received her diagnosis in 2005 and has had disease progression with new lesions on six occasions over the last 8 years. During the first two progressions, only local recurrence was observed. After that, the lungs stayed clear and the patient progressed exclusively in the brain and spinal cord. Initial treatments consisted of chemotherapy and radiotherapy. In 2012, ALK-directed targeted therapy became available, and crizotinib was administered. The treatment was switched to brigatinib 3 years later because of spinal cord lesions. Brigatinib induced partial remission and was followed by lorlatinib and, later on, alectinib, when new metastases arose in the spinal cord and brain. Each of these drugs promoted complete remission of the recent lesions. In November 2018, imaging showed multiple cerebral metastases. As radiotherapy was not an option because of previous irradiation, and as chemotherapy cannot be expected to be active in the brain, the patient underwent brigatinib rechallenge, which led to partial remission. All of the central nervous system relapses were symptomatic, with symptoms resolved rapidly during treatment. This case of a patient with EML4-ALK-rearranged non-small-cell lung cancer shows that sequential treatment with next-generation ALK tyrosine kinase inhibitors, including rechallenge, can induce profound remission even in heavily pretreated patients, especially if the central nervous system is the site of progression.

Topics: Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Organophosphorus Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Spinal Cord Neoplasms

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Meningeal Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Spinal Cord Neoplasms; Sulfones; Treatment Outcome

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Treatment Outcome

Small cell transformation is a well-recognized mechanism of resistance to EGFR-TKI therapy in EGFR-mutant NSCLC, yet it remains a poorly-described phenomenon in ALK-rearranged NSCLC.. Chart and literature review.. We report a case of a patient with ALK-rearranged lung cancer progressing on three-lines of ALK-targeted therapies, with development of acquired resistance to lorlatinib, with both transformation to a neuroendocrine carcinoma, and acquisition of ALK 1196 M.. Given the inevitable development of resistance in ALK + NSCLC, if feasible, re-biopsy on progression should be standard over liquid biopsy. Neuroendocrine carcinoma transformation remains an important mechanism of acquired resistance to lorlatinib.

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; ErbB Receptors; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Liver Neoplasms; Lung Neoplasms; Male; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Pyrazoles; Tomography, X-Ray Computed

Oral anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) have shown significant benefit in the management of ALK-rearranged non-small cell lung cancer (NSCLC). However, almost all patients will experience disease progression after front-line ALK-TKIs such as crizotinib. Treatment with third generation ALK-TKI lorlatinib can have a significant clinical impact following disease progression, even in patients with a very poor performance status. Here, we review two clinical cases with metastatic ALK-rearranged NSCLC who had pulmonary disease control with first-generation ALK inhibitor. However, disease progressed rapidly in the central nervous system with severe neurological symptoms. Treatment with lorlatinib, a third-generation ALK-TKI, led to a rapid radiological and clinical cerebral response in both patients. Lorlatinib can overcome ALK resistance to crizotinib, and the presented cases suggest a potential role for lorlatinib in patients with rapidly progressive cerebral and leptomeningeal metastases.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Nervous System Diseases; Progression-Free Survival; Pyrazoles; Remission Induction; Treatment Outcome

The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples.. Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction.. ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes.. High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Kidney Neoplasms; Lactams; Lactams, Macrocyclic; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Middle Aged; Mutation; Piperidines; Pyrazoles; Xenograft Model Antitumor Assays

Crizotinib is recommended as first-line therapy in ROS1-driven lung adenocarcinoma. However, the optimal first-line therapy for this subgroup of lung cancer is controversial according to the available clinical data.. Here, we describe a 57-year-old man who was diagnosed with stage IIIB lung adenocarcinoma and EGFR/KRAS/ALK-negative tumors. The patient received six cycles of pemetrexed plus cisplatin as first-line therapy and then pemetrexed as maintenance treatment, with a progression-free survival (PFS) of 42 months. The patient relapsed and underwent re-biopsy. EZR-ROS1 fusion mutation was detected by next-generation sequencing (NGS). The patient was prescribed crizotinib as second-line therapy and achieved a PFS of 6 months. After disease progression, lorlatinib was administered as third-line therapy, with a favorable response.. Prolonged PFS in patients receiving pemetrexed chemotherapy might be related to the EZR-ROS1 fusion mutation. Lorlatinib is an optimal choice in patients showing crizotinib resistance.

Topics: Adenocarcinoma; Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Crizotinib; Cytoskeletal Proteins; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Oncogene Fusion; Pemetrexed; Progression-Free Survival; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Time Factors

We report here the first cases, to our knowledge, of pulmonary arterial hypertension induced by lorlatinib. It s the first time that a tyrosine kinase inhibitor for lung cancer is associated with pulmonary arteriel hypertension.

Topics: Aminopyridines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug-Related Side Effects and Adverse Reactions; Dyspnea; Female; Humans; Hypertension, Pulmonary; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Vascular Resistance; Walk Test; Withholding Treatment

Topics: Aminopyridines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Myasthenia Gravis; Pyrazoles

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Point Mutation; Pyrazoles

Topics: Adenocarcinoma of Lung; Aminopyridines; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Nephrosis, Lipoid; Pyrazoles

Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles; Receptor Protein-Tyrosine Kinases

Patients with lung cancer who show EML4-ALK translocation are routinely treated with ALK tyrosine kinase inhibitors, although in the majority of cases, these patients develop resistance over time. The central nervous system is a common of site of recurrence in this population, which calls for next-generation drugs that can penetrate into the brain and achieve clinically meaningful central nervous system activity. Here, I report the case of a female patient diagnosed with adenocarcinoma of the lung in 2005, at the age of 46 years, who underwent lobectomy and then experienced a series of progression episodes 6 years later. Local recurrence was managed by chemotherapy and crizotinib after the patient was included in a named patient use programme in 2012. Over the following years, the patient repeatedly developed lesions at different sites in the brain and spinal cord. Partial remission was obtained twice with local irradiation. When the next-generation ALK tyrosine kinase inhibitors became available, her treatment was switched to brigatinib, which again induced partial remission. Another episode of intrathecal progression prompted the prescription of the third-generation ALK tyrosine kinase inhibitor lorlatinib. This treatment has resulted in complete remission in the patient.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Spinal Cord Neoplasms

BACKGROUND ALK gene rearrangements as oncogenic drivers have been described in many cancers, including inflammatory myofibroblastic sarcoma (IMS). The first-generation ALK inhibitor was limited in its ability to cross the blood-brain-barrier to treat brain metastasis. Drug-resistance invariably develops over time in ALK-rearranged tumors, which leads to disease progression. The newer generations of ALK inhibitors are designed to have higher potency in ALK inhibition and improved CNS penetration. CASE REPORT We report a rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases as initial presentation. After the primary lung tumor and the larger brain metastases were resected, control of residual CNS disease and subsequent progression and CNS spread was achieved with favorable clinical response by all three generations of ALK inhibitors. CONCLUSIONS ALK inhibitors may be an effective therapy for this rare and unusual form of ALK-1-rearranged cancer, even in the presence of multifocal CNS metastases with leptomeningeal involvement.

Topics: Adolescent; Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Meningeal Neoplasms; Myofibroblasts; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sarcoma; Sulfones

Personalized cancer therapy is based on a patient's tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient's living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient-derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co-clinical trial studies to prospectively test the value of drug profiling on tumor-biopsy-derived cultures to direct patient care.

Topics: Acrylamides; Aminopyridines; Anaplastic Lymphoma Kinase; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Crizotinib; ErbB Receptors; Erlotinib Hydrochloride; Feeder Cells; Fluorescent Antibody Technique; Gene Expression; High-Throughput Screening Assays; Humans; Keratin-18; Keratin-8; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Neoplasms; Piperazines; Precision Medicine; Primary Cell Culture; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Tumor Cells, Cultured

Development of the acquired ALK G1202R solvent front mutation and small cell lung cancer (SCLC) transformation have both been independently reported as resistance mechanisms to ALK inhibitors in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients but have not been reported in the same patient. Here we report an ALK+ NSCLC patient who had disease progression after ceritinib and then alectinib where an ALK G1202R mutation was detected on circulating tumor (ct) DNA prior to enrollment onto a trial of another next generation ALK inhibitor, lorlatinib. The patient's central nervous system (CNS) metastases responded to lorlatinib together with clearance of ALK G1202R mutation by repeat ctDNA assay. However, the patient developed a new large pericardial effusion. Resected pericardium from the pericardial window revealed SCLC transformation with positive immunostaining for synaptophysin, chromogranin, and ALK (D5F3 antibody). Comprehensive genomic profiling (CGP) of the tumor infiltrating pericardium revealed the retainment of an ALK rearrangement with emergence of an inactivating Rb1 mutation (C706Y) and loss of exons 1-11 in p53 that was not detected in the original tumor tissue at diagnosis. The patient was subsequently treated with carboplatin/etoposide and alectinib, but had rapid clinical deterioration and died. The patient never received crizotinib. This case illustrates that multiple/compound resistance mechanisms to ALK inhibitors can occur and provide supporting information that loss of p53 and Rb1 are important in SCLC transformation. If clinically feasible, tissue-based re-biopsy allowing histological examination and CGP remains the gold standard to assess resistance mechanism(s) and to direct subsequent rational clinical care.

Topics: Adult; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Crizotinib; Disease Progression; Drug Resistance, Neoplasm; Fatal Outcome; Female; Humans; Lactams; Lactams, Macrocyclic; Liquid Biopsy; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplastic Cells, Circulating; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retinoblastoma Binding Proteins; Small Cell Lung Carcinoma; Ubiquitin-Protein Ligases

Data from a phase I study indicate that the investigational ALK inhibitor lorlatinib is active in patients with ALK- or ROS1-positive non-small cell lung cancer, including those with brain metastases. Objective responses were seen among patients with known ALK resistance mutations who had relapsed following treatment with other tyrosine kinase inhibitors.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALK. Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The orally available novel small molecules PF06463922 [(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile] and PF06471402 [(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(azeno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclo-tetradecine-3-carbonitrile] are second-generation anaplastic lymphoma kinase (ALK) inhibitors targeted to both naïve and resistant patients with non-small cell lung cancer (NSCLC) to the first-generation ALK inhibitor crizotinib. The objectives of the present study were to characterize and compare the pharmacokinetic-pharmacodynamic (PKPD) relationships of PF06463922 and PF06471402 for target modulation in tumor and antitumor efficacy in athymic mice implanted with H3122 NSCLC cells expressing a crizotinib-resistant echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutation, EML4-ALK(L1196M). Furthermore, the PKPD relationships for these ALK inhibitors were evaluated and compared between oral administration and subcutaneous constant infusion (i.e., between different pharmacokinetic [PK] profiles). Oral and subcutaneous PK profiles of these ALK inhibitors were adequately described by a one-compartment PK model. An indirect response model extended with a modulator fit the time courses of PF06463922- and PF06471402-mediated target modulation (i.e., ALK phosphorylation) with an estimated unbound EC50,in vivo of 36 and 20 nM, respectively, for oral administration, and 100 and 69 nM, respectively, for subcutaneous infusion. A drug-disease model based on the turnover concept fit tumor growth curves inhibited by PF06463922 and PF06471402 with estimated unbound tumor stasis concentrations of 51 and 27 nM, respectively, for oral administration, and 116 and 70 nM, respectively, for subcutaneous infusion. Thus, the EC50,in vivo to EC60,in vivo estimates for ALK inhibition corresponded to the concentrations required tumor stasis in all cases, suggesting that the pharmacodynamic relationships of target modulation to antitumor efficacy were consistent among the ALK inhibitors, even when the PK profiles with different administration routes were considerably different.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Female; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mice, Nude; Microtubule-Associated Proteins; Models, Biological; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays