pf-06463922 and alectinib

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

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

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

Overall survival in metastatic lung cancer has been dramatically improved with the use of small molecule kinase inhibitors (SMKIs). Quantification of SMKI in cerebrospinal fluid (CSF) can be used to assess penetration of these drugs into the central nervous system. This paper describes an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantification of the SMKIs alectinib, lorlatinib and osimertinib in human CSF. Alectinib-d8 and dasatinib-d8 were used as internal standards. Aliquots with 25 µL CSF/30% albumin (9:1,v/v) were mixed with 100 µL internal standard solution consisting of 1 ng/mL dasatinib-d8 and alectinib-d8 in acetonitrile. The analytes were separated by an Acquity UPLC® HSS T3 column (2.1 ×150 mm, 1.8 µm), using gradient elution (ammonium formate pH 4.5, acetonitrile) with a flow rate of 0.400 mL/min. All calibration curves were linear for the concentration range from 2.50 to 250 ng/mL. Within-run and between-run precision varied from 0.72% to 11.7%, with accuracy ranging from 95.3% to 113.2%. For all compounds, a high degree of non-specific binding to the vacutainer was observed. This issue could be countered easily by a combination of pre-coating with BSA solution (30%) in phosphate buffer pH 4.2, and immediate sample mixture with BSA solution after collection. To test the clinical applicability, CSF was collected in seven unique patients using alectinib (n = 1), lorlatinib (n = 2), and osimertinib (n = 4). Measured CSF trough concentrations ranged between 3.37 and 116 ng/mL.

Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Dasatinib; Humans; Lactams, Macrocyclic; Reproducibility of Results; Tandem Mass Spectrometry

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

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

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

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

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

Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Biopsy; Carbazoles; Cell Cycle Proteins; Drug-Related Side Effects and Adverse Reactions; Female; Granuloma; Humans; Lactams; Microtubule-Associated Proteins; Neoplasm Staging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Sarcoidosis; Serine Endopeptidases; Skin; Withholding Treatment

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

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

Topics: Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Colorectal Neoplasms; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Neoplasm Metastasis; Piperidines; Pyrazoles; Treatment Outcome

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) 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

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

Topics: Adolescent; Aminopyridines; Anaplastic Lymphoma Kinase; Bone Neoplasms; Carbazoles; Chemoradiotherapy; DNA-Binding Proteins; Female; Humans; Lactams; Lactams, Macrocyclic; Oncogene Proteins, Fusion; Piperidines; Pyrazoles; Rhabdomyosarcoma; RNA-Binding Protein FUS; Transcription Factors

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

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

Topics: Aminopyridines; Animals; Carbazoles; Chromatography, Liquid; Drug Stability; Humans; Lactams; Lactams, Macrocyclic; Male; Mice; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tandem Mass Spectrometry; Tissue Distribution

Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were ceritinib or lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK-NSCLC with acquired resistance to ALK inhibitors.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Mice; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Signal Transduction; src-Family Kinases; Sulfones; Xenograft Model Antitumor Assays