crizotinib and Brain-Neoplasms

Lung cancer is one of the most lethal malignancies in the world, with non-small cell lung cancer (NSCLC) accounting for approximately 80%-85% of all pathological types. Approximately 30%-55% of NSCLC patients develop brain metastases. It has been reported that 5%-6% of patients with brain metastases harbor anaplastic lymphoma kinase (ALK) fusion. ALK-positive NSCLC patients have shown significant therapeutic benefits after treatment with ALK inhibitors. Over the past decade, ALK inhibitors have rapidly evolved and now exist in three generations: first-generation drugs such as Crizotinib; second-generation drugs including Alectinib, Brigatinib, Ceritinib, and Ensartinib; and third-generation drugs like Lorlatinib. These drugs have exhibited varying efficacy in treating brain metastases in ALK-positive NSCLC patients. However, the numerous options available for ALK inhibition present a challenge for clinical decision-making. Therefore, this review aims to provide clinical guidance by summarizing the efficacy and safety of ALK inhibitors in treating NSCLC brain metastases.
.. 【中文题目：ALK抑制剂在治疗NSCLC脑转移中的疗效及安全性研究进展】 【中文摘要：肺癌是全球死亡率最高的恶性肿瘤之一，其中非小细胞肺癌（non-small cell lung cancer, NSCLC）占所有肺癌病理类型的80%-85%。NSCLC中有30%-55%的患者发生脑转移。据估计，5%-6%的脑转移患者存在间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合。ALK融合阳性NSCLC患者在接受ALK抑制剂后获得了非常显著的疗效。经过十余年的迅速发展，ALK抑制剂已经形成三代同堂的局面：即第一代——克唑替尼（Crizotinib）；第二代——阿来替尼（Alectinib）、布格替尼（Brigatinib）、塞瑞替尼（Ceritinib）、恩沙替尼（Ensartinib）；第三代——洛拉替尼（Lorlatinib）。这些药物在ALK融合阳性NSCLC脑转移患者中显示出不同的疗效。由于此类药物众多，ALK抑制剂的选择给临床医生带来了困扰。因此，本文旨在对ALK抑制剂在NSCLC脑转移中的治疗效果和安全性进行综述，以期为临床医生提供治疗选择的依据。】 【中文关键词：肺肿瘤；ALK抑制剂；脑转移；疗效；安全性】.

Topics: Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; 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

This article reviews the role of ALK tyrosine kinase inhibitors (TKIs) in the literature and provides expert commentary on local use in Argentina, Brazil, China, Russia, South Korea, and Turkey. We identified 56 articles involving patients with ALK-positive non-small cell lung cancer (NSCLC) and brain metastases (BM) treated with ALK TKIs published between January 2000 and June 2021. In first-line settings, central nervous system response rates in clinical trials with alectinib (86-94%), brigatinib (67-78%), and lorlatinib (42-82%) were generally higher than those reported with crizotinib (16-71%). Median progression-free survival in patients receiving crizotinib (5.6-7.4 months) was lower than alectinib (not reached), brigatinib (24.0 months), and ceritinib (10.7-25.2 months). Across these counties, next-generation TKIs are preferred for patients with progressing BM lesions. Although next-generation ALK TKIs demonstrate significant activity in these patients and following progression on crizotinib, access remains a challenge for personalized therapy.

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

The proto-oncogene tyrosine-protein kinase ROS1 (ROS1) is a tyrosine kinase that is closely related to anaplastic lymphoma kinase receptor (ALK). We describe a novel KLC1-ROS1 fusion identified in a case of pediatric low-grade glioma. This was detected by RNA sequencing and confirmed by reverse-transcription PCR and fluorescent in situ hybridization. Immunohistochemical staining for ROS1 was positive in the tumor cytoplasm. In vitro analysis demonstrated the oncogenic activity of this fusion, which was suppressed by the ALK/ROS1 inhibitor, crizotinib. Our case and others suggest that various ROS1 fusions might be present in a subset of pediatric gliomas, which could be targeted for therapy.

Topics: Brain Neoplasms; Child, Preschool; Crizotinib; Female; Gene Fusion; Glioma; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Kinesins; Microtubule-Associated Proteins; Molecular Targeted Therapy; Neoplasm Staging; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cranial Irradiation; Crizotinib; Disease Management; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Meningeal Neoplasms; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Neurocognitive Disorders; Observational Studies as Topic; Oncogene Proteins, Fusion; Pemetrexed; Piperidines; Protein Kinase Inhibitors; Radiosurgery

Anaplastic lymphoma kinase (ALK) gene rearrangements as driver genetic alterations occur in approximately 2-4% of non-small-cell lung cancer (NSCLC) patients. Alectinib, a next generation ALK inhibitor, recently demonstrated, in two separate Phase III trials, superior efficacy to crizotinib, the first ALK inhibitor to demonstrate clinical efficacy in ALK-positive NSCLC patients. Alectinib also demonstrated superior efficacy in the CNS. The data from these two Phase III studies suggest that the efficacy of starting with alectinib is superior to the overall clinical efficacy of starting with crizotinib followed by switching to alectinib at the time of disease progression. These results have changed the standard of care to alectinib as front-line therapy for advanced ALK-positive NSCLC patients. Areas covered: this paper reviews the available data on alectinib as front-line therapy in patients with ALK-positive NSCLC patients including its activity against brain metastases. In addition, the paper will review the data with other ALK inhibitors as front-line therapy.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Survival Rate; Treatment Outcome

Anaplastic lymphoma kinase (ALK) rearrangements represent the molecular driver of a subset of non-small cell lung cancers (NSCLCs). Despite the initial response, virtually all ALK-positive patients develop an acquired resistance to the ALK inhibitor crizotinib, usually within 12 months. Several next-generation ALK inhibitors have been developed in order to overcome crizotinib limitation, providing an unprecedented survival for this subset of patients. The aim of this review to summarize the current knowledge on ALK tyrosine kinase inhibitors (TKIs) in the treatment of advanced ALK-positive NSCLC, focusing on the role of novel ALK inhibitors in this setting. In addition, we will discuss their role in the pharmacological management of ALK-positive brain metastasis. Next-generation ALK inhibitors showed an impressive clinical activity in ALK-positive NSCLC, also against the sanctuary site of CNS. Sequential therapy with ALK TKIs appears to be effective in patients who fail a first ALK TKI and translates in clinically meaningful benefit. However, these agents display different activity profiles against crizotinib resistance mutation; therefore re-genotyping the disease at progression in order to administer the right TKI to the right patient is going to be necessary to correctly tailor the treatment. To avoid repeated invasive procedure, noninvasive methods to detect and monitor ALK rearrangement are under clinical investigation.

Topics: Anaplastic Lymphoma Kinase; Animals; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lung Neoplasms; Precision Medicine; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Lung cancer represents the most common cause of brain dissemination. Oncogene-addicted (EGFR- and ALK-positive) non-small cell lung cancers (NSCLCs) are characterized by a unique metastatic neurotropism resulting in a particularly high incidence of brain metastases. The goal of optimal brain metastases management is to improve both overall survival and quality of life, with the focus on neurocognitive function preservation. Neurosurgery is offered to patients presenting with limited intracranial tumor burden located in surgically accessible un-eloquent regions of the brain, whereas stereotactic radiosurgery represents the preferred radiotherapy option for patients not amenable to surgery. Whole brain radiotherapy, owing to its neurocognitive sequelae, should be reserved for patients with multiple lesions. EGFR and ALK tyrosine kinase inhibitors (TKIs) provide significantly superior systemic response rates and progression-free survival compared to standard chemotherapy in the molecularly defined NSCLC subpopulations. An apparent intracranial activity of new generation TKIs triggered the discussion on their role in brain metastases in lieu of local therapies. The aim of this review is to summarize the current therapeutic landscape of brain metastases management in NSCLC, with a particular focus on EGFR-mutated and ALK-rearranged NSCLC subtypes.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; ErbB Receptors; Humans; Lung Neoplasms; Molecular Targeted Therapy; Oncogenes; Protein Kinase Inhibitors

The c-ros oncogene 1 receptor tyrosine kinase (ROS1)-rearrangements represent a new and rare genetic subtype of non-small-cell lung cancer. In recent years, the use of crizotinib in ROS1-rearranged lung cancer exhibits significant clinical efficacy. Crizotinib is generally well tolerated and the most frequent adverse events include visual disorders, gastrointestinal disturbances, cardiac, and endocrine abnormalities. From a cardiac perspective, crizotinib is associated with 2 main cardiac effects, QT interval prolongation and bradycardia.. We reported a case of a 67-year-old man with ROS1-rearranged advanced lung adenocarcinoma.. Crizotinib was initiated as first-line treatment, combined with whole brain radiation therapy.. Interestingly, after treatment of crizotinib, the patient suffered a transient QTc interval prolongation and his persistent atrial fibrillation was changed into sinus bradycardia. Only 22 days after crizotinib treatment, the patient's tumor achieved a partial response. So far the patient has taken crizotinib for >19 months with no evidence of disease progression.. The present study demonstrates dramatic benefit of crizotinib for patients with ROS1 rearrangement. Besides, we should caution the cardiac effects caused by crizotinb and our case provides evidence that crizotinib may be safe for patients with atrial fibrillation under close monitoring.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Antineoplastic Agents; Atrial Fibrillation; Biomarkers, Tumor; Bradycardia; Brain Neoplasms; Crizotinib; Humans; Lung Neoplasms; Male; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines

Crizotinib is an anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) that represents the standard first-line treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). In this setting, crizotinib has demonstrated a response rate of roughly 75% and a median progression-free survival just under one year. However, acquired resistance will emerge in virtually all crizotinib-treated patients, whose management may require a diversified approach according to the pace of the disease and/or the site(s) of disease progression. Crizotinib beyond disease progression is an option in patients with oligoprogressive disease, especially in presence of isolated central nervous system (CNS) relapse, provided that local ablative therapy (mainly radiotherapy) to the brain is administered. On the other hand, novel more potent and highly selective ALK-TKIs with demonstrated anti-tumor activity (CNS included) in crizotinib-refractory patients have been made available in recent years. Therefore, clinicians may well consider switching to a second-generation ALK-TKI as treatment option in case of progression on crizotinib. Therapeutic chances are more limited for patients who progress after crizotinib and a second-generation ALK-TKI, for whom both a third-generation ALK-TKI or pemetrexed-based chemotherapy could prove beneficial, while evidence in support of the use of immunotherapy in patients pretreated with ≥1 ALK-TKI is lacking.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Immunotherapy; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Crizotinib is highly effective for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether crizotinib has a beneficial effect on elderly patients with ALK-positive NSCLC with a poor performance status (PS). We herein present the case of an 85-year-old man with stage IV ALK-positive NSCLC, whose PS score was 4 due to pericardial and pleural effusions. After initiating crizotinib therapy, a drastic response was observed and the PS score improved to 0. Adverse effects were manageable. Our results indicate that crizotinib could be an important choice when treating elderly patients with ALK-positive NSCLC with poor PS.

Topics: Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Fatal Outcome; Humans; Lung Neoplasms; Male; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

ALK rearranged Non Small Cell Lung Cancers (NSCLCs) represent a distinct subgroup of patients with peculiar clinic-pathological features. These patients exhibit dramatic responses when treated with the ALK tyrosine kinase inhibitor Crizotinib, albeit Central Nervous System (CNS) activity is much less impressive than that observed against extracranial lesions. CNS involvement has become increasingly observed in these patients, given their prolonged survival. Several novel generation ALK inhibitors have been developing to increase CNS penetration and to provide more complete ALK inhibition... The CNS activity of Crizotinib and novel generation ALK inhibitors will be summarized in this review, evaluating the strengths and weaknesses of the therapeutic strategies developed to date in this specific subgroup of NSCLCs with a look towards the future. Expert commentary: In the next few years, the results of ongoing comparative head-to-head trials will provide the definitive conclusions on the optimal treatment sequence in ALK-rearranged NSCLCs. Moreover, ongoing clinical trials with novel-generation ALK inhibitors will produce more evidences on the best approach in the growing number of ALK-positive NSCLCs with CNS involvement.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Design; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

In 2007, a chromosomal rearrangement resulting in a gene fusion leading to expression of a constitutively active anaplastic lymphoma kinase (ALK) fusion protein was identified as an oncogenic driver in non-small-cell lung cancer (NSCLC). ALK rearrangements are detected in 3%-7% of patients with NSCLC and are particularly enriched in younger patients with adenocarcinoma and a never or light smoking history. Fortuitously, crizotinib, a small molecule tyrosine kinase inhibitor initially developed to target cMET, was able to be repurposed for ALK-rearranged (ALK+) NSCLC. Despite dramatic and durable initial responses to crizotinib; however, the vast majority of patients will develop resistance within a few years. Diverse molecular mechanisms underlie resistance to crizotinib. This review will describe the clinical activity of crizotinib, review identified mechanisms of crizotinib resistance, and end with a survey of emerging therapeutic strategies aimed at overcoming crizotinib resistance.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Rearrangement; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Molecular profiling of nonsmall cell lung cancer (NSCLC) contributes to better understanding the different molecular subtypes of this heterogeneous group of diseases. The discovery of oncogenic ALK rearrangements in NSCLC and the subsequent success in their therapeutic targeting with crizotinib reinforces the benefits of a precision approach to systemic anticancer therapy. In addition, the rapid development of crizotinib from first discovery thorough accelerated US Food and Drug Administration approval, and late stage confirmatory clinical trials, exemplifies the success of the drug development strategy of close collaboration between clinicians, industry and regulatory authorities. In this review we describe the identification of ALK rearranged NSCLC, clinical characteristics of such patients, and clinical outcomes when treated with crizotinib.

Topics: Anaplastic Lymphoma Kinase; Bradycardia; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Crizotinib; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Hypogonadism; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

With therapeutic approaches based on oncogene addiction offering significant anticancer benefit, the identification of anaplastic lymphoma kinase (ALK) rearrangements is a key aspect of the management of lung cancers. The EML4-ALK gene fusion is detected in 4-8% of all lung cancers, predominantly in light smokers or nonsmokers. Crizotinib, the first agent to be approved in this indication, is associated with a median progression-free survival of 10.9 months when given as first-line treatment and 7.7 months when administered after chemotherapy. Median overall survival with crizotinib in the second-line setting is 20.3 months. Second-generation ALK inhibitors are currently being evaluated, with early studies giving impressive results, notably in patients resistant to crizotinib or with brain metastases. Among available chemotherapies, pemetrexed appears to be particularly active in this population. Despite this progress, several questions remain unanswered. What detection strategies should be favoured? What underlies the mechanisms of resistance and what options are available to overcome them? What are the best approaches for progressing patients? This review provides an overview of current data in the literature and addresses these questions.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Neoplasm Metastasis; Piperidines; Predictive Value of Tests; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Smoking; Sulfones

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

Chemotherapy, as all systemic treatments, is generally effective in brain metastases because the brain blood barrier (BBB) does not affect treatment's diffusion. Platinum-based chemotherapy provides response rates ranging from 23 to 50% for brain metastases. Anti-EGFR therapies are effective mostly when a somatic EGFR activating mutation is detected, or in selected population (adenocarcinoma, Asian population, never-smokers and women): response rate ranges from 38 to 69.6%. Bevacizumab is now allowed for non-small cell lung cancer (NSCLC) patients with brain metastases and non-squamous histology. The presence of untreated brain metastases may not influence its efficacy combined with paclitaxel-carboplatin. The best sequence for multimodality management of brain metastases has to be established but upfront systemic treatments in patients with asymptomatic brain metastases is a valid option.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cisplatin; Crizotinib; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Pyrazoles; Pyridines; Quinazolines

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

Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5-6% of non-small cell lung cancer (NSCLC) cases and associated with increased risks of central nervous system (CNS) involvement. Envonalkib, a novel ALK inhibitor, demonstrated promising anti-tumor activity and safety in advanced ALK-positive NSCLC in the first-in-human phase I study. This phase III trial (ClinicalTrials.gov NCT04009317) investigated the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC cases. Totally 264 participants were randomized 1:1 to receive envonalkib (n = 131) or crizotinib (n = 133). Median independent review committee (IRC)-assessed progression-free survival (PFS) times were 24.87 (95% confidence interval [CI]: 15.64-30.36) and 11.60 (95% CI: 8.28-13.73) months in the envonalkib and crizotinib groups, respectively (hazard ratio [HR] = 0.47, 95% CI: 0.34-0.64, p < 0.0001). IRC-assessed confirmed objective response rate (ORR) was higher (81.68% vs. 70.68%, p = 0.056) and duration of response was longer (median, 25.79 [95% CI, 16.53-29.47] vs. 11.14 [95% CI, 9.23-16.59] months, p = 0.0003) in the envonalkib group compared with the crizotinib group. In participants with baseline brain target lesions, IRC-assessed CNS-ORR was improved with envonalkib compared with crizotinib (78.95% vs. 23.81%). Overall survival (OS) data were immature, and median OS was not reached in either group (HR = 0.84, 95% CI: 0.48-1.47, p = 0.5741). The 12-month OS rates were 90.6% (95% CI, 84.0%-94.5%) and 89.4% (95% CI, 82.8%-93.6%) in the envonalkib and crizotinib groups, respectively. Grade ≥3 treatment-related adverse events were observed in 55.73% and 42.86% of participants in the envonalkib and crizotinib groups, respectively. Envonalkib significantly improved PFS and delayed brain metastasis progression in advanced ALK-positive NSCLC.

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

Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)-based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies.. A total of 75 eligible patients were enrolled from Sun Yat-sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis-free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log-rank test was performed to describe the difference of BMFS risk.. Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C-index], 0.762; 95% confidence interval [CI], 0.663-0.861) and validation cohort (C-index, 0.724; 95% CI, 0.601-0.847).. We have developed a CT-based radiomics model to predict subsequent BM in patients with non-brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Tomography, X-Ray Computed

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

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

Brigatinib is a kinase inhibitor indicated for patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer who progressed on or are intolerant to crizotinib. Approval was based on results from a randomized, dose-ranging phase II study (ALK in Lung Cancer Trial of AP26113 (ALTA)). Despite an apparent dose-response relationship for efficacy in ALTA, an exposure-response relationship was not discernable using static models driven by time-averaged exposure. However, exposure-response modeling using daily time-varying area under the concentration curve as the predictor in time-to-event models predicted that increasing the dose of brigatinib (range, 30 mg once daily (q.d.) to 240 mg q.d.) would result in clinically meaningful improvements in progression-free survival (PFS), intracranial PFS, and overall survival. Grade ≥ 2 rash and amylase elevation were predicted to significantly increase with brigatinib exposure. These results provided support for a favorable benefit-risk profile with the approved dosing regimen (180 mg q.d. with 7-day lead-in at 90 mg) versus 90 mg q.d.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Area Under Curve; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Dose-Response Relationship, Drug; Exanthema; Female; Humans; Hyperamylasemia; Lung Neoplasms; Male; Middle Aged; Organophosphorus Compounds; Predictive Value of Tests; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Safety; Treatment Outcome

Topics: Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Sulfones

At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017).. Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant.. Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib.. Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.

Topics: Adolescent; Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Crizotinib; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Prognosis; Survival Rate; Young Adult

ROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS).. The trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue.. Thirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51-85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1-not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7-20.0 versus 24.1 months, 95% CI: 10.1-not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%).. Crizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Prospective Studies; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Response Evaluation Criteria in Solid Tumors; Survival Rate

In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study.. Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days).. Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient.. Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC.. NCT01828112.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Asian People; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Docetaxel; Female; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pemetrexed; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Taxoids; Treatment Outcome

Despite improved progression-free survival, most patients treated with the first generation ALK inhibitor crizotinib ultimately experience central nervous system (CNS) progression. Brain metastases (BM) are associated with high clinical burden in patients with advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). In this study we estimate the real-world economic burden of BM in newly diagnosed ALK+ NSCLC patients and investigate whether alectinib, a second generation ALK inhibitor that delays CNS progression, may help reduce healthcare costs in patients with ALK+ NSCLC.. Cost of BM was measured in ALK+ NSCLC patients identified from a stacked PharMetrics Plus and MarketScan claims database from January 2008 to March 2016 and December 2015, respectively. Per patient per month (PPPM) cost of BM was calculated as the difference in baseline-adjusted total costs in patients with and without BM over a variable follow-up period of up to 24 months. Cumulative incidence of new BM was derived from 88 alectinib-treated and 93 crizotinib-treated patients without baseline BM in a randomized phase III clinical trial, ALEX (NCT02075840). Costs of BM per patient were then calculated by applying the PPPM BM cost to the number of incident BM patients in each treatment cohort.. 207 patients with no BM and 198 with BM were selected from the claims database. Total cost of BM was estimated at $6,029 PPPM. 24-month cumulative incidence rates of BM from the clinical trial were 7.2% and 45.3% for alectinib and crizotinib, respectively. Over follow-up, alectinib was estimated to reduce BM-related costs by $41,434 per patient compared to crizotinib.. BM is associated with substantial economic burden. Alectinib was estimated to reduce BM-related costs by preventing or delaying the occurrence of BM compared to crizotinib.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cost of Illness; Crizotinib; Follow-Up Studies; Humans; Incidence; Lung Neoplasms; Neoplasm Metastasis; Piperidines; United States

The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX.. Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression.. In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not.. Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy.. ClinicalTrials.gov NCT02075840.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Brain; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Crizotinib; Disease Progression; Female; Humans; Lung; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Treatment Outcome; Tumor Burden; Young Adult

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear.. In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred.. A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted.. Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501 .).

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Organophosphorus Compounds; Progression-Free Survival; Pyrimidines

Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cough; Crizotinib; Diarrhea; Disease Progression; Disease-Free Survival; Female; Headache; Humans; Lung Neoplasms; Male; Middle Aged; Nausea; Organophosphorus Compounds; Prospective Studies; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Retreatment; Treatment Outcome; Young Adult

Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.. J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316).. Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group.. These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study.. Chugai Pharmaceutical Co, Ltd.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Grading; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Single-Blind Method

Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer.. Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed.. Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < .001; median, 10.9 v 7.0 months, respectively).. Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Crizotinib; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Young Adult

Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy.. Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires).. All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment.. Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Gene Order; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib.. We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028.. 47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent.. Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2.. Chugai Pharmaceuticals, F Hoffmann La-Roche.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Patient Selection; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Risk Assessment; Survival Analysis; Treatment Outcome

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

The morbidity and mortality of lung cancer rank the first among all kinds of cancer. In China, anaplastic lymphoma kinase-positive pulmonary tumors account for nearly 5% of non-small cell lung cancer (NSCLC), and these patients are quite likely to develop brain metastases, as high as around 45%. Although anaplastic lymphoma kinase-tyrosine kinase inhibitors crizotinib and alectinib have proved effective for controlling tumor metastases to the brain, drug resistance and disease progression cannot be ignored in the course of treatment.. Most of the literature reports that traditional Chinese medicine (TCM) has produced satisfactory results in the treatment of cancer patients as an adjuvant treatment for various malignancies in a 53-year-old male patient who developed advanced NSCLC with brain metastases. As first-line crizotinib and erlotinib treatments were ineffective and the intracranial lesions progressed extensively, the patient chose to receive TCM treatment alone in the hope of prolonging his life and improving his quality of life.. A 53-year-old male patient who developed advanced NSCLC with brain metastasis. Because first-line crizotinib and alectinib have failed, and the intracranial lesions progressed in a large area.. The patient requested that the final therapeutic strategy be Chinese medicine as monotherapy for long-term treatment. The patient took 30 mL of the decoction 1 hour after a meal, 3 times a day. The patient was not treated with dehydrating agents or diuretics during the TCM treatment.. The improvement was obvious after 3 months of treatment, and significant reduction of cranial lesions. During the follow-up period, the patient developed neither severe liver damage nor kidney damage.. This case is the first 1 in the world where TCM was introduced as monotherapy for severe conditions with extensive brain metastases and achieved remarkable efficacy.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Male; Medicine, Chinese Traditional; Middle Aged; Protein Kinase Inhibitors; Quality of Life

Glioblastoma (GBM) is a highly aggressive form of brain cancer with a poor prognosis and limited treatment options. The ALK and c-MET inhibitor Crizotinib has demonstrated preclinical therapeutic potential for newly diagnosed GBM, although its efficacy is limited by poor penetration of the blood brain barrier. Here, we identify Crizotinib as a novel inhibitor of nuclear factor-κB (NF-κB)-inducing kinase, which is a key regulator of GBM growth and proliferation. We further show that the conjugation of Crizotinib to a heptamethine cyanine dye, or a near-infrared dye (IR-Crizotinib), attenuated glioma cell proliferation and survival

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Crizotinib; Glioblastoma; Glioma; Humans; Mice; NF-kappa B; NF-kappaB-Inducing Kinase

Although ALK-translocated (ALK+) advanced non-small cell lung cancers (aNSCLCs) are currently treated with second- or third-generation ALK inhibitors (ALK-TKIs), some patients respond durably to the first-generation ALK-TKI crizotinib.. This study aimed to describe the clinical characteristics of these long-term responders.. This national, multicenter, retrospective, non-interventional study included patients with ALK+ aNSCLCs and long-term responses to first (L1)- or subsequent (≥ L2)-line crizotinib, defined, respectively, as treatments lasting > 18 and > 10 months. Median treatment duration (mDOT) was the primary endpoint.. A total of 85 patients (32 L1 and 53 ≥ L2 responders) from 23 centers were included (receiving crizotinib between 10/24/2011-10/02/2018): median age of 59 years, 83.6% non-smokers or ex-smokers, 85.9% performance status (PS) 0/1, 94.1% with adenocarcinomas, median of one metastatic site, and 22.4% with brain metastases (BMs). After median follow-up of 73.4 [95% confidence interval, 67.5-79.9] months, respective L1 and ≥ L2 mDOTs were 43.3 [26.7-56.8] and 29.6 [22.6-35.8] months, with overall survival (OS) not reached (NR) and 116.2 [83.4-NR] months. BM presence or absence did not affect mDOT (31.4 versus 32.9 months) but significantly impacted median OS (70.6 versus 158.6 months; p = 0.0008). Progression on crizotinib was paucisymptomatic (74.1%) and oligometastatic (34.8%), especially BMs (42.4%). After crizotinib discontinuation, 65 (76.5%) patients received subsequent systemic therapy: 57 (67.1%) with second-generation ALK-TKIs. Respective mDOTs of first- and second-line post-crizotinib ALK-TKIs lasted 19.4 [14.9-25.6] and 11.1 [4.8-17.9] months, respectively.. Most ALK+ aNSCLC patients with prolonged crizotinib efficacy had paucisymptomatic and oligometastatic disease without BMs. They subsequently benefited from a sequential strategy with other ALK-TKIs.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies

Anaplastic lymphoma kinase (ALK) fusion, an important oncogenic mutation, occurs in 3% to 7% of non-small cell lung cancer (NSCLC) cases, and EML4 is the most common partner gene. With the widespread application of next-generation sequencing (NGS), more gene breakpoint fusions have been discovered and functional fusion transcripts can provide targeted clinical benefits.. A 40-year-old woman was diagnosed with lung adenocarcinoma with brain metastases. A novel CLHC1/RNT4 intergenic region, ALK (Exon20-29) (abundance 39.97%), was identified using lung puncture tissue by NGS analysis (Simceredx), and results of immunohistochemistry and fluorescence in situ hybridization confirmed ALK fusion.. The patient was administered oral crizotinib (250 mg bid) combined with endostar (30 mg d1-7) for 12 cycles from June 18, 2020. The patient's condition was controlled, and the curative effect was evaluated as stable disease (SD). Unfortunately, brain magnetic resonance images showed multiple nodules in the left cerebellar hemisphere, and chest computed tomography showed no significant changes in the progression of the disease. Subsequently, alectinib (600 mg bid) was administered on April 1, 2021. Brain lesions were significantly reduced and partial remission (PR) was achieved. No significant changes were observed in the lung lesions.. ALK fusion is a risk factor for brain metastasis (BM) in patients with advanced non-small NSCLC patients. In our case, a novel CLHC1/RNT4 intergenic region, ALK fusion, was identified for the first time in a lung adenocarcinoma patient with BM, who benefited from crizotinib and endostar sequential alectinib. Our case highlights the advantages of NGS for fusion detection and provides promising treatment options for NSCLC patients with BM harboring ALK fusions.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA, Intergenic; Female; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors

This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non-small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1-5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0-1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Congenital glioblastoma (cGBM) is a brain tumor very rarely observed in newborns and young infants, and differs in several respects from glioblastoma (GBM) of childhood and adulthood. Our aim was the presentation of a cGBM case with 14 days of postnatal survival at the Pediatric Oncology Center of the Markusovszky University Teaching Hospital in 2004. We investigated formalin-fixed, paraffin-embedded autoptic tumor samples of the newborn by immunohistochemical and molecular genetic (FISH and pyrosequencing) methods. We found polysomy of chromosome 2 and 5' deletion of the ALK gene in the glioma cells by ALK FISH. This result indicates the importance of molecular analyses in the diagnostic evaluation of cGBM, and raises the possibility of a personalized, targeted therapy (crizotinib, alectinib).

Topics: Adult; Brain Neoplasms; Crizotinib; Glioblastoma; Humans; Infant, Newborn; Receptor Protein-Tyrosine Kinases

STRN-ALK fusion is a rare ALK rearrangement identified in non-small cell lung cancer (NSCLC) patients. Here, we reported a case of lung adenocarcinomas with brain metastasis, harboring STRN-ALK fusion, responded well to ensartinib. This case report could provide more information for the therapeutic strategy selecting of NSCLC patients harboring STRN-ALK fusion.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Brain Neoplasms; Calmodulin-Binding Proteins; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Membrane Proteins; Nerve Tissue Proteins

Baseline brain metastasis (BBM) commonly occurs in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. Crizotinib prolongs the survival of patients with ALK rearrangement but lacks significant effect on brain metastasis. It remains unclear whether BBM and local therapy affect therapeutic outcomes and progression patterns during crizotinib treatment.Patients with ALK-positive (immunotherapy) non-small cell lung cancer were screened from West China Hospital between May 2013 and January 2019. A total of 155 patients were enrolled in this research, with entirely recorded statistics to analyze retrospectively.Baseline brain metastasis occurred in 64 patients (55.7%). Thirty-seven patients received local therapy, while 24 patients did not. We observed higher overall response rate in patients receiving local therapy (70.2% vs. 41.7%, P = .026), but no statistical difference was found in median progression free survival (mPFS) (12.0 months vs 13.0 months, P = .633). A significantly shorter mPFS was found in patients not receiving local treatment compared with the 16.5 months mPFS of patients without BBM (P = .029). Intracranial progressions were recorded in 35 patients with BBM (71%) and 16 patients who don't have (30%). As for extracranial progression, there is a higher occurrence rate (75.5%) in patients who had baseline extracranial metastases versus 49.0% in BBM patients. A significantly higher occurrence rate of multiple progression was noted in patients with BBM (14/49 vs. 6/53).Baseline intracranial metastasis changes the location and number of progressions after the first-line crizotinib and results in poor prognosis. There is no evidence that local treatment for brain metastasis had a protective effect on intracranial progression.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Gene Rearrangement; Humans; Lung Neoplasms; Middle Aged; Progression-Free Survival; Retrospective Studies

Anaplastic lymphoma kinase (ALK) inhibitors have been approved for patients with ALK-rearrangement lung cancer. The effect is superior to the standard first-line therapy of pemetrexed plus platinum-based chemotherapy. However, ALK inhibitors are associated with rare and sometimes fatal adverse events. Organizing pneumonitis (OP) is a rare and serious adverse event usually caused by ceritinib, and it is easily misdiagnosed as infectious pneumonia, metastasis, or cancer progression.. A 56-year-old female presented with chest tightness and dyspnea for more than 10 days. She was previously healthy with no significant medical history. Workup including chest computed tomography (CT), pathological examination of a biopsy specimen, and next-generation sequencing was consistent with a diagnosis of IVA ALK-rearrangement lung adenocarcinoma. She was treated with pemetrexed plus platinum-based chemotherapy and crizotinib concurrently, followed by maintenance therapy with crizotinib alone and she had an almost complete response. However, about 26 months after beginning treatment she developed multiple brain metastases. Crizotinib was discontinued and she was begun on ceritinib. After about 3 months the brain metastases had almost complete response. After 5 months of ceritinib, however, multiple patchy lesions appeared in the bilateral upper lungs.. Treatment with antibiotics had no effect and blood and sputum cultures are negative. A CT-guided biopsy of the upper lung was performed, and pathological hematoxylin-eosin staining and immunohistochemical studies were consistent with OP.. Ceritinib was discontinued, she was begun on prednisone 0.5 mg/kg orally every day, and regular follow-up is necessary.. CT of the chest 2 and 4 weeks after beginning prednisone showed the lung lesions to be gradually resolving, and she was continued on prednisone for 2 months and gradually reduced the dose of prednisone every 2 weeks. No related adverse events were occurred in patient.. OP must be differentiated from infectious pneumonia, metastasis, or cancer progression. The mechanism of OP is still unknown and needs further research. Biopsy plays a role in making a diagnosis of OP. In our patient, discontinuing ceritinib and treating her with prednisone resulted in a good outcome.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy; Brain Neoplasms; Crizotinib; Cryptogenic Organizing Pneumonia; Drug Substitution; Enzyme Inhibitors; Female; High-Throughput Nucleotide Sequencing; Humans; Lung; Lung Neoplasms; Middle Aged; Pemetrexed; Prednisone; Pyrimidines; Sulfones; Tomography, X-Ray Computed; Treatment Outcome

Anaplastic lymphoma kinase (ALK) is an important therapeutic target for advanced non-small cell lung cancer (NSCLC). In recent years, with the emergence of several ALK tyrosine kinase inhibitors (TKI), the overall survival (OS) of ALK fusion positive patients is gradually extended. This paper reports the treatment of a late stage non-small cell lung cancer (NSCLC) patient with ALK fusion positive for more than 5 years, and analyzes the treatment process and effect evaluation, so as to provide experience for the follow-up treatment of patients.. The diagnosis and treatment process of a patient with advanced ALK fusion mutation positive lung cancer admitted to the third ward of Department of oncology, Chifeng hospital, Inner Mongolia on July 3, 2015 was retrospectively analyzed.. A 42 years old male patient was admitted to our department on July 3, 2015 for "intermittent cough, chest tightness for 2 months, diagnosed with lung adenocarcinoma for 1 day". Imaging examination showed a space occupying lesion in the left lower lobe of the lung, accompanied by mediastinal lymphadenopathy and left encapsulated pleural effusion. Bronchoscopic pathology showed non-small cell carcinoma, and adenocarcinoma was tentatively suggested.. left lower lobe adenocarcinoma T1bN2M1a stage IV. Fluorescence in situ hybridization (FISH) indicated the translocation of ALK (2p23) chromosome. After 2 cycles of docetaxel+cisplatin (DP) regimens chemotherapy, disease progression occurred, so we used 6 cycles of pemetrexed+carboplatin to apply combination chemotherapy, 4 cycles of pemetrexed monotherapy were used after that. The efficacy evaluation: PR. On April 9, 2016, the patient was treated with crizotinib. In August 2019, multiple intracranial metastases were found and whole brain radiotherapy was given. Since September 4, 2019, oral administration of nsatinib has been carried out. As of March 1, 2021, the patients were followed up well.. The advanced ALK fusion positive lung adenocarcinoma patients, though the first-line and the second-line chemotherapy, and the follwing application of ALK-TKI treatment, has procured a total OS has reached 68 months, and the current follow-up is good.. 【中文题目：晚期ALK融合阳性非小细胞肺癌治疗
全程管理1例】 【中文摘要：背景与目的 间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）是晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）的重要治疗靶点。近几年来，随着多个ALK酪氨酸酶抑制剂（tyrosine kinase inhibitor, TKI）的出现，ALK融合阳性患者的总生存期（overall survival, OS）也在逐渐延长。现报道1例晚期ALK融合阳性NSCLC患者5余年的治疗经过，分析其治疗过程及效果评价，为后续患者的治疗提供经验。方法 回顾性分析内蒙古赤峰市医院肿瘤内科三病区2015年7月3日收治的1例晚期ALK融合突变阳性肺癌患者的诊疗过程。结果 患者男性，42岁，因“间断咳嗽、胸闷2个月，确诊肺腺癌1天”于2015年7月3日入我科。影像学检查提示左肺下叶占位，合并纵隔淋巴结肿大及左侧包裹性胸腔积液。支气管镜病理提示非小细胞癌，考虑腺癌。诊断：左肺下叶腺癌 T1bN2M1a IV期。荧光原位杂交技术（fluorescence in situ hybridization, FISH）提示ALK（2p23）染色体易位。给予多西他赛+顺铂方案化疗2个周期，病情进展，改为培美曲塞+卡铂方案联合化疗6个周期，后续应用培美曲塞单药维持4个周期，疗效评估：部分缓解（partial remission, PR）。2016年4月9日给予克唑替尼治疗，2019年8月发现颅内多发转移，给予全脑放疗。2019年9月4日始口服恩沙替尼治疗至今。截至2021年3月1日，患者随访良好。结论 该晚期ALK融合阳性肺腺癌患者，一线及二线选用化疗，后线应用ALK-TKI治疗，总OS达68个月，目前随访良好。
】 【中文关键词：间变性淋巴瘤激酶；克唑替尼；恩沙替尼；靶向治疗；肺肿瘤】.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Cisplatin; Crizotinib; Disease Progression; Docetaxel; Humans; Lung Neoplasms; Male; Mutation; Oncogene Proteins, Fusion; Pemetrexed; Protein Kinase Inhibitors; Survival Analysis; Treatment Outcome

The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carnitine; Cell Line, Tumor; Cell Proliferation; Cell Respiration; Crizotinib; Drug Synergism; Epoxy Compounds; Fatty Acids; Gene Expression Profiling; Glioblastoma; Glycolysis; Guanidines; Humans; Lactams, Macrocyclic; Metabolomics; Mice; Mitochondria; Mitochondrial Dynamics; Oxidative Phosphorylation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Proteomics; Proto-Oncogene Proteins c-met; Reactive Oxygen Species; Xenograft Model Antitumor Assays

ROS1 gene fusion represents a specific subtype of non-small cell lung cancer (NSCLC). Crizotinib is recommended for ROS1-positive NSCLC due to its favorable outcome in published clinical trials. However, due to the low incidence of ROS1-positive NSCLC, there is limited information on real-world clinical outcomes in patients treated with either crizotinib or platinum-based doublet chemotherapy.. Outcomes were recorded in 102 patients with stage Ⅲb or Ⅳ NSCLC who were treated at four Chinese hospitals between April, 2010 and June, 2019.. Of the 102 patients followed, 71.6% were females, 81.4% were non-smokers, and 98.0% had adenocarcinoma. First-line treatment with crizotinib achieved a significantly longer median progression-free survival (PFS) compared with platinum-based chemotherapy (14.9 months vs 8.5 months, respectively; P < .001). Next-generation sequencing (NGS) identified 61 patients who had ROS1 fusion variants, including CD74 (n = 33) and non-CD74 (n = 28) variants. In patients harboring CD74 fusion variants, the median PFS with first-line crizotinib treatment was significantly longer than in those harboring non-CD74 fusion variants (20.1 months vs 12.0 months, respectively; P = .046). However, in patients treated with platinum-based chemotherapy, there was no significant difference in PFS between the CD74 and non-CD74 variant groups (8.6 months vs 4.3 months, respectively; P = .115). Overall survival (OS) was not reached.. First-line therapy with crizotinib is more beneficial than platinum-based chemotherapy in patients with advanced NSCLC with different ROS1 fusion variants. Patients harboring CD74 fusion variants appear to respond better to crizotinib.

Topics: Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cisplatin; Crizotinib; Deoxycytidine; Docetaxel; Female; Gemcitabine; Histocompatibility Antigens Class II; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oncogene Fusion; Paclitaxel; Pemetrexed; Platinum Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Retrospective Studies; Treatment Outcome

Anaplastic lymphoma kinase (ALK) rearranged metastatic non-small cell lung cancer (NSCLC) comprises 5%-7% of all lung cancer and carries a good prognosis with available ALK-inhibitors. Majority of registration trials in ALK-inhibitors did not include Indian patients. Hence, this study was planned to analyze the outcome of Indian patients treated with ALK-inhibitors and associated challenges.. This is a multi-center study in 5 major tertiary care cancer centers across India treating ALK-rearranged NSCLC patients from April 2013 to April 2019. ALK rearrangement was determined by Ventana immunohistochemistry with D5F3 clone and/or by break-apart FISH. Patients treated with ALK-inhibitors in any lines of treatment were included in this study. Patients were evaluated for clinicopathologic features, patterns of ALK-inhibitors use and outcome. Progression free-survival (PFS) and overall survival (OS) were calculated and data were censored on April 30, 2019.. A total of 274 patients were studied, out of which 250 patients received ALK inhibitor and were analyzed further for outcome. The median age was 50 years (range: 24-82) and male to female ratio of 1.17:1. ALK was evaluated by immunohistochemistry in majority of patients (97%), 3 patients by FISH and 3 more patients were evaluated by both methods. Sixty-five percent (n = 162) of the patients received ALK-inhibitor as first line therapy, 51 patients received ALK-inhibitor as switch maintenance therapy after initial chemotherapy. Crizotinib and Ceritinib were used in 88% and 12%, respectively. One patient received Alectinib. Forty-one percent of patients had CNS progression. After median follow up of 27 months (1-72 months), the median OS was 24.7 months with OS rate of 72%, 51%, and 18% at 1, 2, and 4-years respectively. Median OS was 21.2, 26, and 38 months in the first line ALK-inhibitors use (n = 162), switch maintenance group (n = 51) and second line ALK-inhibitors use (postchemotherapy progression) (n = 33), respectively. No baseline variable predicted PFS. Presence of brain metastasis (P = 0.039) and first line ALK-inhibitors use (P = 0.032) emerged as poor prognostic factor for OS on multivariate analysis. PFS rate was 70%, 47%, and 31% at 6, 12, and 18 months respectively.. This is one of the largest real-world data on outcome of ALK inhibitors in ALK-rearranged NSCLC from Asia. In absence of second line ALK inhibitor, initial chemotherapy followed by ALK-inhibitors (switch maintenance) had better outcome. This fact may be studied in individual patient data meta-analysis. Poor performance status and brain metastases at presentation are poor prognostic factors for overall survival. Second-line ALK inhibitor use crucial for better outcome and access to clinical trials are much needed in Indian patients.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Follow-Up Studies; Gene Rearrangement; Humans; India; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Pyrimidines; Retrospective Studies; Sulfones; Survival Rate; Young Adult

Platinum-based postoperative adjuvant chemotherapy is the standard treatment for stage II-IIIA non-small cell lung cancer (NSCLC). Novel therapeutic modalities are required to improve the outcome of an early stage NSCLC. Patients with advanced NSCLC having anaplastic lymphoma kinase (ALK) fusion protein are sensitive to ALK inhibitors such as crizotinib. This study aimed to further explore the clinicopathological characteristics of postoperative patients with early-stage lung cancer harboring ALK fusion protein and provide a basis to carry out postoperative adjuvant crizotinib treatment. A total of 19 patients were retrospectively reviewed, and the clinicopathological parameters and follow-up data were collected and analysed. ALK rearrangements easily exist in male and in non-smokers patients with adenocarcinoma histology. Brain metastasis occurs easily, and prognosis of patients with stage IIIA is relatively poor. Detection of ALK fusion protein should be a routine testing. Postoperative adjuvant crizotinib treatment for patients with stage IIIA NSCLC harboring ALK fusion protein is promising.

Topics: Adenocarcinoma; Adrenal Gland Neoplasms; Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Chemoradiotherapy, Adjuvant; Crizotinib; Disease-Free Survival; Female; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Oncogene Proteins, Fusion; Pneumonectomy; Retrospective Studies

Topics: Adult; Age Factors; Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Comorbidity; Cost of Illness; Crizotinib; Female; Health Expenditures; Health Resources; Health Services; Humans; Insurance Claim Review; Lung Neoplasms; Male; Middle Aged; Patient Acceptance of Health Care; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Regression Analysis; Residence Characteristics; Retrospective Studies; Sex Factors; Socioeconomic Factors; Sulfones

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Crizotinib; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Proto-Oncogene Proteins c-met

We describe the synthesis of drug-dye conjugate 1 between anaplastic lymphoma kinase inhibitor Crizotinib and heptamethine cyanine dye IR-786. The drug-dye conjugate 1 was evaluated in three different patient-derived glioblastoma cell lines and showed potent cytotoxic activity with nanomolar potency (EC

Topics: Antineoplastic Agents; Brain Neoplasms; Carbocyanines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crizotinib; Cytostatic Agents; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fluorescent Dyes; Glioblastoma; Humans; Molecular Structure; Optical Imaging; Structure-Activity Relationship

ALK is a prognostic and predictive tumor marker in non-small cell lung carcinoma (NSCLC), and is more often found in lung adenocarcinomas.. The clinical and pathological data of 87 patients confirmed to have NSCLC by pathology or cytology were selected from April 2014 to January 2017 at the Tumor Hospital of Hebei Province.. Of the 87 ALK-positive-patients, 47 patients were treated with oral administration of crizotinib. The objective response rate (ORR) was 61.7%, the disease control rate (DCR) was 93.6%, and the mPFS was 19 months. In an analysis of the number of metastatic sites, the patients who had more than three metastatic sites, the ORR, DCR, and mPFS were 63.9%, 94.5%, and 19 months, compared with the 45.5%, 91%, and 11 months in the patients with less sites (P = 0.040). For patients of 60 years or older, ORR and DCR were 40% and 100%, the other group was 71.9% and 90.6%, respectively(P = 0.036). The timing of treatment was analyzed. At the first application of crizotinib, ORR and DCR were 78.2% and 100% corresponding 45.8% and 87.5% at the second and final application of crizotinib group (P = 0.022). Baseline brain metastases were present in 25.5% (12/47) of patients in this study. 9 of the patients who developed disease progression during crizotinib treatment had new brain metastases or increased preexisting cranial foci. Most of them took the treatment strategy of continuing crizotinib or replacing the second/third generation ALK-TKI treatment combined with local radiotherapy for brain metastases.. The efficacy of crizotinib in patients with advanced NSCLC is related to the number of metastatic organs, age and timing of treatment. The use of crizotinib is prone to intracranial progression, and progression of simple brain metastases is not an indication that crizotinib is discontinued. Patients will continue to benefit from combination of local radiotherapy.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; China; Cranial Irradiation; Crizotinib; Disease Progression; Female; Humans; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Signal Transduction; Time Factors

Topics: Aged; Anilides; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyridines; Pyrimidines; Retreatment; Sulfones

The central nervous system is a common site of relapse in patients receiving crizotinib, which is presumed to be associated with the low concentration of crizotinib in the cerebrospinal fluid (CSF). Our patient received surgical treatment for anaplastic lymphoma kinase-positive stage IIA lung adenocarcinoma. His cancer recurred with brain metastases and carcinomatous meningitis. We started whole-brain radiation therapy (WBRT) and subsequently administered crizotinib. The concentration of crizotinib on day 15 in the plasma was 158 ng/mL, and that in the spinal fluid was 4.32 ng/mL. WBRT may elevate the CSF/plasma crizotinib concentration ratio; clinicians may therefore consider performing WBRT prior to crizotinib initiation.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Crizotinib; Disease Progression; Fatal Outcome; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Middle Aged; Neoplasm Recurrence, Local

Clinical variables describing the natural history and longitudinal therapy outcomes of stage IV anaplastic lymphoma kinase gene rearrangement positive (ALK-positive) NSCLC and their relationship with long-term overall survival (OS) have not previously been described in detail.. Patients with stage IV NSCLC treated with an ALK inhibitor at the University of Colorado Cancer Center from 2009 through November 2017 were identified retrospectively. OS curves were constructed by using Kaplan-Meier methods. Multivariate Cox proportional hazard analysis was used to determine the relationship of variables with OS.. Of the 110 patients with ALK-positive NSCLC who were identified, 105 received crizotinib as their initial ALK inhibitor. With a median follow-up time of 47 months, the median OS time from diagnosis of stage IV disease was 81 months (6.8 years). Brain metastases at diagnosis of stage IV disease (hazard ratio = 1.01, p = 0.971) and year of stage IV presentation (p = 0.887) did not influence OS. More organs with tumor at diagnosis of stage IV disease was associated with worse OS (HR = 1.49 for each additional organ with disease, including the CNS [p = 0.002]). Each additional month of pemetrexed-based therapy was associated with a 7% relative decrease in risk of death.. Patients with stage IV ALK-positive NSCLC can have prolonged OS. Brain metastases at diagnosis of stage IV disease does not influence OS. Having more organs involved with tumor at stage IV presentation is associated with worse outcomes. Prolonged benefit from pemetrexed is associated with better outcomes.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Survival Analysis

Lung cancer is the most common tumor and the leading cause of cancer-related death worldwide. Approximately 6.7% of non-small-cell lung cancers (NSCLCs) show anaplastic lymphoma kinase (ALK) rearrangement and could benefit from ALK-targeted treatment. Various anti-ALK drugs have been developed during the past years, but it is actually controversial which sequence and which ALK inhibitor is recommended for a single patient. Leptomeningeal carcinomatosis (LC) is associated with a poor prognosis, with an overall survival of 2-4 months for treated patients. The data about LC management derive mainly from retrospective studies, being an exclusion criterion for most trials. Intrathecal chemotherapy and whole-brain radiotherapy (WBRT), associated with a systemic treatment, are the most commonly used approach. Here we present a case of NSCLC harboring an ALK translocation treated with four lines of ALK inhibitors and receiving WBRT for LC, showing an overall survival of ∼5 years from the diagnosis of metastatic disease. This case report focuses mainly on several controversial clinical aspects, that is, the sequence of treatment in ALK-positive NSCLC, the ALK inhibitors' efficacy on brain disease and beyond progression, the management of LC, and the role of WBRT despite the risk of cognitive impairment.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Cisplatin; Crizotinib; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Pemetrexed; Prognosis

Despite development of several next-generation tyrosine kinase inhibitors (TKIs), crizotinib remains one of the first-line treatment options for advanced ALK-positive NSCLC and is widely used in situations where next-generation TKIs aren't yet approved or economically inaccessible. However, the pattern of failure and clinical value of radiotherapy in metastatic crizotinib-treated ALK-mutant lung cancer, with or without baseline brain metastases (BBM), are largely unknown.. Consecutive crizotinib-treated NSCLC patients with adequate imaging and measurable disease were retrospectively enrolled. Disease progression in original sites (primary/metastatic), new sites, or both, are classified as original failure (OF), distant failure (DF) and ODF, respectively. Progression free survival, from crizotinib initiation to the first disease progression, and from that to the second disease progression, were calculated as PFS1 and PFS2.. Ninety-three patients were identified. With a median follow up of 22.0 (range, 2.0-72.0) months, 52 patients had crizotinib-treatment failure. The frequencies of OF, ODF, and DF, were 50.0, 26.9, and 23.1%, respectively. Histology, primary tumor size and presence of BBM, were independently associated with OF, using competing risks analyses. The brain was the most common site of initial disease progression. Patients with BBM had a significant higher possibility developing multiple-progressive lesions in the brain (p = 0.002). Importantly, four of the ten patients who had baseline oligo-metastatic cranial disease but didn't receive upfront brain radiation, developed multiple-progressive disease in the brain. Brain radiation before crizotinib could alter the disease failure patterns and improve PFS1 among patients with BBM (p = 0.006). Extracranial radiation was efficient in controlling symptoms but it was not associated with PFS1 (p = 0.223), and the majority of patients were eligible for salvage radiotherapy upon disease progression to crizotinib. By the time of data cut-off, 28 patients had second disease progression, with a median PFS2 of 7.0 (95% CI 5.4-8.6) months and salvage radiotherapy significantly prolonged PFS2 (p = 0.003). Additionally, patients receiving any radiotherapy during their treatment course had a significant longer overall survival (p = 0.048).. Among patients with baseline oligo-metastatic brain lesions which are suitable for stereotactic radiosurgery, upfront brain radiotherapy provides considerable clinical benefits. While, extracranial radiation may be deferred in asymptomatic patients with multiple-metastatic lesions.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Crizotinib; Female; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Survival Rate; Young Adult

Approximately 1-2% of patients with non‒small-cell lung cancer (NSCLC) harbor ROS1 rearrangements. Crizotinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET, and ROS1, has shown marked antitumor activity in patients with ROS1-positive advanced NSCLC.. Our objective was to analyze the efficacy and safety of crizotinib treatment in Chinese patients with advanced NSCLC with ROS1 rearrangement in real-world clinical practice.. We included 35 patients with ROS1-positive NSCLC in this retrospective analysis. All received crizotinib 250 mg twice daily between March 2016 and April 2018 at the Fudan University Shanghai Cancer Center. All had histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangements, which were identified by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or next-generation sequencing. The main outcome measures were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events.. The median age of the patients was 51.0 years; 23 (65.7%) were female and 28 (80.0%) were never smokers. All were diagnosed as having adenocarcinoma; eight patients (22.9%) had brain metastases at baseline. The ORR and DCR were 71.4% and 94.3%, respectively. The estimated median PFS was 11.0 months (95% confidence interval [CI] 7.8-14.2). The estimated median OS was 41.0 months (95% CI 22.5-59.5). Elevated transaminases (54.3%), vision disorder (25.7%), elevated blood creatinine (22.9%), diarrhea (20.0%), and vomiting (20.0%) were the most commonly reported adverse effects.. Crizotinib was effective and well tolerated in Chinese patients with ROS1-positive advanced NSCLC in real-world clinical practice. The progression sites and patterns, as well as treatments after first disease progression on crizotinib were diverse. Crizotinib beyond progressive disease and local therapy after failure of crizotinib treatment were feasible and effective in clinical practice.

Topics: Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Biomarkers, Tumor; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Retrospective Studies; Salvage Therapy; Survival Rate

The efficacy of crizotinib for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) patients with brain metastasis is controversial. Real-world research data are needed as further evidence.. We conducted a multicenter, retrospective study to explore how crizotinib affects the control of brain metastasis and the survival outcomes among Chinese patients.. We reviewed the medical records of unselected ALK-rearranged NSCLC patients treated with crizotinib at five hospitals in China from January 1, 2013 to November 30, 2017. Patients developing brain metastasis either before or during crizotinib treatment were included. Survival outcomes were analyzed by the Kaplan-Meier method, and prognostic factors were analyzed by multivariate Cox regression.. A total of 174 patients were included in the analysis; 95 of these patients had baseline brain metastasis, while 79 patients developed brain metastasis during crizotinib treatment. Among patients with baseline brain metastasis, the median intracranial time to progression was 19.3 months (95% confidence interval [CI] 12.5-26.2) and the median overall survival (OS) was 53.4 months (95% CI not reached). A total of 135 patients experienced intracranial progression, and 94 of these patients continued crizotinib beyond progressive disease (CBPD). There was no significant difference in the median OS between patients with CBPD and without CBPD (48.3 months vs 53.4 months; p = 0.296).. ALK-rearranged advanced NSCLC patients with baseline brain metastasis can still achieve OS benefits from crizotinib treatment. However, patients with intracranial progression may not obtain a long-term survival benefit from continuation of CBPD.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; China; Crizotinib; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Retrospective Studies; Salvage Therapy; Survival Rate; Young Adult

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

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

Glioblastoma multiforme (GBM) defies the currently practiced management of radiotherapy, chemotherapy and surgery and hence, it is associated with a high fatality rate with a median survival of 14.6 months. In our previous work investigating different tyrosine kinase inhibitors (TKIs), we established that a combination of Crizotinib and Dasatinib exerted the most potent effect on different GBM cell lines. In this work, to improve targeted therapy at the site of the tumour and avoid systemic toxicity, we exploited the enhanced permeability and retention effect by designing micellar formulations of these two TKIs. Crizotinib and Dasatinib were successfully encapsulated in poly(styrene-co-maleic acid) (SMA) micelles which were then evaluated for their physicochemical characteristics, anti-proliferative effect, mode of cell death, efficacy in spheroid models, effect on cell signalling, antiangiogenic potential and in vivo anticancer activity. Our results showed that this combination had induced a potent anti-proliferative effect in four GBM cell lines grown as a monolayer and as a spheroid. The combination was also efficacious in in vitro models of angiogenesis and vascular mimicry. In vivo data showed the enhanced activity of the micellar TKIs compared to free drugs. In conclusion, we proved that micellar formulations of Crizotinib and Dasatinib carry promising in vitro and in vivo efficacy that warrant further investigation.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Crizotinib; Dasatinib; Glioblastoma; Humans; Micelles

ROS1 rearrangement-positive NSCLC can be treated effectively with an anaplastic lymphoma kinase/ROS1/mesenchymal-epithelial transition factor inhibitor such as crizotinib; however, the rate of response remains variable. Although several ROS1 fusion partners have been identified, the efficacy of crizotinib in patients with different types of ROS1 fusion partners is poorly understood.. We reviewed clinicopathological data of patients with ROS1 rearrangement who received crizotinib therapy at our institution between April 2014 and December 2016. ROS1 fusion partners were evaluated by using Sanger sequencing for available tumor tissue.. During the study, 49 patients were found to have ROS1 rearrangement and were subsequently treated with crizotinib. Tumor specimens were available for 36 patients, of whom 19 were found to have CD 74 molecule gene (CD74)-ROS1 fusion partners. Before therapy, those in the CD74-ROS1 group were found to have a higher rate of brain metastases (six versus 0 [p = 0.020]). The objective response rate for crizotinib was 83.3% in all patients, whereas it was 94.11% and 73.68% in the non-CD74-ROS1 and CD74-ROS1 groups, respectively. As compared with the CD74-ROS1 group, the non-CD74-ROS1 group had both a significantly longer progression-free survival (17.63 months versus 12.63 months [p = 0.048]) and a significantly longer overall survival (44.50 months versus 24.33 months [p = 0.036]). On multivariable analysis, the only factor associated with overall survival was presence of brain metastases before therapy (p = 0.010). There were no significant factors associated with progression-free survival in the multivariable analysis.. These findings suggests that patients with CD74-ROS1 fusion partners are more likely to present with brain metastases. Although not independently significant, a trend toward improved survival was observed in patients in the non-CD74-ROS1 group when they were treated with crizotinib.

Topics: Adenocarcinoma; Adult; Aged; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Follow-Up Studies; Gene Rearrangement; Histocompatibility Antigens Class II; Humans; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Survival Rate

Central nervous system (CNS) metastases in lung cancer are a frequent cause of morbidity and mortality. There are conflicting data on the incidence of CNS metastases in stage IV ROS1-positive NSCLC and the rate of CNS progression during crizotinib therapy.. A retrospective review of 579 patients with stage IV NSCLC between June 2008 and December 2017 was performed. Brain metastases and oncogene status (ROS1, ALK receptor tyrosine kinase gene [ALK], EGFR, KRAS, BRAF, and others) were recorded. We measured progression-free survival and time to CNS progression in ROS1-positive and ALK-positive patients who were taking crizotinib.. We identified 33 ROS1-positive and 115 ALK-positive patients with stage IV NSCLC. The incidences of brain metastases for treatment-naive, stage IV ROS1-positive and ALK-positive NSCLC were 36% (12 of 33) and 34% (39 of 115), respectively. There were no statistically significant differences in incidence of brain metastases across ROS1, ALK, EGFR, KRAS, BRAF, or other mutations. Complete survival data were available for 19 ROS1-positive and 83 ALK-positive patients. The median progression-free survival times for ROS1-positive and ALK-positive patients were 11 and 8 months, respectively (p = 0.304). The CNS was the first and sole site of progression in 47% of ROS1-positive (nine of 19) and 33% of ALK-positive (28 of 83) patients, with no statistically significant differences between these groups (p = 0.610).. Brain metastases are common in treatment-naive stage IV ROS1-positive NSCLC, though the incidence does not differ from that in other oncogene cohorts. The CNS is a common first site of progression in ROS1-positive patients who are taking crizotinib. This study reinforces the importance of developing CNS-penetrant tyrosine kinase inhibitors for patients with ROS1-positive NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Female; Gene Rearrangement; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Retrospective Studies; Young Adult

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Disease Progression; Genetic Predisposition to Disease; Humans; Lung Neoplasms; Mutation; Phenotype; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Time Factors

Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK-positive non-small-cell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK-positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes.ALK-positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib.At time of analysis, 209 (65.7%) of the 318 included patients had died. Median OS with crizotinib was 16.6 months. The line of crizotinib therapy did not impact survival outcomes. Of the 263 patients with PD, 105 received best supportive care, 74 subsequent drugs other than next-generation ALKi and 84 next-generation ALKi. Next-generation ALKi treatment correlated with better survival outcomes in multivariate analysis. These patients had a median post-PD survival of 25.0 months and median OS from metastatic disease diagnosis of 89.6 months.Unselected ALK-positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Survival Rate; Young Adult

Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is a distinct subtype with patients showing peculiar clinicopathological features and dramatic responses to the ALK tyrosine kinase inhibitor crizotinib. Patients with this cancer variant have a dismal prognosis and limited treatment options when it has progressed to intracranial metastasis because of inadequate drug penetration into the central nervous system (CNS). Factors associated with response to TKI therapy have been reported to include pharmacokinetic and biodynamic resistance phenomena.. In our NSCLC patient with multiple intracranial metastases, we administered high-dose pulsatile crizotinib therapy (1000 mg/d) on a one-day-on/one-day-off basis. A significant central nervous system (CNS) response was achieved, and time to neurological progression was prolonged to 6 months.. High-dose pulsatile therapy may be an effective dosing strategy for crizotinib in NSCLC showing progression to metastasis in the brain.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Lung Neoplasms; Male; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

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

The treatment of non-small cell lung cancer (NSCLC) has now changed dramatically in recent years and anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitors are developing rapidly.. Here we reported a 57-year-old ALK-positive NSCLC man with brain metastases.. A case of lung adenocarcinoma with brain metastases.. Crizotinib was administered orally at a dose of 250mg twice a day until the brain metastases were found. Treatment with orally administered ceritinib at a dose of 450mg/d was initiated after crizotinib treatment.. The patient is currently receiving maintenance ceritinib treatment, with no evidence of extracranial or intracranial tumor progression for 25 months.. Ceritinib may be a good choice for ALK-positive NSCLC patients with brain metastases who acquire resistance to crizotinib.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Middle Aged; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

MET proto-oncogene, receptor tyrosine kinase gene exon 14 skipping (METex14) alterations represent a unique subset of oncogenic drivers in NSCLC. Preliminary clinical activity of crizotinib against METex14-positive NSCLC has been reported. The full spectrum of resistance mechanisms to crizotinib in METex14-positive NSCLC remains to be identified.. Hybrid capture-based comprehensive genomic profiling performed on a tumor specimen obtained at diagnosis, and a hybrid capture-based assay of circulating tumor DNA (ctDNA) at the time of progression during crizotinib treatment was assessed in a pairwise fashion.. A METex14 alteration (D1010H) was detected in the pretreatment tumor biopsy specimen, as was MET proto-oncogene, receptor tyrosine kinase (MET) Y1230C, retrospectively, at very low frequency (0.3%). After a confirmed response during crizotinib treatment for 13 months followed by progression, both MET proto-oncogene, receptor tyrosine kinase gene Y1230C and D1010H were detected prospectively in the ctDNA.. Emergence of the preexisting MET Y1230C likely confers resistance to crizotinib in this case of METex14-positive NSCLC. Existence of pretreatment MET Y1230C may eventually modulate the response of METex14-positive NSCLC to type I MET tyrosine kinase inhibitors. Noninvasive plasma-based ctDNA assays can provide a convenient method to detect resistance mutations in patients with previously known driver mutations.

Topics: Aged; Biomarkers, Tumor; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA, Neoplasm; Drug Resistance, Neoplasm; Exons; Female; Humans; Lung Neoplasms; Mutation; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines

Topics: Adult; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis.. A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling.. Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001).. Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cranial Irradiation; Crizotinib; Disease-Free Survival; Female; Follow-Up Studies; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Karnofsky Performance Status; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Piperidines; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Radiosurgery; Receptor Protein-Tyrosine Kinases; Risk Assessment; Risk Factors; Smoking; Sulfones

Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cranial Irradiation; Crizotinib; Disease Progression; Female; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome; Young Adult

Topics: Adenocarcinoma; Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Cell Cycle Proteins; Codon; Crizotinib; DNA-Binding Proteins; Female; Genomics; Histone-Lysine N-Methyltransferase; Humans; Lung Neoplasms; MAP Kinase Kinase 4; Microtubule-Associated Proteins; Nuclear Proteins; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiography; Receptor Protein-Tyrosine Kinases; Ribonucleoproteins; Serine Endopeptidases; Splicing Factor U2AF; Transcription Factors; Translocation, Genetic; Treatment Outcome

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Crizotinib; Humans; Neoplasm Metastasis; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases

Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Brain; Brain Neoplasms; Carbazoles; Crizotinib; Disease Progression; Humans; Lung Neoplasms; Male; Middle Aged; Necrosis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiation Injuries; Receptor Protein-Tyrosine Kinases; Treatment Outcome

The central nervous system (CNS) is a preferential progression site related to poor penetration of crizotinib into the CNS in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients treated with crizotinib. We evaluated the clinical impact of crizotinib on central nervous system progression in ALK-positive NSCLC.. Between January 2006 and September 2015, 59 ALK-positive NSCLC patients treated with crizotinib as the initial ALK inhibitor were retrospectively evaluated for baseline characteristics, initial response to crizotinib, brain metastasis (BM) status at baseline, and progression patterns.. Among 59 patients, 48 (81%) received crizotinib as first-line or second-line treatment for advanced or recurrent disease. Out of the 26 (44%) patients who had BM, 13 had untreated BM, and 13 had previously undergone intracranial radiotherapy or surgery. The overall response rate for crizotinib was 66%, with a median progression-free survival (PFS) of 9.7 months. Disease progression assessed by response evaluation criteria in solid tumors-progressive disease (RECIST-PD) occurred in 48 patients. The CNS was the common initial progression site in 24 patients, which included isolated CNS progression in 18 patients. There was a significantly shorter median PFS in the BM versus the non-BM patients before crizotinib treatment (median PFS: 6.7 months vs. 10.2 months, P=0.0347). Multivariate analysis revealed that poor performance status (PS) (≥2) or untreated BM were associated with the PFS duration (poor PS: hazard ratio (HR) 3.322, 95% CI 1.402-7.353, P=0.0078; untreated BM: HR 2.314, 95% CI 1.153-4.400, P=0.0196). In addition, the time to the occurrence of CNS progression from the start of crizotinib was significantly shorter in the BM versus non-BM patients (11.1 vs. 22.1 months, P=0.0255).. The common progression site in ALK-positive patients treated with crizotinib was the CNS. BM status was significantly associated with both PFS in crizotinib-treated patients and the occurrence of CNS progression.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Crizotinib; Disease Progression; Disease-Free Survival; Female; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Glioblastoma multiforme (GBM) is the most frequent and the most malignant tumor among adult brain tumors. Previous reports led us to hypothesize that the proto-oncogene mesenchymal-epithelial transition (MET) expressed in glioma stem cell-like cells (GSCs) would be a potent therapeutic target for GBM.. To address this question, we analyzed 113 original samples of tumors from patients based on immunohistochemistry. During this process, we were able to establish GSC lines from patients with GBM that were MET-positive and MET-negative. Using these cells, we tested the therapeutic impact of a MET inhibitor, crizotinib, both in vitro and in vivo.. Patients with MET-positive GBM exhibited poor survival. GSC-based experiments revealed that treatment with crizotinib, both in vitro and in vivo, exhibited therapeutic efficacy particularly against MET-positive GSCs.. Based on these findings, we conclude that MET expressed in GSCs might be a potent therapeutic target for GBM.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Crizotinib; Female; Glioblastoma; Humans; Male; Mice, Inbred NOD; Mice, SCID; Middle Aged; Molecular Targeted Therapy; Neoplastic Stem Cells; Proto-Oncogene Mas; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Xenograft Model Antitumor Assays

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is an important subtype of lung cancer. The standard modality of ALK-positive NSCLC with brain metastases remains uncertain.. We collected data on clinical characteristics and treatment of patients with ALK-positive NSCLC and brain metastases between March 2013 and March 2016 and retrospectively analyzed patient outcomes.. In 84 ALK-positive patients with advanced NSCLC, 22 (26.2%) had brain metastases during the initial diagnosis of lung cancer, among which 3 patients with EGFR mutation were excluded, and 19 patients were analyzed. Median intracranial progression-free survival (PFS) was 12.0 months. PFS for patients who received first-line local brain therapy (P=0.021) and crizotinib therapy (P=0.030) was superior to PFS for patients without such therapies. PFS for patients who received first-line crizotinib combined with local brain therapy was 27.0 months and only 4.2 months for those who received crizotinib alone.. First-line crizotinib therapy combined with local brain treatment can improve intracranial PFS for ALK-positive NSCLC with brain metastases. This finding should be confirmed further through multicenter, prospective clinical trials with large sample size.. 背景与目的 间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）阳性非小细胞肺癌（non-small cell lung cancer, NSCLC）是肺癌的一个重要亚型。ALK阳性NSCLC脑转移患者的治疗尚无标准模式。方法 本研究对我院2013年3月-2016年3月期间确诊的ALK阳性NSCLC脑转移患者的临床资料和治疗情况进行回顾性分析，探讨不同治疗模式患者的转归。结果 84例晚期ALK阳性NSCLC患者中，22例初诊时有脑转移，剔除3例合并表皮生长因子受体（epidermal growth factor receptor, EGFR）双突变患者，共19例纳入分析。中位颅内疾病进展时间（progression-free survival, PFS）为12.0个月，一线脑部局部治疗（P=0.021）及一线克唑替尼治疗（P=0.030）可延长PFS；一线克唑替尼联合脑部局部治疗的中位颅内PFS为27.0个月，而单纯克唑替尼治疗的PFS仅为4.2个月。结论 一线克唑替尼联合脑部局部治疗有助于延长ALK阳性晚期NSCLC患者的颅内PFS，因例数少，尚有待大样本多中心前瞻性临床研究证实。.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Treatment Outcome

Lung cancer with brain metastasis had poor prognosis. Crizotinib had been confirmed to be used in ROS1 (C-ros oncogene 1 receptor tyrosine kinase) rearranged lung adenocarcinoma, but its efficacy in lung cancer with brain metastasis was poor due to the blood brain barrier. In the present study, we reported one case of ROS1 fusion lung adenocarcinoma with symptomatic brain matastasis, who was treated with brain metastases resection, crizotinib, and whole brain radiotherapy plus boost to residual brain metastasis. The safety and efficacy was summarized.. At first, surgical resection was used to relive mass effect and to biopsy. Then crizotinib (250 mg, bid) was chosen for the existence of ROS1 fusion gene. Whole brain radiotherapy plus boost to residual brain metastasis were used after surgery. Objective response was evaluated by Response Evaluation Criteriation in Solid Tumours (RECIST) v1.1 and brain metastasis were evaluated by computer tomography (CT)/magnetic resonance imaging (MRI) image. Adverse events were evaluated according to Common Terminology Criteria for Adverse Events (CTC AE) v4.0.. After taking crizotinib for 3 months, the lung lesions were close to complete response (CR), the brain metastasis were partial response (PR), the abdomen metastasis were CR and the symptom of blurred vision relieved.. Crizotinib combined with palliative operation and radiation therapy (WBRT plus boost to residual brain metastasis) in the treatment of ROS1 fusion gene positive lung adenocarcinoma with symptomatic brain metastases, can effectively control intracranial lesions with good tolerance.. 背景与目的 伴有脑转移的肺癌预后差。克唑替尼可有效治疗ROS1（C-ros oncogene 1 receptor tyrosine kinase）融合基因阳性的肺癌，但由于血脑屏障通透率较低，对脑转移灶的治疗效果不佳。本文总结1例综合运用手术、全脑放疗+残留灶补量放疗及克唑替尼等手段治疗ROS1融合基因阳性伴有症状脑转移的肺腺癌患者，并对其有效性及安全性进行讨论和分析。 方法 采用手术切除占位效应明显、引起头疼症状的颅内病灶，获得病理；因ROS1融合基因阳性，给予克唑替尼治疗，250 mg，2次/d；术后进行全脑放疗+残留灶补量放疗。按照实体瘤疗效评价标准1.1版（Response Evaluation Criteriation in Solid Tumours, RECIST v1.1）评价客观疗效。按照不良反应通用术语标准4.0版（ Common Terminology Criteria for Adverse Events v4.0, CTC AE v4.0）评估用药期间发生的不良事件。 结果 该患者服用克唑替尼3个月后，肺部病变接近完全缓解（complete remission, CR），颅内病变部分缓解（partial response, PR），腹腔病变CR，视物模糊症状减轻。 结论 综合运用手术、全脑放疗+残留灶补量放疗、克唑替尼治疗ROS1融合基因阳性伴有症状脑转移的肺腺癌患者，可有效控制颅内颅外病灶，耐受性好。.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Crizotinib; Female; Gene Rearrangement; Humans; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Safety; Treatment Outcome

Crizotinib is a novel targeted anticancer agent for non-small cell lung cancer. In this study, we report our clinical outcomes from Gamma Knife radiosurgery (GKS) for brain metastasis (BM) under crizotinib treatment in non-small cell lung cancer patients.. We performed a retrospective review of 29 patients who underwent a total of 51 GKS procedures for BM while continuing on crizotinib. We compared 2 groups on the basis of the number of BMs: oligometastases (≤5) and polymetastases (>5).. The actuarial 1- and 2-year overall survival rates from initial GKS were 73.5% and 42.6%, respectively. The estimated local progression-free survival (PFS) rates of the oligometastases group were 91.8% at 6 months and 84.2% at 12 months, whereas the local PFS rates of the polymetastases group at 6 and 12 months were 91.6% and 58.2%, respectively (P = 0.153). The estimated distant PFS rates of the oligometastases group were 50.7% at 6 months and 20.3% at 12 months, whereas the distant PFS rates of the polymetastases group were 32.7% at 6 months and only 6.5% at 12 months (P = 0.029).. GKS combined with crizotinib showed effective local tumor control and excellent outcome, especially in oligometastases. However, distant progression of BM during crizotinib after GKS occurred in most of the cases within a year. Thus brain surveillance after GKS is important for adequate and timely salvage treatment even when extracranial disease is well controlled by crizotinib.

Topics: Adenocarcinoma; Adult; Aged; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiosurgery; Retrospective Studies

Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.

Topics: Adolescent; Adult; Anilides; Animals; Brain Neoplasms; Cell Line, Tumor; Child; Child, Preschool; Crizotinib; DNA, Neoplasm; Female; Glioblastoma; Humans; Infant; Male; Mice; Mice, SCID; Microtubule-Associated Proteins; Mitogen-Activated Protein Kinases; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Proteins; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Quinolines; Receptor-Like Protein Tyrosine Phosphatases, Class 5; RNA, Messenger; Sequence Analysis, DNA; Signal Transduction; Xenograft Model Antitumor Assays; Young Adult

Identification of the anaplastic lymphoma kinase (ALK) gene has refined the classification of non-small cell lung cancer (NSCLC) and promoted research on molecularly targeted drugs such as crizotinib, an ALK inhibitor with good efficacy, in ALK-rearranged NSCLC. At present, few studies have reported the efficacy of crizotinib in patients with ALK-rearranged NSCLC with brain metastases. In a patient with NSCLC harboring ALK-rearrangement who had brain metastases and poor performance status (PS), we obtained a durable response with crizotinib administered following multi-line chemotherapy regimens.

Topics: Adult; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Karnofsky Performance Status; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Brain metastasis in non small cell lung cancer (NSCLC) patients is often considered as a terminal stage of advanced disease. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) for ALK-rearranged NSCLC patients. Herein, we conducted a retrospective study to explore how Crizotinib affects the control of brain metastases and the overall prognosis in advanced ALK-rearranged NSCLC patients with brain metastases in Chinese population. A total of 34 patients were enrolled, of whom 20 (58.8%) patients had baseline brain metastases before Crizotinib treatment. Among patients with brain metastases before Crizotinib, overall survival (OS) after brain metastases was significantly longer than that of patients with brain metastases after Crizotinib (median OS, not reached vs. 10.3 months, respectively, p = 0.001). There was also a significant difference in systemic progression-free survival (PFS) between patients developing brain metastases before and after Crizotinib treatment (21.2 months vs. 13.9 months, p = 0.003). In conclusion, ALK-rearranged NSCLC patients with brain metastases before Crizotinib may benefit more from Crizotinib than those developing brain metastases during Crizotinib treatment.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Asian People; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; China; Crizotinib; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Survival Analysis; Young Adult

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Antineoplastic Agents; Blindness; Brain Neoplasms; Cranial Irradiation; Crizotinib; Disease Progression; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Muscle Weakness; Oncogene Proteins, Fusion; Optic Nerve Diseases; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Signal Transduction; Translocation, Genetic

Crizotinib is a potent and specific small-molecule inhibitor of both anaplastic lymphoma kinase (ALK) and c-MET tyrosine kinases, and patients with ALK rearrangement tumor benefit from crizotinib treatment; however, its penetration into calculated cerebrospinal fluid (CSF) is considered to be poor. Alectinib is a highly selective, next-generation ALK inhibitor, and both preclinical and clinical studies have indicated that alectinib is also effective in crizotinib-resistant tumors. A recent in vitro study demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALK-positive non-small-cell lung cancer. In this paper, we report a first case alectinib was highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable.

Topics: Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Pyrazoles; Pyridines

Brain metastases (BM) are highly prevalent among anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) patients; yet little is known about their real-world treatment patterns and clinical and economic burdens. This study aimed to describe these patients' treatment patterns, symptoms, and costs.. Retrospective study pooling data from three large administrative databases in the US (08/2011-06/2013). ALK+ NSCLC patients with BM and continuous enrollment for ≥ 60 days before and ≥ 30 days after the first observed BM diagnosis were identified by pharmacy records for crizotinib among patients with lung cancer and BM diagnostic codes.. Treatment patterns, symptoms, healthcare resource utilization, and costs, before and after BM diagnosis.. Of the 213 crizotinib patients with BM diagnoses meeting the selection criteria, 23.0% had BM prior to NSCLC diagnosis; 47.4% had BM prior to crizotinib initiation; 19.2% during crizotinib treatment; and 10.3% post-crizotinib treatment. For those diagnosed with BM after NSCLC diagnosis, the median time between the NSCLC and BM diagnoses was 88 days. Following the first observed BM diagnosis, 88.7% used chemotherapy, 63.4% had radiotherapy, and 31.9% had stereotactic radiosurgery. The prevalence of BM-related symptoms substantially increased post-BM-diagnosis: fatigue (from 15% to 39%), headaches (from 5% to 24%), and depression (from 5% to 15%). Monthly costs per patient averaged $5983 before the BM diagnosis and $22,645 after diagnosis. Patients' resource utilization increased significantly post-BM-diagnosis, with a 3-fold increase in OP visits and a 6-fold increase in IP stays. Post-BM-diagnosis costs were driven by pharmacy (42.0%), inpatient (29.6%), and outpatient costs (26.0%).. The study sample was limited to crizotinib-treated patients.. Post-BM-diagnosis, patients experience high symptom burden. Post-BM-diagnosis, treatment is highly variable and costly: average monthly costs per patient almost quadrupled post-BM-diagnosis.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Comorbidity; Crizotinib; Cross-Sectional Studies; Female; Health Resources; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; United States

EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Bone Neoplasms; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Crizotinib; Female; Humans; Lung Neoplasms; Male; Mice; Mice, SCID; Microtubule-Associated Proteins; Oncogene Proteins, Fusion; Piperidines; Pleural Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiography; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases

Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied.. Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1).. At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases.. Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cranial Irradiation; Crizotinib; Disease-Free Survival; Female; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiosurgery; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome

Up to now, several clinical studies have been started investigating the relevance of receptor tyrosine kinase (RTK) inhibitors upon progression free survival in various pediatric brain tumors. However, single targeted kinase inhibition failed, possibly due to tumor resistance mechanisms. The present study will extend our previous observations that vascular endothelial growth factor receptor (VEGFR)-2, platelet derived growth factor receptor (PDGFR)β, Src, the epidermal growth factor receptor (ErbB) family, and hepatocyte growth factor receptor (HGFR/cMet) are potentially drugable targets in pediatric low grade astrocytoma and ependymoma with investigations concerning growth-factor-driven rescue. This was investigated in pediatric low grade astrocytoma and ependymoma cell lines treated with receptor tyrosine kinase (RTK) inhibitors e.g. sorafenib, dasatinib, canertinib and crizotinib. Flow cytometry analyses showed high percentage of cells expressing VEGFR-1, fibroblast growth factor receptor (FGFR)-1, ErbB1/EGFR, HGFR and recepteur d'origine nantais (RON) (respectively 52-77%, 34-51%, 63-90%, 83-98%, 65-95%). Their respective inhibitors induced decrease of cell viability, measured with WST-1 cell viability assays. At least this was partially due to increased apoptotic levels measured by Annexin V/Propidium Iodide apoptosis assays. EGF, HGF and FGF, which are normally expressed in brain (tumor) tissue, showed to be effective rescue inducing growth factors resulting in increased cell survival especially during treatment with dasatinib (complete rescue) or sorafenib (partial rescue). Growth-factor-driven rescue was less prominent when canertinib or crizotinib were used. Rescue was underscored by significantly activating downstream Akt and/or Erk phosphorylation and increased tumor cell migration. Combination treatment showed to be able to overcome the growth-factor-driven rescue. In conclusion, our study highlights the extensive importance of environmentally present growth factors in developing tumor escape towards RTK inhibitors in pediatric low grade astrocytoma and ependymoma. It is of great interest to anticipate upon these results for the design of new therapeutic trials with RTK inhibitors in these pediatric brain tumors.

Topics: Apoptosis; Astrocytoma; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Crizotinib; Dasatinib; Ependymoma; Extracellular Signal-Regulated MAP Kinases; Humans; Intercellular Signaling Peptides and Proteins; Niacinamide; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridines; Signal Transduction; Sorafenib

Epidermal growth factor receptor (EGFR) is highly amplified, mutated, and overexpressed in human malignant gliomas. Despite its prevalence and growth-promoting functions, therapeutic strategies to inhibit EGFR kinase activity have not been translated into profound beneficial effects in glioma clinical trials. To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Using combined genetic and pharmacologic interventions, we revealed that EGFR*-driven gliomas were insensitive to EGFR tyrosine kinase inhibitors, although they could efficiently inhibit EGFR* autophosphorylation in vitro and in vivo. This is in contrast with the genetic suppression of EGFR* induction that led to significant tumor regression and prolonged animal survival. However, despite their initial response to genetic EGFR* extinction, all tumors would relapse and propagate independent of EGFR*. We further showed that EGFR*-independent tumor cells existed prior to treatment and were responsible for relapse following genetic EGFR* suppression. And, the addition of a PI3K/mTOR inhibitor could significantly delay relapse and prolong animal survival. Our findings shed mechanistic insight into EGFR drug resistance in glioma and provide a platform to test therapies targeting aberrant EGFR signaling in this setting.

Topics: Animals; Brain Neoplasms; Crizotinib; Cyclin-Dependent Kinase Inhibitor p16; Doxycycline; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Glioma; Humans; Imidazoles; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Phosphorylation; Protein Processing, Post-Translational; PTEN Phosphohydrolase; Pyrazoles; Pyridines; Quinazolines; Quinolines; Tumor Cells, Cultured

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Middle Aged; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bone Neoplasms; Brain Neoplasms; Carcinoma; Crizotinib; Fatal Outcome; Gene Rearrangement; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retreatment

With the widespread availability of biological antitumor drugs, the current scene of chemotherapies is changing. New chemotherapy agents, such as crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK) and ROS1, usually used in pretreated advanced ALK-positive non-small-cell lung carcinoma, are more often used, and a description of the onset of side effects with suggestions for their management could be of interest for physicians. We describe a case of diffuse and aggressive renal polycystosis induced by crizotinib, which regressed after therapy, which could be of interest considering its wide extension and disappearance after the end of treatment. We also suggest some considerations from the literature and from the case reported that could be helpful in the management of this condition, which is known to be caused by crizotinib treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy, Needle; Bone Neoplasms; Brain Neoplasms; Contrast Media; Crizotinib; Cysts; Humans; Kidney Diseases; Liver Neoplasms; Lung Neoplasms; Male; Microscopy, Electron; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Tomography, X-Ray Computed; Translocation, Genetic

Topics: Brain Neoplasms; Crizotinib; Female; Humans; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines

Limited post-crizotinib treatment options for ALK-positive non-small cell lung cancer (NSCLC) might lead to poor survival and high economic burden.. To evaluate real-world treatment patterns, overall survival (OS), and costs following crizotinib discontinuation.. This study used chart review and claims data. First, 27 participating US oncologists reviewed medical records of ALK-positive NSCLC patients who discontinued crizotinib monotherapy and reported patient demographic and clinical information, including post-crizotinib treatment and mortality. OS was estimated using Kaplan-Meier analyses. Second, three large administrative US claims databases were pooled. NSCLC patients were selected if they discontinued crizotinib monotherapy. Post-crizotinib costs were analyzed separately for patients who did or did not discontinue antineoplastic treatment after crizotinib monotherapy. All data were collected prior to ceritinib approval for this patient population.. A total of 119 ALK-positive NSCLC patients discontinued crizotinib monotherapy. Upon discontinuation, 42% had no additional antineoplastic treatment and 13% received radiation therapy only. The median OS post-crizotinib was 61 days; patients with brain metastases had shorter OS than those who did not (44 vs. 69 days, P = 0.018), and patients without further antineoplastic treatment had shorter OS than those who did (17 vs. 180 days, P < 0.001). From claims data, 305 ALK-positive NSCLC patients discontinued crizotinib monotherapy. After discontinuation, 72% had no additional antineoplastic treatment. Among patients who continued antineoplastic treatment, monthly healthcare costs averaged $22,160, driven by pharmacy ($9202), inpatient ($6419), and outpatient radiotherapy ($2888) and imaging ($1179) costs. Among patients who discontinued any antineoplastic treatment, monthly healthcare costs averaged $3423, mostly driven by inpatient costs ($2074).. After crizotinib monotherapy, most patients either received radiotherapy only or discontinued antineoplastic treatment altogether. OS after discontinuing crizotinib was poor and shorter among those with brain metastases than without, and among those without subsequent antineoplastic treatment than with. Patients who continued antineoplastic treatment incurred substantial healthcare costs.

Topics: Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Health Care Costs; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Topics: Adult; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Crizotinib; Female; Humans; Lung Neoplasms; Microtubule-Associated Proteins; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases; Translocation, Genetic

Two patients with an unmethylated MGMT promoter and IDH1 (R132H) wild-type recurrent glioblastoma were treated with crizotinib. Prolonged stabilization of the disease (17 months) was achieved in the first case. Interestingly, anaplastic lymphoma kinase (ALK) expression and c-MET protein overexpression was observed. Conversely, no response to crizotinib was obtained in the second case with MET protein overexpression and c-MET amplification but no ALK expression or ALK gene amplification. These case studies suggest that novel targeted ALK inhibitors may provide relevant clinical benefit in selected cases in which driver mutations are demonstrable.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain; Brain Neoplasms; Crizotinib; DNA Modification Methylases; DNA Repair Enzymes; Female; Follow-Up Studies; Glioblastoma; Humans; Immunohistochemistry; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Male; Middle Aged; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Tumor Suppressor Proteins

Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. We show that the RTKs MET, EGFR, and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human tumors and cancer stem cells and that its expression inversely correlates with the activation of MET, EGFR, and PDGFR. We demonstrate that miR-134 inhibits cancer cell and stem-cell proliferation, survival, and xenograft growth, as well as cancer stem-cell self-renewal and stemness. We identify KRAS and STAT5B as targets of miR-134, and establish molecular and functional links between RTKs, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. We show that miR-134 induction is required for the anti-tumor effects of RTK inhibitors. We also uncover the molecular pathways through which RTKs regulate miR-134 expression and demonstrate the involvement of MAPK signaling and the KLF4 transcription factor. We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Growth Processes; Cell Line, Tumor; Crizotinib; Glioblastoma; Humans; Kruppel-Like Factor 4; Mice; MicroRNAs; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyrazoles; Pyridines; ras Proteins; Receptor Protein-Tyrosine Kinases; STAT5 Transcription Factor; Transfection

Topics: Adult; Anaplastic Lymphoma Kinase; Bone Neoplasms; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Drug Resistance, Multiple; Female; Gene Fusion; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases

Although crizotinib manifests marked antitumor activity in individuals with non-small-cell lung cancer positive for ALK abnormalities, all treated patients ultimately develop resistance to this drug. The central nervous system (CNS) is a frequent site of disease progression in such patients, with palliative radiotherapy usually being administered for the CNS metastasis. However, subsequent chemotherapy has not been optimized in these patients.. We retrospectively evaluated the continuation of crizotinib treatment after radiotherapy for isolated CNS progression in ALK-rearrangement-positive non-small-cell lung cancer patients.. Among 21 ALK-rearrangement-positive patients treated with crizotinib, seven individuals resumed daily crizotinib administration after the completion of radiotherapy for isolated CNS failure. All these patients continued to receive crizotinib for at least 4 months after radiotherapy without disease progression. One patient experienced a recurrent isolated CNS failure during the second period of crizotinib administration but subsequently resumed crizotinib treatment again for at least 8.5 months after another application of radiotherapy.. Development of isolated CNS metastasis is emerging as a clinical concern for patients treated with crizotinib. Our data suggest that continued administration of crizotinib after radiotherapy for isolated CNS progression is a potential treatment option for such patients.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Disease-Free Survival; Female; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiosurgery; Radiotherapy; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Topics: Adenocarcinoma; Adult; Bone Neoplasms; Brain Neoplasms; Crizotinib; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrazoles; Pyridines

Anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC) is highly responsive to crizotinib, an oral ATP-competitive selective inhibitor of ALK. However, crizotinib exhibits extremely poor blood-brain barrier penetration; therefore, it is considered to play a limited role in the treatment of brain metastases. We present a case of a 50-year-old man with a diagnosis of ALK-rearranged NSCLC with brain metastasis and malignant pleural effusion. Despite the several systemic chemotherapy regimens and whole brain radiotherapy, brain metastasis was refractory; therefore, crizotinib was initiated. A CT scan showed a slight reduction in the brain metastasis and no change in intrathoracic disease 17 weeks after initiating crizotinib. Moreover, CT obtained 12 months after crizotinib treatment revealed brain metastasis without progression. To our knowledge, the present case is the second report of crizotinib-responsive brain metastases due to echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK)-rearranged NSCLC.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Humans; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA, Neoplasm; Female; Gene Rearrangement; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Middle Aged; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Crizotinib; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Pemetrexed; Pyrazoles; Pyridines; Radiosurgery; Receptor Protein-Tyrosine Kinases

Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis.

Topics: Analysis of Variance; Animals; Brain Neoplasms; Breast Neoplasms; Chemoradiotherapy; Crizotinib; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Mice; Piperidines; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Radiation Tolerance; Real-Time Polymerase Chain Reaction; RNA, Small Interfering; Signal Transduction; Tumor Cells, Cultured

Topics: Brain Neoplasms; Crizotinib; Epithelial-Mesenchymal Transition; Female; Gene Amplification; Glioblastoma; Humans; Middle Aged; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Radiography

Topics: Abdominal Neoplasms; Aftercare; Brain Neoplasms; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Middle Aged; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines

Advanced non-small lung cancer (NSCLC) remains almost uniformly lethal with marginal long-term survival despite efforts to target specific oncogenic addiction pathways that may drive these tumors with small molecularly targeted agents and biologics. The EML4-ALK fusion gene encodes a chimeric tyrosine kinase that activates the Ras signaling pathway, and this fusion protein is found in approximately 5% of NSCLC. Targeting EML4-ALK with Crizotinib in this subset of NSCLC has documented therapeutic efficacy, but the vast majority of patients eventually develop recurrent disease that is often refractory to further treatments. We present the clinicopathologic features of three patients with metastatic NSCLC harboring the EML4-ALK translocation that developed isolated central nervous system (CNS) metastases in the presence of good disease control elsewhere in the body. These cases suggest a differential response of NSCLC to Crizotinib in the brain in comparison to other sites of disease, and are consistent with a previous report of poor CNS penetration of Crizotinib. Results of ongoing clinical trials will clarify whether the CNS is a major sanctuary site for EML4-ALK positive NSCLC being treated with Crizotinib. While understanding molecular mechanisms of resistance is critical to overcome therapeutic resistance, understanding physiologic mechanisms of resistance through analyzing anatomic patterns of failure may be equally crucial to improve long-term survival for patients with EML4-ALK translocation positive NSCLC.

Topics: Adult; Brain; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Translocation, Genetic

Few descriptions of miliary brain metastases have been reported. We report the case of an adenocarcinoma of the lung associated with metachronous miliary brain and lung metastases with an echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) gene translocation. The patient was treated with crizotinib and showed a twelve-month progression-free survival. Clinicians should be attentive of the evolution of brain metastases with patients presenting EML4-ALK translocation.

Topics: Adenocarcinoma; Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Cisplatin; Crizotinib; Deoxycytidine; DNA Mutational Analysis; Fatal Outcome; Female; Gemcitabine; Humans; Lung Neoplasms; Molecular Diagnostic Techniques; Oncogene Proteins, Fusion; Pyrazoles; Pyridines; Translocation, Genetic

Many patients with oncogene-driven non-small-cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to central nervous system (CNS) and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively.. Patients with metastatic ALK+ NSCLC treated with crizotinib (n = 38) and EGFR-MT NSCLC treated with erlotinib (n = 27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression-free survival (PFS1), and site of first progression were recorded. A subset of patients with either nonleptomeningeal CNS and/or four sites or fewer of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same tyrosine kinase inhibitors. The subsequent median progression-free survival from the time of first progression (PFS2) and pattern of progression were recorded.. Median progression-free survival in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. Twenty-five of 51 patients (49%) who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, one with surgery) and continuation of the same targeted therapy. Post-LAT, 19 of 25 patients progressed again, with median PFS2 of 6.2 months.. Oncogene-addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with more than 6 months of additional disease control.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Catheter Ablation; Combined Modality Therapy; Crizotinib; Disease Progression; ErbB Receptors; Erlotinib Hydrochloride; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Quinazolines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Survival Rate; Young Adult