Trial Of Crizotinib Research Articles

Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study.

MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. UMIN000031623.

O13-5 Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: Co-MET study

Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in <1%. Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases showed activity in cancer models with various types of MET activation.

CNS Metastases in Patients With MET Exon 14-Altered Lung Cancers and Outcomes With Crizotinib.

Although MET exon 14 (METex14)-altered lung cancers were first identified more than a decade and a half ago, the frequency of CNS metastatic disease remains poorly defined. Furthermore, the seminal trial of crizotinib in these patients (PROFILE 1001) did not report patterns of CNS response or progression. Patients with pathologically confirmed, advanced non-small-cell lung cancers (NSCLC) harboring a METex14 alteration by targeted DNA/RNA sequencing were studied. The incidence of brain metastases and the outcomes of MET inhibition with crizotinib were analyzed. Eighty-three patients with METex14-altered metastatic NSCLC were identified. The incidence of CNS metastases at diagnosis was 17% (95% CI, 10% to 27%). The lifetime incidence was 36% (95% CI, 26% to 47%); 83% of patients had parenchymal disease, and 17% had leptomeningeal disease. The probability of having brain metastasis at 1, 2, and 3 years was 24%, 35%, and 38%, respectively. Fifty-four patients received crizotinib. The median time to radiologic CNS progression was 5.8 months (range, 3.7-20.0 months). Patterns of crizotinib progression were as follows: intracranial only in 10% of patients, intracranial and extracranial in 12%, and extracranial only in 78%. In patients with brain metastases before treatment, the median time on crizotinib was 7.5 months (range, 7.2-11.7 months). CNS metastases, including leptomeningeal disease, occurred in more than a third of patients with METex14-altered lung cancers. In crizotinib-treated patients with or without CNS metastases, CNS failure was seen in less than a quarter of patients on progression.

Ophthalmological assessment of crizotinib in advanced non-small-cell lung cancer

ObjectivesDuring crizotinib clinical evaluation, visual disturbances, generally of grade 1 severity, were frequently reported adverse events (AE). Consequently, ophthalmologic assessments were included in a patient subgroup enrolled in PROFILE 1001 (NCT00585195), a phase 1, open-label, single-arm trial of crizotinib in patients with advanced non-small-cell lung cancer and are reported here. Materials and methodsAt least 30 patients were required to undergo ophthalmologic assessments, including: best-corrected visual acuity (BCVA), refractive error, pupil size, slit-lamp anterior segment biomicroscopy, intraocular inflammation, intraocular pressure, retinal fundoscopic exams, fundus photography, ocular characteristics, and optical coherence tomography (OCT). Scheduled assessments included those at baseline, Cycle 1 Day 15, Cycle 3 Day 1 (C3D1), annually during treatment, and end of treatment (28 days after last crizotinib dose). ResultsThirty-three patients completed all required ophthalmologic assessments through C3D1, and 22 (66.7 %) had abnormal findings on ≥1 ophthalmologic test. Clinically important changes were ≥2-line loss in BCVA in 10 patients (30.3 %), >±1.25-diopter change in refractive error in 3 patients (9.1 %), >±2-mm change pupillary diameter change in 3 patients (9.1 %), and >50 μm increase in OCT center point thickness in 7 patients (21.2 %). Three patients (15 %) reported clinically significant abnormalities in anterior segment biomicroscopy (grade 1 cataract [n = 2], grade 1 Visual Impairment [n = 1]). No permanent treatment discontinuations were associated with ophthalmologic findings changes. Twenty-four patients (72.7 %) reported ≥1 ocular all-causality treatment-emergent AE (TEAE); none required dose reduction or permanent discontinuation, but 2 required temporary dosing interruption. Although TEAEs and ophthalmologic findings may not have occurred concurrently, of 24 patients with ≥1 all-causality ocular TEAE, 18/24 (75.0 %) had ≥1 abnormal ophthalmologic finding and 6/24 (25 %) had none; and of 9 patients without an all-causality ocular TEAE, 4/9 (44.4 %) had ≥1 abnormal ophthalmologic finding and 5/9 (55.6 %) had none. Of the 18 patients with ≥1 abnormal ophthalmologic finding, 9 (50 %) had preexisting ocular conditions. ConclusionDuring crizotinib treatment, ophthalmologic changes from baseline did not appear to be associated with patient-reported ocular TEAEs. Abnormal ophthalmologic findings occurred in the context of preexisting conditions for a number of patients. No ophthalmologic changes from baseline or ocular all-causality TEAEs required permanent treatment discontinuation.

Phase II, open-label, multicenter trial of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study

BackgroundMET-deregulated non-small cell lung cancer represents an urgent clinical need because of the lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET gene alterations, no conclusive data are currently available. Therefore, we designed the Co-MET study, a single-arm phase II study to assess the efficacy and safety of crizotinib in patients with advanced non-small cell lung cancers harboring MET gene alterations.MethodsCo-MET is an open-label, multi-center, single-arm, phase II trial to assess the safety and efficacy of oral crizotinib in patients with advanced non-small cell lung cancer harboring MET exon 14 skipping mutation (cohort 1) or a high MET gene copy number of ≥ 7 (cohort 2). We will identify MET gene alterations using RT-PCR and/or next-generation sequencing. Oral crizotinib 250 mg BID will be administered until disease progression or unacceptable toxicity. A radiology committee will review tumor scans according to the RECIST criteria. The primary endpoint is the objective response rate. Assuming a null hypothesis of 20% objective response rate and an alternative hypothesis of 50% objective response rate for cohort 1, and a one-sided alpha error of 0.05 and 80% power based on the exact binomial distribution, the required number of evaluable patients is 19. We set the exploratory sample size for cohort 2 at 10 patients.DiscussionThe results of this study are expected to provide evidence regarding the usefulness of oral crizotinib for advanced MET exon 14 skipping mutation-positive or MET high gene copy number-positive non-small cell lung cancer.Trial registrationThis study was registered with the University Hospital Medical Information Network Clinical Trials Registry as UMIN000031623 on 3 March 2018.

Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

Abstract CT045: Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 "CREATE"

Abstract Background: The multi-tumor phase 2 trial EORTC 90101 (NCT01524926) assessed the activity and safety of the ALK/MET/ROS1 inhibitor C in IMFT, an orphan malignancy associated with ALK rearrangement or copy number changes. Methods: Pts with local diagnosis of advanced/metastatic IMFT consented for shipment of a tumor tissue block and were screened for treatment after central confirmation of the diagnosis by reference pathology. Eligible ALK positive (+) and negative (-) pts received oral C 250 mg bid until RECIST 1.1 progression (PD). ALK+ was defined as at least 15% of tumor cells with rearrangement on FISH (Vysis LSI ALK Dual Color Break Apart Probe, Abbott Molecular) and/or immunohistochemical positivity (ALK MAb Clone CD246, DAKO). A Simon's optimal 2 stage design was implemented. If at least 2 out of the first 12 eligible and evaluable ALK+ pts achieved a confirmed RECIST 1.1 partial or complete response (PR, CR), a maximum of 35 pts were enrolled. If at least 6 had a confirmed PR/CR, the trial would be deemed successful. Results: Between 10/2012 and 04/2017, 13 sites in 8 European countries recruited 35 pts with a local diagnosis of IMFT, of whom only 20 had centrally confirmed IMFT and were treated with C. Among 12 eligible and evaluable ALK+ pts, 6 achieved a confirmed PR or CR, 1 a non-confirmed PR and 5 had stable disease (SD) as best response (ORR 50.0%, 95% confidence interval: 21.1-78.9%). Further efficacy endpoints in ALK+ pts: disease control rate (DCR = CR/PR/SD as best response) 100.0% (73.5-100.0%), 1-year (y) progression free rate (PFR) 73.3 % (37.9-90.6%), 1-y OS rate (OSR) 81.8% (44.7-95.1%). Among 7 eligible and evaluable ALK- pts, 1 achieved a PR, 5 had SD and 1 PD (ORR 14.3%, 0.0-57.9%). Further data in ALK- cases: DCR 85.7% (59.8-100.0%), 1-y PFR 53.6 % (13.2-82.5%), 1-y OSR 83.3% (27.3-97.5%). One additional ALK- case was non evaluable (no measurable disease at baseline). Common related adverse events were nausea (11/20 [55%]), fatigue (9/20 [45%]), blurred vision (9/20 [45%]), vomiting (7/20 [35%]), diarrhea (7/20 [35%]). Conclusions: EORTC can perform precision medicine phase II trials in ultra-rare cancers such as IMFT, with mandatory collection of tissue, real time reference pathology and genetic profiling. With an ORR of 50% and a DCR of 100% in ALK+ disease, C met pre-specified response rate criteria in this trial. The drug achieves long-lasting disease control in the vast majority of ALK+ pts. Sporadic responses and disease stabilization in ALK- cases either suggest limitations of the assays and their cut-offs for target positivity, or the presence of other oncogenic drivers/alternative fusions that may be sensitive to C. Based on the findings of this prospective trial, C should be considered as systemic treatment standard of care for this orphan disease. Citation Format: Patrick Schoffski, Jozef Sufliarsky, Hans Gelderblom, Jean-Yves Blay, Sandra J. Strauss, Silvia Stacchiotti, Piotr Rutkowski, Lars H. Lindner, Michael G. Leahy, Antoine Italiano, Nicolas Isambert, Maria Debiec-Rychter, Raf Sciot, Thomas Van Cann, Sandrine Marréaud, Axelle Nzokirantevye, Sandra Collette, Agnieszka Wozniak. Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 "CREATE" [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT045.

PD-L1 expression and response to immunotherapy in patients with MET exon 14-altered non-small cell lung cancers (NSCLC).

8512 Background: MET exon 14 skipping alterations ( METΔ14) are present in 4% of NSCLCs. Response to MET inhibition has been observed in ongoing prospective trials (44% response rate, phase 1 trial of crizotinib; Drilon et al ASCO 2016), however responses to other types or therapy, such as immunotherapy, is unknown. We evaluated the immunophenotype of METΔ14 lung cancers and response to PD-(L)-1-based immunotherapy. Methods: Pts with recurrent/metastatic NSCLC were eligible. METΔ14 was identified by broad hybrid capture-based next-generation sequencing (MSK-IMPACT). PD-L1 expression was determined by immunohistochemistry. Response to immune therapy was evaluated by RECIST v1.1. Results: 63 pts with METΔ14-positive non-small cell lung cancers were identified; 41 (65%) had sufficient tissue for PD-L1 analysis. Patient characteristics: median age 71 years, 58% female, median pack year smoking 5.85 years, histology: 73% (30/41) adenocarcinoma, 20% (8/41) pleomorphic carcinoma, 7% (3/41) squamous cell. Tumor PD-L1 expression was ≥50% in 44% (18/41, 95% CI 30-59%), 1-49% in 17% (7/41, 95% CI 8-32%), and &lt; 1 in 39% (16/41, 95% CI 26-54%). The median age for patients with METΔ14 and PD-L1 positive (≥1%) tumors was 65 years (range 49-87); 60% (15/25) of patients were female; Histology: 72% (18/25) adenocarcinoma, 24% (6/25) sarcomatoid carcinoma, and 4% (1/25) squamous cell carcinoma. Immunotherapy was given to 15 pts: nivolumab (5), pembrolizumab (3), atezolizumab (2), durvalumab (1), and ipilimumab+nivolumab (4). The overall response rate to immunotherapy was 13% (2/15, 95% CI 3-39%). Overall response was 33% (1/3; 95% CI 6-80%) in patients with tumors PD-L1 ≥50%, and 20% (1/5, 95%CI 2-64%) in patients with tumors PD-L1 0%. Time on therapy ranged from 2 weeks to 9.6+ months. Conclusions: A substantial proportion of NSCLCs harboring METΔ14 alterations express PD-L1. Despite frequent PD-L1 expression, responses to immunotherapy were overall uncommon and lower than that observed with targeted therapy for this genomically defined subset of patients with lung cancers. Further exploration of this subset may reveal important mechanisms of immunotherapy resistance in PD-L1 expressing tumors.

A Sensitive ALK Immunohistochemistry Companion Diagnostic Test Identifies Patients Eligible for Treatment with Crizotinib

IntroductionThe availability of high-quality, rigorously validated diagnostic tests that can be broadly implemented is necessary to efficiently identify patients with anaplastic lymphoma kinase (ALK)-positive NSCLC who can potentially benefit from treatment with crizotinib. Here we present data on the recently approved Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Tucson, AZ), the only immunohistochemistry (IHC)-based assay linked to treatment outcome. MethodsNSCLC specimens prospectively tested for anaplastic lymphoma receptor tyrosine kinase gene (ALK) status by flourescent in situ hybridization (FISH) in the PROFILE 1014 clinical trial of crizotinib versus chemotherapy (N = 1018, including 179 ALK-positive and 754 ALK-negative specimens) were evaluated using the ALK (D5F3) CDx assay. Hazard ratios for progression-free survival comparing crizotinib and chemotherapy for ALK IHC–positive patients and ALK FISH–positive patients, as well as for concordance with the enrollment ALK FISH assay, were determined. ResultsResults from both assays were obtained for 933 cases. Percent positive, negative, and overall agreement rates were 86.0% , 96.3%, and 94.3%, respectively. There were 53 discrepant cases, of which 25 were ALK FISH–positive/ALK IHC–negative and 28 were ALK FISH–negative/ALK IHC–positive. The hazard ratios using observed outcomes were 0.401 for ALK FISH–positive/ALK IHC–positive cases and 0.407 for all ALK FISH–positive cases tested with ALK IHC versus 0.454 for all ALK FISH–positive cases enrolled in the trial. Outcome data for ALK FISH–negative/ALK IHC–positive cases were not available for analysis. Between-reader agreement rates for ALK IHC involving three independent laboratories exceeded 98%. ConclusionsThe ALK (D5F3) CDx assay is a stand-alone companion diagnostic test for identification of patients for treatment with crizotinib. This automated assay provides an effective option to accurately and rapidly identify patients with ALK-positive NSCLC. The simple binary scoring algorithm results in high reader-to-reader precision.

MA07.05 EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results

MA07.05 EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results

ALK FISH positivity and crizotinib efficacy in patients (pts) with non-small cell lung cancer (NSCLC).

9062Background: Crizotinib trials provide a large dataset to evaluate the distribution of % ALK+ cells by FISH in ALK+ NSCLC and the association between degree of ALK positivity and clinical outcom...

Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma.

The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations. Thus, understanding mechanisms of resistance and defining circumvention strategies for the clinic is critical. The sensitivity of human neuroblastoma-derived cell lines, cell line-derived, and patient-derived xenograft (PDX) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide (topo/cyclo) was examined. Cultured cells and xenografts were evaluated for effects of these drugs on proliferation, signaling, and cell death, and assessment of synergy. In neuroblastoma murine xenografts harboring the most common ALK mutations, including those mutations associated with resistance to crizotinib (but not in those with wild-type ALK), crizotinib combined with topo/cyclo enhanced tumor responses and mouse event-free survival. Crizotinib + topo/cyclo showed synergistic cytotoxicity and higher caspase-dependent apoptosis than crizotinib or topo/cyclo alone in neuroblastoma cell lines with ALK aberrations (mutation or amplification). Combining crizotinib with chemotherapeutic agents commonly used in treating newly diagnosed patients with high-risk neuroblastoma restores sensitivity in preclinical models harboring both sensitive ALK aberrations and de novo-resistant ALK mutations. These data support clinical testing of crizotinib and conventional chemotherapy with the goal of integrating ALK inhibition into multiagent therapy for ALK-aberrant neuroblastoma patients.

Targeted Therapies for Lung Cancer.

Targeted therapies have become standard therapies for patients with non-small cell lung cancer (NSCLC). A phase III trial of carboplatin and paclitaxel with and without bevacizumab in patients with advanced NSCLC with non-squamous histology demonstrated a statistically significant improvement in efficacy. In patients with NSCLC with an activating epidermal growth factor receptor (EGFR) mutation (defined as exon 19 deletion and exon 21 L858R point mutation), phase III trials of EGFR tyrosine kinase inhibitors (TKI) compared to platinum-based chemotherapy have demonstrated superior efficacy in the first-line setting. In patients with NSCLC with anaplastic lymphoma kinase (ALK) rearrangements, phase III trials of crizotinib have demonstrated superior efficacy compared to platinum-pemetrexed in the first-line setting and standard chemotherapy in the second-line setting. A second-generation ALK inhibitor, ceritinib, is available for patients who have progressed after or were intolerant of crizotinib. Crizotinib has also demonstrated activity on patients with ROS1 rearrangements, and BRAF inhibitors (dabrafenib, vemurafenib) have demonstrated activity in patients with NSCLC with BRAF V600E mutation. The oncogenic mutations that are susceptible to targeted therapy are mainly found in non-squamous NSCLC. The development of targeted therapy in patients with squamous NSCLC has been more challenging due to the genomic complexity observed in the squamous histology and the low prevalence of EGFR, ALK, and ROS1 molecular alterations. A phase III trial of cisplatin and gemcitabine with and without necitumumab in patients with advanced NSCLC with squamous histology demonstrated a statistically significant improvement in progression-free and overall survival.

Recent advances in the treatment of non-small cell and small cell lung cancer.

Recent presentations at the American Society of Clinical Oncology (ASCO) meeting from 30 May to 3 June, 2014, will impact routine clinical care and the development of clinical trials in non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (ES-SCLC). Patients with activating epidermal growth factor receptor (EGFR) mutations, defined as exon 19 and exon 21 L858R point mutations, experience a high objective response rate and prolonged progression-free survival with EGFR tyrosine kinase inhibitors. However, inevitably, patients experience disease progression and the most common mechanism of acquired resistance is an EGFR exon 20 T790M mutation. Several agents (AZD9291, CO-1686 and HM61713) have demonstrated impressive activity in patients with T790M resistance mutations. Additional data on the efficacy of first-line therapy with afatinib and the combination of erlotinib and bevacizumab for patients with EGFR mutant NSCLC were presented. The results of a phase III trial of crizotinib compared to platinum-pemetrexed in the first-line setting, and a phase I trial and expansion cohort of ceritinib, provided additional efficacy and toxicity data for patients with anaplastic lymphoma kinase rearranged NSCLC. A phase III trial of cisplatin and gemcitabine, with and without necitumumab, revealed an improvement in overall survival with the addition of necitumumab in patients with squamous NSCLC. In the second-line setting, a phase III trial of docetaxel with ramucirumab or placebo revealed an improvement in overall survival with the addition of ramucirumab. In extensive stage small cell lung cancer phase III trials of consolidative thoracic radiation therapy and prophylactic cranial radiation failed to reveal an improvement in overall survival.

Patient-Reported Outcomes and Quality of Life in PROFILE 1007: A Randomized Trial of Crizotinib Compared with Chemotherapy in Previously Treated Patients with ALK-Positive Advanced Non–Small-Cell Lung Cancer

The main objective of the current post hoc analysis was to compare patient-reported outcomes between crizotinib (N = 172) and chemotherapy subgroups (pemetrexed [N = 99] and docetaxel [N = 72]) in previously treated patients with advanced ALK-positive non-small-cell lung cancer, in PROFILE 1007 study (Pfizer; NCT0093283). Patient-reported outcomes were assessed at baseline, day 1 of each cycle, and end of treatment. General health status was measured using the EuroQol-5D visual analog scale and health utility index scores were assessed using the EuroQol-5D descriptive system. Functioning, lung cancer symptoms, and global quality of life (QOL) were assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and the QLQ-LC13 lung cancer module. Repeated measures mixed-effects analyses compared overall scores and change from baseline scores, controlling for baseline scores. The overall mean EQ-5D health utility index scores (95% CI) on treatment were significantly greater (p < 0.05) for crizotinib (0.82 [0.79-0.85]) than for chemotherapy (0.73 [0.70-0.77]; 0.74 [0.70-0.79] for pemetrexed and 0.66 [0.58-0.74] for docetaxel). A significantly greater improvement from baseline was observed with crizotinib versus pemetrexed and versus docetaxel treatment groups for general health status, physical functioning, global QOL, dyspnea, fatigue, and pain. Improvement rates for fatigue, cough, pain, dyspnea, and global QOL were significantly greater on crizotinib compared with pemetrexed and docetaxel, respectively. Worsening rates for diarrhea and constipation were higher with crizotinib. The benefits of crizotinib in improving symptoms and QOL are demonstrated regardless of whether the comparator is pemetrexed or docetaxel.

Detecting ALK Fusions in Lung Cancer: Multiple Choice Testing?

173 ISSN 1758-1966 10.2217/LMT.13.15 © 2013 Future Medicine Ltd Lung Cancer Manage. (2013) 2(3), 173–175 ALK rearrangements to EML4 and other partners, such as KIF5B and TFG, are found in approximately 3–5% of nonsmall-cell lung cancer (NSCLC) cases [1,2]. As a result of the chromosomal re arrangements, a chimeric ALK protein containing the tyrosine kinase domain of ALK fused to the N-terminal region of its fusion partner becomes expressed, which mediates aberrant signal transduction, leading to uncontrolled cell growth. These ALK-driven tumors specifically rely on the fusion oncoprotein for growth and define a distinct patient subgroup that has been demonstrated to greatly benefit from targeted ALK inhibition. Crizotinib, an ALK/ROS1/MET kinase inhibitor, was approved by the US FDA for the treatment of locally advanced or metastatic NSCLC that is ALK positive as detected by an FDA-approved test in August 2011 [3]. The diagnostic methodologies for detecting ALK fusions include FISH, immunohistochemistry (IHC) and reverse transcription PCR (RT-PCR), each test having its own advantages and disadvantages. Clinical trials of crizotinib utilized a FISH-based test, the only test approved by the FDA as a companion diagnostic test for crizotinib treatment [1]. This assay uses two neighboring, differentially labeled ‘break-apart probes’, which specifically detect the 5 and 3 ends of the ALK gene, respectively [4]. Normally, the corresponding orange and green fluorescent signals are in very close proximity, whereas any ALK rearrangement spatially separates the probes and thereby their signals, resulting in distinct and isolated orange and green spots. At least 15% of all analyzed cells must be positive to score a break-apart signal [3,5,6]. The FISH test has been vigorously evaluated in clinical trials and is currently the gold standard for detecting ALK fusions. The major challenge of this diagnostic assay is that the ‘split’ signal can be subtle and requires specialized technical expertise to interpret. ALK fusions leading to overexpression of the C-terminal of the ALK protein (i.e., the kinase domain) offer the potential to use standard IHC to detect the rearrangement indirectly, as ALK expression is normally absent in lung tissue. IHC has been considered as a screening tool and can be quickly adopted by pathology laboratories. The test

Screening for RET and ROS1 fusions in an enriched cohort of pan-negative never-smokers with advanced lung adenocarcinomas to identify patients for treatment in targeted therapy trials.

8067 Background: RET and ROS1 fusions have been identified pre-clinically as drivers of tumor growth in lung adenocarcinomas. In addition, based on response to crizotinib in ROS1-positive tumors and emerging data on RET inhibition in some tumors, these fusions represent druggable targets. While each occurs in 1-2% of unselected patients, a screening paradigm based on testing never-smokers whose tumors have no known oncogenic mutations or fusions may enrich identification for ongoing clinical trials. Methods: Patients with a never-smoking history (&lt;100 lifetime cigarettes) and advanced pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MEK1, and AKT, and ALK fusions) were selected for testing. Screening for RET and ROS1 fusions was performed in real-time via dual-probe FISH breakapart assays, RT-PCR, and next-generation sequencing in selected cases. We enrolled patients onto a phase II trial of cabozantinib for RET fusion-positive lung cancers (NCT01639508) and, as part of the Lung Cancer Mutation Consortium (LCMC), a phase I trial of crizotinib for ROS1-positive lung cancers (NCT00585195). Results: Thirty five (n=35) never-smokers with advanced pan-negative lung adenocarcinomas were identified. A RET or ROS1 fusion was found in 31% [n=10/32, 95% CI, 15-47%] of patients. RET and ROS1 fusions were found in 15% [n=5/34, 95% CI, 3% - 27%] and 15% [n=5/33, 95% CI, 2%-27%] of patients, respectively. 1 patient had a novel TRIM33-RET fusion. 3 of 5 patients with RET fusion-positive tumors were eligible for treatment with cabozantinib, 2 of which had partial responses to therapy. 1 of 5 patients with ROS1 fusion-positive tumors was treated on-protocol with crizotinib and achieved a partial response. Conclusions: 31% of never-smokers with pan-negative advanced lung adenocarcinomas harbor a gene fusion involving either RET or ROS1. Until multiplexed mutation and fusion testing is routinely available, targeting this population for screening represents an interim enrichment strategy for patient identification and enrollment on clinical trials where responses are already being documented.

Heart rate decrease during crizotinib treatment and potential correlation to clinical response

Crizotinib is used for the treatment of advanced anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC). Sinus bradycardia (SB) is a side effect listed in its package insert. We investigated the frequency and timing of SB, patient characteristics associated with SB during crizotinib treatment, and potential correlation between heart rate (HR) changes and clinical response to crizotinib. A retrospective chart review was conducted of the timing and frequency of SB, patient characteristics, and clinical response of patients to crizotinib treatment. Forty-twp patients who had ALK-rearranged or mesenchymal epithelial transition (MET)-amplified NSCLC and received treatment with oral crizotinib 250 mg twice daily who were enrolled in 2 crizotinib trials (PROFILE 1001 and PROFILE 1005) were analyzed. There was an average decrease of 26.1 beats per minute (bpm) from the pretreatment HR among all patients during crizotinib treatment. Twenty-nine patients (69%) experienced at least 1 episode of SB (HR, <60 bpm). The average time to the lowest HR recorded was 18.6 weeks (range, 5-72 weeks). Patients who experienced SB were significantly older (aged 55.8 years vs 47.8 years; P = .0336), had a lower pretreatment HR (mean, 77.9 bpm vs 100.6 bpm; P = .002), and were on crizotinib longer (52.9 weeks vs 24.6 weeks; P = .0050) than patients who did not experience SB. The overall response rate (P = .0195) and the maximum tumor shrinkage (P = .0205) were significantly greater in patients who experienced SB. HR decrease is common during crizotinib treatment. It remains to be determined whether the correlation between HR decrease and clinical response to crizotinib reflects a biomarker of drug efficacy or a time/cumulative dose-dependent phenomenon.

AJ-5 - Biomarker-Based Drug Development in NSCLC

ABSTRACT Clinical trials of targeted therapies in genetically defined patient populations of non-small-cell lung cancer (NSCLC) patients have been very successful. Compelling clincal examples include gefitinib or erlotinib in epidermal growth factor receptor (EGFR) mutant NSCLC and crizotinib in anaplastic lymphoma kinase (ALK) rearranged NSCLC. Multiple clinical trials have demonstrated an improvement in both response rate (RR) and progression-free survival (PFS) for gefitinib or erlotinib compared with chemotherapy in EGFR mutant NSCLC. However, clinical trials in broader populations of NSCLC (not selected for an EGFR mutation) demonstrated either equivalence or worsening of outcomes compared with chemotherapy. Phase III clinical trials of crizotinib compared with chemotherapy are underway in ALK rearranged NSCLC. Although genomic alterations, especially those involving kinases, make compelling therapeutic targets in NSCLC, several challenges remain. Many of these, including HER2 mutations, BRAF mutations, ROSI rearrangements and RET rearrangements, represent small subsets of NSCLC. Thus a systematic method of identifying such patients is necessary. The presentation will discuss approaches currently underway to identify a broad range of genomic alterations. In addition, the challenges of performing clinical trials in small populations are discussed. Given that there are not sufficient numbers of patients to test every therapeutic approach, model systems such as mouse models of lung cancer are needed to prioritize which therapies ultimately to pursue through clinical trials.

SY14-3 - Treatment of EML4-ALK Rearranged NSCLC

ABSTRACT Rearrangements in the anaplastic lymphoma kinase (ALK) gene have been detected in ∼3–7% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, an ALK tyrosine kinase inhibitor (TKI), is clinically effective in NSCLC patients with ALK rearrangements. In the phase I clinical trial, a radiographic response rate of 54% was observed. Crizotinib was recently approved by the FDA for the treatment of ALK-positive NSLC. Current clinical trials of crizotinib include two randomized phase III clinical trials. The first compares crizotinib to second-line chemotherapy (either pemetrexed or docetaxel) in ALK-positive NSCLC patients that have failed first-line platinum-based chemotherapy. The second trial compares crizotinib with cisplatin (or carboplatin) and pemetrexed in treatment naive advanced NSCLC ALK positive patients. In addition to ALK TKIs, inhibitors of heat shock protein (HSP) 90 have demonstrated some clinical activity in EML4-ALK NSCL and are undergoing additional clinical evaluation. However, despite the impressive clinical efficacy of crizotinib, it is fully anticipated that acquired drug resistance will emerge. Drug resistance mechanisms can in general be divided into two categories: those that result in secondary mutations in the target itself (i.e. ALK) or those that activate parallel signaling pathways. For ALK-positive cancers both mechanisms have been identified to date. Secondary mutations in ALK to date include L1196M, F1174L, C1156Y and L1152R. One example of an alternative signaling pathway that leads to ALK TKI resistance is EGFR. In vitro, some ALK TKI-resistant cell lines have activated EGFR signaling (via EGFR ligands) that promote crizotinib resistance. The knowledge of a specific drug resistance mechanism is important for choosing the next treatment of ALK positive patients that have developed Crizotinib resistance. In those with evidence of an ALK secondary mutation a more potent ALK inhibitor may be effective. There are several such in preclinical and at least three in phase I clinical development. In cancers harboring activated signaling pathways (such as EGFR) an alternative strategy, a combination of an ALK and EGFR inhibitor, may be effective. A phase I clinical trial is underway combining Crizotinib with the pan-ERBB inhibitor PF299804.