Lung Cancer Harboring MET Exon Research Articles

Health Utility Analysis of Tepotinib in Patients With Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping

ObjectivesThe VISION trial showed durable activity of tepotinib in MET exon 14 (METex14) skipping non-small cell lung cancer. We analyzed health state utilities using patient-reported outcomes from VISION. Methods5-level version of EQ-5D (EQ-5D-5L) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 responses were collected at baseline, every 6 to 12 weeks during treatment, and at the end of treatment and safety follow-up. EQ-5D-5L and European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D) utilities were derived using United States, Canada, United Kingdom, and Taiwan value sets, where available. Utilities were analyzed with linear mixed models including covariates for progression or time-to-death (TTD). ResultsUtilities were derived for 273/291 patients (EQ-5D-5L, 1545 observations; QLU-C10D, 1546 observations). Mean (± SD) US EQ-5D-5L utilities increased after tepotinib initiation, from 0.687 ± 0.287 at baseline to 0.754 ± 0.250 before independently assessed progression, and decreased post progression (0.704 ± 0.288). US QLU-C10D utilities showed similar trends (0.705 ± 0.215, 0.753 ± 0.195, and 0.708 ± 0.209, respectively). Progression-based models demonstrated a statistically significant impact of progression on utilities and predicted higher utilities pre versus post progression. TTD-based models showed statistically significant associations of TTD with utilities and predicted declining utilities as TTD decreased. Prior treatment (yes/no) did not significantly predict utilities in progression- or TTD-based models. Utilities for Canada, United Kingdom, and Taiwan showed comparable trends. ConclusionsIn this first analysis of health state utilities in patients with METex14 skipping non-small cell lung cancer, who received tepotinib, utilities were significantly associated with progression and TTD, but not prior treatment.

EP08.02-126 The MOMENT Disease Registry of Patients with Advanced Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping

MET exon 14 (METex14) skipping activates oncogenic MET signaling in 3-4% of patients with non-small cell lung cancer (NSCLC). The low frequency of this alteration has influenced the investigation of MET inhibitors, often leading to an open-label, single-arm trial design, in order to maximize the number of patients receiving these compounds. One example is the global Phase II VISION single-arm study of the oral, highly selective MET inhibitor tepotinib in patients with METex14 skipping NSCLC, in which tepotinib demonstrated robust and durable activity with an objective response rate of 49.1% (data cut off: Feb 1, 2021).

Translational pharmacokinetic-pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose.

Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first‐in‐human (FIH) trial, an efficacy‐driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP‐4 pancreatic cell‐line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model. Further clinical PK and target inhibition data (derived from predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs and target inhibition profiles from the mouse xenograft study to establish a translational PK/pharmacodynamic (PD) model. Preclinical data showed that tumor regression with tepotinib treatment in KP‐4 xenograft tumors corresponded to 95% target inhibition. We therefore concluded that a PD criterion of sustained, near‐to‐complete (>95%) phospho‐MET inhibition in tumors should be targeted for tepotinib to be effective. Simulations of dose‐dependent target inhibition profiles in human tumors that exceeded the PD threshold in more than 90% of patients established an RP2D of tepotinib 500 mg once daily. This translational mathematical modeling approach supports an efficacy‐driven rationale for tepotinib phase II dose selection of 500 mg once daily. Tepotinib at this dose has obtained regulatory approval for the treatment of patients with non‐small cell lung cancer harboring MET exon 14 skipping.

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.

Sensitivity and Resistance of MET Exon 14 Mutations in Lung Cancer to Eight MET Tyrosine Kinase Inhibitors In Vitro

BackgroundMNNG HOS transforming gene (MET) exon 14 mutations in lung cancer, including exon 14 skipping and point mutations, have been attracting the attention of thoracic oncologists as new therapeutic targets. Tumors with these mutations almost always acquire resistance, which also occurs in other oncogene-addicted lung cancers. However, the resistance mechanisms and treatment strategies are not fully understood. MethodsWe generated Ba/F3 cells expressing MET exon 14 mutations by retroviral gene transfer. The sensitivities of these cells to eight MET-tyrosine kinase inhibitors (TKIs) were determined using a colorimetric assay. In addition, using N-ethyl-N-nitrosourea mutagenesis, we generated resistant clones, searched for secondary MET mutations, and then examined the sensitivities of these resistant cells to different TKIs. ResultsBa/F3 cells transfected with MET mutations grew in the absence of interleukin-3, indicating their oncogenic activity. These cells were sensitive to all MET-TKIs except tivantinib. We identified a variety of secondary mutations. D1228 and Y1230 were common sites for resistance mutations for type I TKIs, which bind the active form of MET, whereas L1195 and F1200 were common sites for type II TKIs, which bind the inactive form. In general, resistance mutations against type I were sensitive to type II, and vice versa. ConclusionsMET-TKIs inhibited the growth of cells with MET exon 14 mutations. We also identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 mutations.

Impact of MET inhibitors on survival among patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis

ObjectivesAlthough dramatic responses to MET inhibitors have been reported in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC), the impact of these treatments on overall survival in this population is unknown. MethodsWe conducted a multicenter retrospective analysis of patients with METex14 NSCLC to determine if treatment with MET inhibitors impacts median overall survival (mOS). Event-time distributions were estimated using the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox models were fitted to estimate hazard ratios. ResultsWe identified 148 patients with METex14 NSCLC; the median age was 72; 57% were women and 39% were never smokers. Of the 34 metastatic patients who never received a MET inhibitor, the mOS was 8.1 months; those in this group with concurrent MET amplification had a trend toward worse survival compared to cancers without MET amplification (5.2 months vs 10.5 months, P = 0.06). Of the 27 metastatic patients who received at least one MET inhibitor the mOS was 24.6 months. A model adjusting for receipt of a MET inhibitor as first- or second-line therapy as a time-dependent covariate demonstrated that treatment with a MET inhibitor was associated with a significant prolongation in survival (HR 0.11, 95% CI 0.01-0.92, P = 0.04) compared to patients who did not receive any MET inhibitor. Among 22 patients treated with crizotinib, the median progression-free survival was 7.4 months. DiscussionFor patients with METex14 NSCLC, treatment with a MET inhibitor is associated with an improvement in overall survival.

Abstract A097: Phase II trial of the c-Met inhibitor tepotinib in patients with advanced non-small cell lung cancer harboring MET exon 14-skipping mutations

Abstract Background: Approximately 3-4% of non-small cell lung cancers (NSCLCs) harbor activating mutations of the MET proto-oncogene that cause exon 14 skipping (METex14) and accumulation of c-Met lacking a juxtamembrane domain. Such tumors are sensitive to nonselective kinase inhibitors with activity against c-Met, so selective c-Met inhibitors may have greater efficacy and/or tolerability. This single-arm phase II trial (NCT02864992) is investigating the efficacy and safety of the potent and selective c-Met inhibitor tepotinib in patients (pts) with NSCLC harboring METex14. Methods: Eligible patients (pts) are adults with stage IIIB/IV NSCLC and METex14 mutations identified in tumor and/or circulating tumor DNA (ctDNA) in plasma (liquid biopsy) by a central laboratory. Pts with EGFR-activating mutations, ALK rearrangements, or >2 lines of prior therapy are excluded. Pts receive tepotinib 500 mg QD on a 21-day cycle until disease progression, intolerable toxicity, or withdrawal from treatment for other reasons. Primary endpoint: objective response rate (ORR). Secondary endpoints: progression-free and overall survival, safety, pharmacokinetics, and quality of life. Recruitment of up to 120 (minimum 60 tumor, 60 ctDNA METex14-positive) pts in Europe, USA, and Japan is planned. Results: Five pts (age 55-77 years; 4 stage IV, 1 stage IIIB; all male; 4 Caucasian, 1 Asian) have been enrolled. Pts have currently completed 0-8 cycles of tepotinib therapy. Most adverse events observed to date have been grade 1/2 in severity, mostly unrelated to tepotinib treatment. One grade ≥3 tepotinib-related AE has occurred: grade 3 increased serum amylase. One pt has died due to his disease. Of the four pts with post-baseline tumor evaluations, two have confirmed partial response, one unconfirmed partial response, and one (with only one post-baseline assessment) stable disease. Conclusions: Initial data suggest that tepotinib 500 mg QD has promising activity in METex14 NSCLC. The safety profile of tepotinib appears favorable. Recruitment to the trial is ongoing. Citation Format: Enriqueta Felip, Remi Veillon, Santiago Viteri, Jürgen Scheele, Rolf Bruns, Paul K. Paik. Phase II trial of the c-Met inhibitor tepotinib in patients with advanced non-small cell lung cancer harboring MET exon 14-skipping mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A097.

MTE11.01 The Clinical Impact of the 2015 WHO Classification of Lung Tumors

MTE11.01 The Clinical Impact of the 2015 WHO Classification of Lung Tumors