A Phase 2 Study of Capmatinib in Patients With MET-Altered Lung Cancer Previously Treated With a MET Inhibitor

Abstract

Introduction: Capmatinib is approved for MET exon 14-altered NSCLC on the basis of activity in targeted therapy-naive patients. We conducted a phase 2 study to assess the efficacy of capmatinib in patients previously treated with a MET inhibitor.

Methods: Patients with advanced NSCLC harboring MET amplification or MET exon 14 skipping alterations received capmatinib 400 mg twice daily. The primary end point was the objective response rate. Secondary end points included progression-free survival, disease control rate (DCR), intracranial response rate, and overall survival. Circulating tumor DNA was analyzed to identify capmatinib resistance mechanisms.

Results: A total of 20 patients were enrolled between May 2016 and November 2019, including 15 patients with MET skipping alterations and five patients with MET amplification. All patients had received crizotinib; three had also received other MET-directed therapies. The median interval between crizotinib and capmatinib was 22 days (range: 4-374). Two patients (10%) achieved an objective response to capmatinib and 14 had stable disease, yielding a DCR of 80%. Among five patients who discontinued crizotinib for intolerance, the DCR was 83%, including two patients with the best tumor shrinkage of -25% and -28%. Intracranial DCR among four patients with measurable brain metastases was 100%, with no observed intracranial objective responses. Overall, the median progression-free survival and overall survival were 5.5 (95% confidence interval: 1.3-11.0) and 11.3 (95% confidence interval: 5.5-not reached) months, respectively. MET D1228 and Y1230 mutations and MAPK alterations were recurrently detected in postcrizotinib, precapmatinib plasma. New and persistent MET mutations and MAPK pathway alterations were detected in plasma at progression on capmatinib.

Conclusions: Capmatinib has modest activity in crizotinib-pretreated MET-altered NSCLC, potentially owing to overlapping resistance mechanisms.

Keywords: Capmatinib; Lung cancer; MET amplification; MET skipping.

Figure 1.. Activity of Capmatinib in MET-Altered Lung Cancer.

(A) Waterfall plot depicts best tumor response as assessed by RECIST version 1.1. Secondary MET mutations detected in plasma analyzed immediately prior to treatment with capmatinib are listed above bars corresponding to individual patients. MET copy number is listed under the bars for patients with MET amplification, as determined by fluorescence in-situ hybridization using MET: centromeric probe 7 ratio or plasma genotyping. Absolute copy number was not provided for one patient. For patients who discontinued crizotinib for reasons other than extracranial progression, reason for stopping crizotinib is indicated by asterisk or chevron. (B) The treatment history for MGH9252 is illustrated above contrast enhanced CT images demonstrating decrease in the size of a right upper lobe mass (asterisk) after 6 weeks of treatment with capmatinib. (C) MGH9235’s treatment history is outlined above serial CT scans demonstrating decrease in a lingula mass (arrowhead), lymphangitic carcinomatosis (arrow), and pleural effusion (asterisk) after 6 weeks on capmatinib. *Capmatinib was discontinued after 8 weeks due to a stroke that was unrelated to study drug. (D) Swimmer plot illustrates progression-free survival on capmatinib for each patient (row). For patients with MET amplification, MET copy number is noted, as determined by fluorescence in-situ hybridization (ratio of MET to centromeric probe 7) or plasma next-generation sequencing (asterisk). A patient found to have MET amplification by FoundationOne next-generation sequencing assay for whom absolute copy number was not available is indicated with double asterisk (**). CNS: central nervous system; Carbo: carboplatin; pem: pemetrexed; Pembro: pembrolizumab; SD: stable disease; PR: partial response; PD: disease progression, Tx: treatment.

Figure 1.. Activity of Capmatinib in MET-Altered Lung Cancer.

(A) Waterfall plot depicts best tumor response as assessed by RECIST version 1.1. Secondary MET mutations detected in plasma analyzed immediately prior to treatment with capmatinib are listed above bars corresponding to individual patients. MET copy number is listed under the bars for patients with MET amplification, as determined by fluorescence in-situ hybridization using MET: centromeric probe 7 ratio or plasma genotyping. Absolute copy number was not provided for one patient. For patients who discontinued crizotinib for reasons other than extracranial progression, reason for stopping crizotinib is indicated by asterisk or chevron. (B) The treatment history for MGH9252 is illustrated above contrast enhanced CT images demonstrating decrease in the size of a right upper lobe mass (asterisk) after 6 weeks of treatment with capmatinib. (C) MGH9235’s treatment history is outlined above serial CT scans demonstrating decrease in a lingula mass (arrowhead), lymphangitic carcinomatosis (arrow), and pleural effusion (asterisk) after 6 weeks on capmatinib. *Capmatinib was discontinued after 8 weeks due to a stroke that was unrelated to study drug. (D) Swimmer plot illustrates progression-free survival on capmatinib for each patient (row). For patients with MET amplification, MET copy number is noted, as determined by fluorescence in-situ hybridization (ratio of MET to centromeric probe 7) or plasma next-generation sequencing (asterisk). A patient found to have MET amplification by FoundationOne next-generation sequencing assay for whom absolute copy number was not available is indicated with double asterisk (**). CNS: central nervous system; Carbo: carboplatin; pem: pemetrexed; Pembro: pembrolizumab; SD: stable disease; PR: partial response; PD: disease progression, Tx: treatment.

Figure 2.. Progression-Free and Overall Survival of Patients Treated with Capmatinib.

Kaplan-Meier curves depict progression-free (A) and overall survival (B) on capmatinib among study participants.

Figure 3.. Genetic Alterations in Pre- and Post-Capmatinib Plasma Specimens.

(A) Heatmap illustrates findings in pre-capmatinib and post-capmatinib plasma specimens from 10 patients with paired specimens. Colors in legend correspond to reason for discontinuing crizotinib (crizotinib row) and best response to capmatinib (capmatinib row). Gray box: not applicable (crizotinib and capmatinib rows). PD: disease progression; PR: partial response; SD: stable disease; tox: toxicity. (B) Molecular alterations detected in plasma from 13 patients relapsing on capmatinib. Each slice corresponds to a single patient. Amp: amplification; del: deletion; mut: mutation.