BACKGROUNDAmong patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODSWe conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTSA total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONSCapmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.
9004 Background: Capmatinib is a highly potent and selective MET inhibitor. Previous data of GEOMETRY mono-1 study showed a clinically meaningful overall response rate (ORR) and manageable toxicity profile in patients (pts) with METΔex14–mutated NSCLC who received 1–2 prior lines of treatment (tx) (Cohort 4) and in particular a high ORR in tx-naïve pts (Cohort 5b). Here we report the results in METΔex14–mutated NSCLC for duration of response (DOR) and progression-free survival (PFS) as well as the updated results for ORR. Methods: GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in pts with METΔex14-mutated or MET-amplified advanced NSCLC across 6 cohorts. Pts (≥18 yrs) with ECOG PS 0–1, ALK and EGFR wt, and stage IIIB/IV NSCLC were eligible. Pts with METΔex14 mutation (centrally confirmed) were assigned (regardless of MET amplification status/gene copy number) to Cohorts 4 and 5b and received capmatinib tablets 400 mg BID. Primary endpoint was ORR by Blinded Independent Review Committee (BIRC) per RECIST v1.1. Key secondary endpoint was DOR by BIRC. Results: As of Nov 08, 2018, 97 pts with METΔex14-mutated NSCLC (Cohort 4: 69 pts; Cohort 5b: 28 pts) were evaluable for efficacy. ORR (95% CI) by BIRC was 39.1% (27.6-51.6) in Cohort 4 and 71.4% (51.3-86.8) in Cohort 5b. While still immature at the time of this analysis, data on durability are promising: median DOR (95% CI) by BIRC was 9.72 (4.27-11.14) and 8.41 (5.55-NE) mo for Cohorts 4 and 5b, respectively; median PFS (95% CI) by BIRC was 5.42 (4.17-6.97) and 9.13 (5.52-13.86) mo for Cohorts 4 and 5b, respectively. Safety profile remains favourable and unchanged. Most common AEs (≥25% all grades) across all cohorts (n = 315), were peripheral edema (49.2%), nausea (43.2%), and vomiting (28.3%); majority of the AEs were grade 1/2. Final efficacy analysis (12-mo f-u on DOR) including biomarker data will be presented during meeting. Conclusions: These data confirm capmatinib to be a promising new treatment option for pts with METΔex14-mutated advanced NSCLC regardless of the line of therapy with deep and durable responses and manageable toxicity profile. Clinical trial information: NCT02414139.
Gefitinib and erlotinib have different antitumor activity according to the type of the EGFR mutation borne. Report of cases harboring rare mutations can support the decision-making process in this subset of patients.
Background: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%e4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. Patients and methods: Eligible patients [18 years; Eastern Cooperative Oncology Group (ECOG) performance status 2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2þ or 3þ or H-score 150, or MET/centromere ratio 2.0 or gene copy number (GCN) 5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3þ, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. Results: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4e33.0). In patients with MET GCN 6 (n ¼ 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN 6 was 9.3 months (95% confidence interval, 3.8e11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). Conclusions: MET GCN 6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).
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