Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study.

Abstract

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.

Capmatinib for the treatment of non-small cell lung cancer

“…The remaining ongoing cohorts are: cohort 1a with pretreated patients with MET GCN ≥ 10; cohort 4 with pre-treated patients with MET exon 14 mutations regardless of GCN; cohort 5 with treatment-naive patients with MET dysregulation (5a: MET GCN ≥ 10 and 5b: MET exon 14 mutations regardless of GCN); cohort 6 (expansion cohort) with pretreated patients with either MET GCN ≥ 10 without MET exon 14 mutations or MET exon 14 mutations regardless of GCN; and cohort 7 (expansion cohort) with treatment-naive patients with MET exon 14 mutation regardless of MET GCN. At the cutoff date for this interim analysis of 8 November 2018, enrollment into MET mutated cohorts 4 (n = 69) and 5b (n = 28) had been completed [67].…”

“…Preliminary data are available for cohorts 4 and 5b, and these have been presented at the 2019 ASCO congress [67]. By BIRC analysis, an ORR of 39.1% was achieved in patients in cohort 4 (pretreated patients with MET exon 14 mutations regardless of GCN; second/third line [2/3 L]).…”

“…Additionally, the median PFS was 5.42 months in cohort 4 (2/3 L) and 9.13 months in cohort 5b (1L), however the PFS results for cohort 5b were not mature at this cut-off date for analysis. The differential benefit observed between treatmentnaive and pre-treated patients highlights the need for an early diagnosis for patients with MET exon 14 skipping mutation advanced NSCLC [67].…”

“…Capmatinib is known to cross the blood-brain barrier and showed preliminary activity in brain metastasis [67]. A case report of a patient from cohort 4 (pre-treated patients with MET mutations regardless of GCN) showed a complete resolution of brain metastasis at the first post-baseline CT scan (after 42 days of capmatinib treatment) [27].…”

Targeted therapy in lung cancer—ASCO 2019 update

“…In the first-line setting, capmatinib showed an ORR by independent review (IR) of 67.9% and a DCR of 96.4%; in pretreated patients, the ORR by IR was 40.6% and the DCR was 78.3% according to data from the phase II GEOMETRY trial [3], which was presented by J. Wolf. The GEOMETRY trial examined capmatinib in different cohorts; cohort 4 contained pretreated patients with MET exon 14 alterations in the secondor third-line setting (n = 69), while cohort 5b included treatment-naive patients (n = 28).…”