Updated results from GEOMETRY mono-1 confirm capmatinib as an effective first-line treatment for MET exon 14-mutated advanced NSCLC

Results from Cohort 7 of the phase II GEOMETRY mono-1 study confirm the MET exon 14 skipping mutation (METex14) as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for the first‑line treatment of patients with this genetic aberration.

Capmatinib is an orally bioavailable, highly selective, and potent MET inhibitor. Previously published data from the open-label, multicohort GEOMETRY mono-1 Phase II study demonstrated clinically meaningful efficacy and a manageable safety profile of this agent in the treatment of patients with metastatic non‑small cell lung cancer (NSCLC) and METex14 who were either treatment-naive (Cohort 5b) or pretreated (Cohorts 4 and 6). To generate more data in the first line setting and confirm the results from Cohort 5b METex14 Cohort 7 including treatment-naive patients was implemented in the GEOMETRY mono-1 study. During ELCC 2022 results were presented from the primary efficacy analysis of this additional cohort, alongside updated efficacy and safety data for all treatment-naive patients enrolled in the trial.

Study design

GEOMETRY mono-1 enrolled adult advanced NSCLC patients (EGFR wild-type, ALK rearrangement-negative) with ≥1 measurable lesion and a METex14 or MET amplification. Patients were stratified into several cohorts based on previous lines of therapy and the MET status. Patients were treated with capmatinib 400 mg twice daily, administered under fasting conditions in Cohort 5b, and without fasting restrictions in Cohort 7. The primary endpoint of the study was overall response rate (ORR), with duration of response (DoR), progression-free survival (mPFS), overall survival (OS); and adverse events (AEs) as secondary study outcomes.

Results

Cohort 7 enrolled a total of 32 treatment-naive patients with NSCLC and METex14 of whom 8 (25%) patients were still receiving treatment at the data cutoff date. The median duration of exposure to capmatinib was 42.6 weeks. The median age of patients in Cohort 7 was 73 years (44% ≥75 years), 71.9% were female, and 62.5% of included patients were never smokers. Most patients had adenocarcinoma (90.6%), and 18.8% had brain metastases at baseline.

The ORR in Cohort 7 was reported at 68.8%, including 1 complete and 21 partial responses. This ORR is in line with the previously reported ORR of 67.9% for Cohort 5b. Responses to capmatinib proved to be durable in treatment-naive patients with a median DoR of 16.6 months in Cohort 7 and 12.6 months for Cohort 5b.  Responses also occurred early, with about two thirds of patients having a response within the first 2 months of treatment. Some tumor size reduction was seen in most treatment-naive patients, with 40 patients having a reduction of >30% from baseline. The median PFS in Cohort 7 was similar to that of Cohort 5b, at 12.5 and 12.4 months, respectively.

Overall, capmatinib came with a manageable safety profile, without any no new safety signals in Cohort 7. The most common treatment-related adverse events (TRAEs) (≥10%, all grades in all patients) were peripheral edema, nausea, increased blood creatinine, vomiting, fatigue, decreased appetite, and diarrhea.

Conclusions

With an ORR of 68.8%, Cohort 7 independently confirms the previously reported findings from Cohort 5b (ORR 67.9%) in treatment-naive patients with METex14. Of note, these ORRs compare favorably to response rates in clinical trials of immunotherapy (with or without chemotherapy) in MET-unselected patients with NSCLC. A clinically meaningful mature median PFS (Cohorts 5b and 7: ≈12.5 months) and mature median OS (Cohort 5b: 20.8 months) indicate the long-term benefit of capmatinib as a first-line treatment in these patient populations. Finally, the first-line safety data align with the overall safety data, underscoring the manageable safety profile of capmatinib. As such, these updated results confirm METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for the first‑line treatment of patients with METex14 NSCLC.

Reference

J. Wolf, et al. Capmatinib in treatment‑naïve MET exon 14-mutated (METex14) advanced non‑small cell lung cancer (aNSCLC): Updated results from GEOMETRY mono-1. Presented at ELCC 2022; Abstract 26P.