Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial

Background Capmatinib has previously shown activity in treatment-naive and previously treated patients with non- small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). MET ex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib. Methods In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged >= 18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 MET ex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all MET ex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed. Findings Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had MET ex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46<middle dot>4 months (IQR 41<middle dot>8-65<middle dot>4) for the treatment-na & iuml;ve patients and 66<middle dot>9 months (56<middle dot>7-73<middle dot>9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55<middle dot>0-79<middle dot>7) of 60 treatment-naive patients and 44 (44%; 95% CI 34<middle dot>1-54<middle dot>3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported. Interpretation These long-term results support MET ex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with MET ex14 NSCLC.