GEOMETRY duo-1: A phase (Ph) Ib/II, multicenter trial of oral cMET inhibitor capmatinib (INC280) ± erlotinib vs platinum + pemetrexed in adult patients (pts) with epidermal growth factor receptor (EGFR)-mutated, cMET-amplified, locally advanced/metastatic non-small cell lung cancer (NSCLC) with acquired resistance to prior EGFR tyrosine kinase inhibitor (TKI) therapy

Background: Despite high overall response rates (ORR) to EGFR TKIs, most pts with EGFR-mutated NSCLC develop acquired resistance; secondary activation of cMET as gene amplification, occurs in ∼20% of cases. Capmatinib (INC280) is a potent and selective cMET inhibitor. Preliminary clinical activity of INC280 + gefitinib was reported in pts with EGFR-mutated, cMET-amplified, EGFR TKI-resistant NSCLC. Methods: This multicenter, Ph Ib/II study (NCT02468661 ) will commence with a dose-escalation safety phase of INC280 + erlotinib. This will be followed by a randomized Ph II part, which will study the safety and efficacy of INC280 ± erlotinib compared with platinum + pemetrexed, in pts with EGFR TKI-resistant advanced NSCLC due to cMET amplification (EGFR T790M-negative). cMET gene copy number will be determined by fluorescence in situ hybridization. Eligible pts ( ≥ 18 years of age; ECOG PS 0-1) must have had prior therapy with a 1st/2nd-generation EGFR TKI ( ≥ 1 in Ph Ib: only 1 in Ph II). Pts in Ph II must be chemo therapy-naive. In Ph Ib (N≈O-15), erlotinib 150 mg tablets once daily (QD), and increasing doses of rNC280 with a starting dose of 200 mg tablets twice daily (BID), will be administered on a continuous dosing schedule. In Ph II (N ≈120), pts will undergo central testing for cMET and T790M, and be randomized 1:1:1 in 3 arms: 1. INC280 (400 mg BID); 2. INC280 (recommended Ph II dose [RP2D]) + erlotinib (150 mg QD); 3. Cisplatin (75 mg/m2)/carboplatin (AUC 5 or 6) + pemetrexed (500 mg/m2; every 21 days). The primary objectives are to determine the maximum tolerated dose/RP2D of INC280 + erlotinib (Ph Ib), and to compare the investigator-assessed antitumor activity of INC280 ± erlotinib vs platinum + pemetrexed therapy, measured by progression-free survival (Ph II). Secondary objectives include investigator-assessed ORR, disease control rate, duration of response, overall survival, safety, and pharmacokinetics. Enrollment is ongoing. (Table Presented).