Capmatinib plus nazartinib in patients with EGFR-mutated non–small cell lung cancer

Purpose: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC). Methods: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200–400 mg bid plus nazartinib 50–150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1–3 prior lines; EGFR^{L858R/ex19del}; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0–2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFR^{L858R/ex19del}; T790M−; any MET); group 4 (with food; 0–2 prior lines; EGFR^{L858R/ex19del}; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1–3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. Results: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET− (n = 42), T790M+ (n = 29), and T790M− (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). Conclusion: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. Clinical trial registration: ClinicalTrials.gov