Osimertinib with or without savolitinib as first-line treatment for MET-aberrant, EGFR-mutant NSCLC: randomized phase 2 trial (FLOWERS).

To investigate the efficacy and safety of osimertinib plus savolitinib for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and de novo MET aberrations, we conducted a randomized, multicenter, open-label, phase 2 study (ClinicalTrials.gov identifier: NCT05163249). Treatment-naïve patients with locally advanced or metastatic NSCLC harboring de novo MET amplification or overexpression and EGFR mutations were randomized to receive osimertinib monotherapy (cohort 1, 80 mg orally once daily) or combination therapy (cohort 2, osimertinib 80 mg orally once daily and savolitinib 300 mg orally twice daily). The primary endpoint was the confirmed objective response rate (ORR). A total of 44 patients were randomized to either cohort 1 (n = 23) or cohort 2 (n = 21). The pre-specified study endpoint was achieved. The confirmed ORR was 60.9% (95% confidence interval [CI]: 38.5-80.3) in cohort 1 and 90.5% (95% CI: 69.6-98.8) in cohort 2, with disease control rates of 87% (95% CI: 66.4-97.2) and 95.2% (95% CI: 76.2-99.9). Treatment-related adverse events of grade 3 or higher occurred in 2 patients (8.7%) in cohort 1 and 12 patients (57.1%) in cohort 2. Osimertinib plus savolitinib showed promising antitumor activity and manageable safety.