Osimertinib–Savolitinib in Advanced NSCLC after Progression during EGFR-TKI Therapy

BackgroundSavolitinib is an oral, potent, highly selective MET–tyrosine kinase inhibitor (TKI). Combination therapy with savolitinib and osimertinib, an epidermal growth factor receptor (EGFR)–TKI, has shown activity in patients with EGFR-mutated, advanced non–small-cell lung cancer (NSCLC) with MET overexpression, MET amplification, or both, after progression during EGFR-TKI therapy. MethodsIn this international, phase 3, open-label trial, we randomly assigned, in a 1:1 ratio, patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression (staining intensity of 3+ for MET in ≥90% of tumor cells on immunohistochemical analysis), MET amplification (≥10 gene copies on fluorescence in situ hybridization), or both whose disease had progressed during osimertinib therapy to receive osimertinib (at a dose of 80 mg once daily) plus savolitinib (300 mg twice daily) or intravenous platinum–pemetrexed. The primary end point was progression-free survival, as assessed by blinded independent central review. Secondary end points included overall survival and safety. ResultsOf the 1746 patients screened, 338 were randomly assigned to receive osimertinib–savolitinib (171 patients) or platinum–pemetrexed (167 patients). Osimertinib–savolitinib led to significantly longer progression-free survival than platinum–pemetrexed (hazard ratio for disease progression or death, 0.55; 95% confidence interval [CI], 0.42 to 0.72; P<0.001), as well as significantly longer overall survival (hazard ratio for death, 0.68; 95% CI, 0.50 to 0.91; P=0.01; final analysis). The Kaplan–Meier estimate of 12-month progression-free survival was 36% in the osimertinib–savolitinib group and 10% in the platinum–pemetrexed group, and the estimate of 12-month overall survival was 70% and 53%, respectively. The most frequently reported adverse events that occurred during treatment in the osimertinib–savolitinib group were peripheral edema (in 49% of the patients), anemia (in 26%), and diarrhea (in 26%). Grade 3 or higher adverse events during treatment were reported in 64% of the patients in the osimertinib–savolitinib group and in 63% of those in the platinum–pemetrexed group. ConclusionsOsimertinib–savolitinib led to significantly longer progression-free and overall survival than platinum–pemetrexed among patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression, MET amplification, or both that had progressed during osimertinib therapy (Funded by AstraZeneca; SAFFRON ClinicalTrials.gov number, NCT05261399.)