Savolitinib Plus Osimertinib in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Advanced Non-Small Cell Lung Cancer: A Randomized Phase II trial

Background MET amplification is the most common resistance mechanism to first-line osimertinib. We report safety and efficacy data from a phase 2 study assessing savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated, MET-amplified, advanced non-small cell lung cancer (NSCLC). Patients and methods Patients with EGFR-mutated, MET-amplified (MET gene copy number ≥5 or MET:CEP7 ratio ≥2), advanced NSCLC post-osimertinib were enrolled. Patients received savolitinib 300 mg once daily (QD) plus osimertinib 80 mg QD or savolitinib plus placebo. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Exploratory analysis included retrospective efficacy assessment by higher MET cutoffs (immunohistochemistry 3+ staining ≥90% tumor cells and / or MET gene copy number ≥10). Results Thirty patients were randomized (14 savolitinib-osimertinib; 16 savolitinib-placebo). Among all patients, ORR (95% confidence interval [CI]) was 57% (29-82) vs. 13% (2-38); median PFS (95% CI) was 7.4 months (5.6-not calculable [NC]) vs. 1.6 months (1.3-4.1) for savolitinib-osimertinib and savolitinib-placebo, respectively. In patients with higher MET cutoffs, ORR was 63% (24-91) and 29% (4-71); median PFS was 8.2 months (4.1-NC) and 4.0 months (1.3-NC) for savolitinib-osimertinib (n = 8) and savolitinib-placebo (n = 7), respectively. There were no new safety signals. This study was terminated early and the contribution of osimertinib to savolitinib is being assessed further in SAVANNAH (NCT03778229) in patients with higher MET biomarker cutoffs. Conclusions Savolitinib plus osimertinib demonstrated numerically higher clinical activity vs. savolitinib plus placebo in all patients and patients with higher MET biomarker cutoffs. Micro abstract MET amplification is a genetic change associated with more aggressive cancers and specifically with osimertinib resistance. This randomized, phase 2, double-blind, multicenter trial demonstrated numerically higher clinical activity of savolitinib-osimertinib combination therapy vs. savolitinib-placebo in advanced NSCLC. This study was terminated early because savolitinib-osimertinib in this setting with higher MET cutoffs is being further assessed in SAVANNAH (NCT03778229).