CNS Efficacy of Osimertinib Plus Savolitinib in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small Cell Lung Cancer With MET Overexpression and/or Amplification: A Brief Report

Introduction In the phase 2 SAVANNAH study (NCT03778229), osimertinib plus savolitinib demonstrated clinical activity in patients with EGFR -mutated advanced non-small cell lung cancer (NSCLC) with MET overexpression and/or amplification following progression on first-line osimertinib. As the central nervous system (CNS) is a common metastatic site, we present a prespecified exploratory CNS efficacy analysis. Methods A subset of SAVANNAH, including patients with EGFR -mutated advanced NSCLC with MET overexpression (IHC 3+ intensity in ≥90% of tumor cells) and/or amplification (≥10 MET gene copies by FISH) following progression on first-line osimertinib (asymptomatic stable brain metastases permitted), were randomized 2:1 to osimertinib 80 mg QD plus savolitinib 300 mg BID or savolitinib 300 mg BID plus placebo. Endpoints included: CNS progression-free survival (PFS), CNS objective response rate (ORR), and CNS duration of response in patients with baseline CNS metastases (CNS BICR per modified RECIST 1.1 neuroradiology review), and presence/absence of CNS lesions at progression in patients without baseline CNS metastases (CNS BICR). Results Of 73 patients randomized, 18 had ≥1 baseline CNS metastasis (osimertinib-savolitinib, n=14; savolitinib-placebo, n=4). With osimertinib-savolitinib and savolitinib-placebo, respectively, CNS PFS events occurred in 36% and 50% of patients; confirmed CNS ORR (95% confidence interval) was 43% (18–71) and 25% (1–81). In patients without baseline CNS metastases, new CNS lesions occurred in 0/13 patients with osimertinib-savolitinib versus 6/11 patients with savolitinib-placebo. Conclusions Osimertinib plus savolitinib 300 mg BID showed promising CNS activity in patients with EGFR-mutated advanced NSCLC with high MET overexpression and/or amplification following progression on first-line osimertinib.