P1.01-134 SAVANNAH: Phase II Trial of Osimertinib + Savolitinib in EGFR-Mutant, MET-Driven Advanced NSCLC, Following Prior Osimertinib

The toxicity profile of the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) osimertinib makes it an attractive backbone for combination with other targeted agents, possibly overcoming acquired resistance mechanisms. Combination with a MET-inhibitor is an intuitive approach as MET-amplification was identified as the most common mechanism of resistance to osimertinib in preliminary ctDNA data from the Phase III FLAURA (15% of patients) and AURA3 (19% of patients) studies. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI that had an acceptable safety profile when combined with osimertinib in the Phase Ib TATTON study, providing the basis for this Phase II SAVANNAH study (NCT03778229). Other mechanisms of acquired resistance to osimertinib, including secondary EGFR mutations (e.g. C797S), RAS/RAF activation, and oncogenic gene fusions, provide additional opportunities for developing osimertinib-based combinations. Eligible patients will have histologically or cytologically confirmed EGFR-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC), and MET-driven (MET+) disease by central fluorescence in situ hybridization (FISH), central immunohistochemistry (IHC), or local next-generation sequencing (NGS; retrospectively confirmed by central FISH/IHC). Patients must have documented radiological progression following 1–3 lines of prior therapy (must include osimertinib). Patients will receive osimertinib plus savolitinib in 28-day cycles. The primary objective is efficacy (RECIST 1.1) by overall response rate (ORR) in patients who are MET+ by central FISH. Secondary endpoints include: ORR (MET+ by central IHC and all patients); progression-free survival, overall survival, duration of response, percent change in tumor size, HRQoL, and EGFR mutation ctDNA clearance (MET+ by central FISH, central IHC, and all patients); safety, and pharmacokinetics (all patients). Based on the TATTON study, we anticipate enrolling ∼172 patients with MET+ disease, to include ≥117 patients with MET+ disease by central FISH. Enrolment began in Q1 2019. Ongoing development of complementary trials targeting other osimertinib resistance mechanisms will also be discussed. Section not applicable Section not applicable