Background: The toxicity profile of the third-generation 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 pts) and AURA3 (19% of pts) 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. Methods: Eligible pts will have histologically/cytologically confirmed EGFR-mutant NSCLC, and MET+ disease by central FISH, central IHC, or local NGS (retrospectively confirmed by central FISH/IHC). Pts must have documented radiological progression following 1–3 lines of prior therapy (must include osimertinib). Pts will receive osimertinib 80 mg plus weight-based dosing with savolitinib 300 or 600 mg PO QD, in 28-day cycles. The primary objective is efficacy (RECIST 1.1) by overall response rate (ORR) in pts who are MET+ by central FISH. Secondary endpoints include: ORR (MET+ by central IHC and all pts); 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 pts); safety, and pharmacokinetics (all pts). Based on the TATTON study, we anticipate enrolling ~172 MET+ pts to include ≥117 pts 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. Clinical trial information: NCT03778229