SAVANNAH: A Phase II trial of osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-driven (MET+), locally advanced or metastatic non-small cell lung cancer (NSCLC), following disease progression on osimertinib.

Abstract

TPS9119 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.

A Fusion Transcription Factor–Driven Cancer Progresses to a Fusion-Independent Relapse via Constitutive Activation of a Downstream Transcriptional Target

“…Currently, even a highly specific targeted therapy, when applied as a monotherapy, is generally not sufficient to eradicate all tumor cells and often leads to tumor recurrence. Based on genomic profiling of resistant and recurrent tumors, combined therapies have been developed for a number of cancer types to reduce the occurrence of resistance and recurrence (44,45). For instance, recent studies have shown that a MET inhibitor combined with a third generation EGFR inhibitor impairs the growth of cancer cells harboring MET amplification (46).…”

A pharmacokinetic–pharmacodynamic model for the MET tyrosine kinase inhibitor, savolitinib, to explore target inhibition requirements for anti‐tumour activity

“…Building a mathematical PK/PD modelling framework is a valuable means to integrate extensive datasets of exposure, pharmacodynamic response, and tumour growth to define the target inhibition requirements (and potential variability) for optimal efficacy. Savolitinib is being investigated in combination with osimertinib in NSCLC (SAVANNAH: NCT03778229, TATTON: NCT02143466, and ORCHARD: NCT 03944772), and the modelling approach presented here provides a relevant starting point for the combination setting (Ahn et al, 2019; Choueiri et al, 2017; Oxnard et al, 2019; Sequist et al, 2020; Yu et al, 2019). A PK/PD model relating osimertinib exposure to effects on EGF receptor phosphorylation and TGI has been previously published (Yates et al, 2016).…”

Combination of Crizotinib and Osimertinib in T790M+ EGFR-Mutant Non-Small Cell Lung Cancer with Emerging MET Amplification Post-Osimertinib Progression in a 10-Year Survivor: A Case Report

“…Interim data have shown a response rate of 52% for patients who had previously received first- or second-generation TKIs and 28% for those who had previously received third-generation EGFR-TKIs, with an acceptable safety profile [14]. Based on these data, SAVANNAH, a phase II study that is further investigating osimertinib in combination with savolitinib in patients with EGFR -mutant and MET -amplified NSCLC after progression on osimertinib, is ongoing [15]. NCT02335944 is a phase Ib/II study testing the combination of capmatinib, a highly selective and potent MET inhibitor, and nazartinib, a third-generation EGFR-TKI, while the multidrug phase II platform study ORCHARD is studying different treatment modalities depending on the resistance mechanism involved in the development of resistance to first-line osimertinib, including osimertinib in combination with savolitinib, in patients with MET amplification.…”