Abstract CT033: TATTON Phase Ib expansion cohort: Osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)
Authors: Sequist Lecia V. , Lee Jong Seok , Han Ji-Youn , Su Wu-Chou , Yang James Chih-Hsin , Yu Helena , Ottesen Lone H. , Verheijen Remy B. , Mellemgaard Anders , Wessen Jonathan , Oxnard Geoffrey , Cho Byoung Chul 
Published: August 2019

MET amplification is a common mechanism of resistance to EGFR-TKI treatment, observed in ~20% of EGFR-mutant NSCLCs after third-generation EGFR-TKIs (including osimertinib). Combined MET/EGFR inhibition is, therefore, a compelling therapeutic approach. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent and highly selective MET-TKI. Preliminary findings from the expansion cohort of the open-label, multi-center, Phase Ib TATTON study (NCT02143466) demonstrated an acceptable safety profile and preliminary anti-tumor activity with savolitinib plus osimertinib in pts with EGFR-mutant, MET-amplified NSCLC. Here we report updated interim data from this expansion phase, in a cohort of pts who progressed on prior third-generation EGFR-TKI.

Pts eligible for the analysis were aged ≥18 years, WHO performance status 0-1, had locally advanced or metastatic EGFR-mutant NSCLC, and had progressed on ≥1 prior EGFR-TKI (including a third-generation EGFR-TKI). Pts could initially be enrolled based on local testing for MET-positive status (NGS, FISH [MET gene copy ≥5 or MET/CEP7 ratio ≥2], or immunohistochemistry [+3 in ≥50% of tumor cells]). Pts received osimertinib 80 mg QD plus savolitinib 600 mg QD. The primary objective was safety and tolerability; secondary objectives included preliminary assessment of anti-tumor activity (RECIST v1.1).

At data cut-off (Feb 2018), 48 pts had received study treatment. Median age was 59 years (range 28-82), 27 (56%) pts were male, and 37 (77%) pts were Asian. The most common (≥20%) all-causality AEs were nausea (n=25, 52%), vomiting (n=18, 38%), diarrhea (n=13, 27%), fatigue (n=12, 25%), decreased appetite (n=11, 23%), and pyrexia (n=10, 21%). Treatment-related AEs were reported for 43 (90%) pts, and classified as CTCAE grade ≥3 in 11 (23%) pts. Serious AEs were reported in 14 (29%) pts. Ten (21%) and 5 (10%) pts discontinued savolitinib and osimertinib due to AEs, respectively. Two (4%) pts died, both considered unrelated to study treatment by the investigator. At data cut-off, 43 pts who had ≥1 post baseline scan (or who progressed, withdrew or died prior to first post baseline scan) were eligible for efficacy analysis. Objective response rate was 28% (12 pts, all confirmed partial responses). Median duration of response was 9.7 months.

Osimertinib plus savolitinib had an acceptable safety profile and demonstrated preliminary anti-tumor activity. These findings support further investigation of this combination in this setting. SAVANNAH (NCT03778229) is a Phase II study investigating osimertinib plus savolitinib in pts with EGFR-mutant, MET-amplified NSCLC who have progressed on osimertinib.

Citation Format: Lecia V. Sequist, Jong Seok Lee, Ji-Youn Han, Wu-Chou Su, James Chih-Hsin Yang, Helena Yu, Lone H. Ottesen, Remy B. Verheijen, Anders Mellemgaard, Jonathan Wessen, Geoffrey Oxnard, Byoung Chul Cho. TATTON Phase Ib expansion cohort: Osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT033.