Abstract CT024: Acquired resistance in patients with EGFRm NSCLC following treatment with osimertinib plus savolitinib in the Ph1b TATTON study Parts B and D

Abstract Background/Purpose: MET-amplification is a resistance mechanism seen in ≤22% of patients (pts) with epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC) following progression on osimertinib, a third generation (3G), irreversible, oral EGFR tyrosine kinase inhibitor (TKI). In the Ph1b TATTON (NCT02143466) expansion cohorts (Parts B and D), pts with MET-amplified EGFRm advanced NSCLC and progression on a prior EGFR TKI, received osimertinib 80 mg + savolitinib 600 or 300 mg once daily; savolitinib is an oral, potent and highly selective MET TKI. Part B was split into three cohorts by prior therapy and tumor T790M status. Part D pts had received no prior 3G EGFR TKI and were T790M negative. For pts who eventually develop resistance to the combination, it is unclear which driver mutation(s) mediates this resistance. Methods: In this analysis, paired plasma samples collected at baseline and following disease progression and/or treatment discontinuation up to data cut-off date 4 March 2020, were assessed. Next generation sequencing (Guardant Health, Guardant360 73 gene panel or Omni 500 gene panel) was used to analyze the plasma ctDNA samples. All 73 genes on the Guardant360 panel were included in the Omni 500 gene panel. Analyses from each pt were reported only for genes included across the panels used. Genomic alterations were identified using Guardant Health's pipeline, which included mutations and amplifications of EGFR and MET. Disease progression was assessed by the investigator, according to the RECIST version 1.1. Assessments were completed for pts with progression-free survival (PFS) of over 2 months. Results: Of 180 pts who received study treatment, 70 provided baseline and progression/discontinuation ctDNA plasma samples. Of these, 45 pts were used for the analysis: 18/70 were not evaluable for ctDNA detection and 7/70 had a PFS of 2 months or shorter. Of the evaluable samples, the following acquired mutations were recorded (exclusivity between genes in most pts): MET D1228X, Y1230X, L1212X (20%, 9/45), EGFR C797X (16%, 7/45), KRAS G12X, G13X (11%, 5/45) and PIK3CA E545K (4%, 2/45). Most pts who developed MET-based resistance (7/9) developed more than one MET mutation, suggestive of polyclonal resistance. Across both Parts B and D, the resistance profiles appeared similar by prior EGFR TKI status and by savolitinib dose. Conclusions: In this analysis, approximately half of all evaluable pts had an identifiable acquired resistance mechanism; resistance appeared to be predominantly mediated by either MET, EGFR or KRAS. Co-occurring mutations across multiple genes were rarely detected. However, multiple acquired mutations were often detected in a specific gene, particularly MET, suggesting individual tumors showed inherent resistance dependencies. Citation Format: Aleksandra Markovets, Ji-Youn Han, Byoung Chul Cho, Mireille Cantarini, Pasi A. Janne, Ryan Hartmaier. Acquired resistance in patients with EGFRm NSCLC following treatment with osimertinib plus savolitinib in the Ph1b TATTON study Parts B and D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT024.