Abstract CT303: The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive (EGFRm) MET-amplified NSCLC in the TATTON study
Authors: Hartmaier Ryan , Han Ji-Youn , Ahn Myung-Ju , Cho Byoung Chul , Cantarini Mireille , Frewer Paul , Frigault Melanie M. , Oxnard Geoffrey 
Published: September 2020

Abstract
MET-amplification is a resistance mechanism seen in &gt;25% of pts with EGFRm non-small cell lung cancer (NSCLC) and progression on osimertinib (1st/later line), a 3rd gen, irreversible, oral EGFR-TKI. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI. In Phase 1b 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 600/300 mg. Part B was split into cohorts (B1, B2 and B3) by prior therapy and T790M status. Pts in Part D (no prior 3rd gen EGFR-TKI, T790M negative; savolitinib 300 mg) had similar response rates and progression-free survival (PFS) to pts in cohort B2 (analogous cohort; savolitinib 600 mg). In osimertinib-treated pts with EGFRm NSCLC (AURA3, FLAURA), circulating tumor (ct)DNA clearance has been shown to correlate with PFS. We report EGFRm (Ex19del/L858R) ctDNA clearance at two doses of savolitinib + osimertinib 80 mg in TATTON Parts B and D. For this next generation sequencing-based analysis (Resolution Bioscience), ctDNA samples were collected pre-dose, cycle (C) 1 day (D) 1 and at least every 3-8 weeks until discontinuation. Part B pts evaluable for efficacy and with a baseline plus ≥1 longitudinal ctDNA sample at/before C6D1 were included. Data from ctDNA evaluable Part B pts (n=49) identified ctDNA clearance correlates with longer PFS and C3D1/C4D1 as optimal time points for PFS prediction, thus the first 20 pts from Part D with available plasma samples at C1D1 and C4D1 were included. The proportion of pts with detectable EGFRm at baseline was similar across groups (Table). ctDNA clearance was comparable at C3D1/C4D1 for cohort B2 and Part D. ctDNA clearance was similar between the two doses of savolitinib, suggesting efficacy is maintained at the lower dose (300 mg). These data also indicate that ctDNA clearance may be predictive of PFS in EGFRm MET-amplified NSCLC.
TATTON Part B and Part D ctDNA analysisPart B: osimertinib 80 mg QD + savolitinib 600 mg QD (n=107)*Part D: osimertinib 80 mg QD + savolitinib 300 mg QD (n=42)#All Part BCohort B2 No prior third-generation EGFR-TKI (T790M negative)All Part D No prior third-generation EGFR-TKI (T790M negative)Number of patients492020Detectable EGFRm at baseline, n (%)38 (78)15 (75)16 (80)ctDNA clearanceNumber of pts evaluable at C3D1/C4D1451820ctDNA clearance at C3D1/C4D1, n (%)22 (45)10 (50)13 (65)‡*Interim data cut-off: 28 Feb 2018 #Interim data cut-off: 29 Mar 2019 ‡ctDNA clearance for patients at Part D was only assessed at C4D1
Citation Format: Ryan Hartmaier, Ji-Youn Han, Myung-Ju Ahn, Byoung Chul Cho, Mireille Cantarini, Paul Frewer, Melanie M. Frigault, Geoffrey Oxnard. The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive (EGFRm) MET-amplified NSCLC in the TATTON study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT303.