Activity of brigatinib (BRG) in crizotinib (CRZ)-resistant ALK+ NSCLC patients (pts) according to ALK plasma mutation status.

Abstract

9065 Background: BRG is a potent and selective ALK inhibitor with preclinical and clinical activity against wild-type ALK and a broad range of mutants associated with clinical CRZ resistance, including G1202R. Herein we examine the association between BRG efficacy and ALK mutation status using plasma specimens from the initiation of BRG treatment (baseline [BL]) and the end of BRG treatment (EOT) in CRZ-resistant ALK+ NSCLC pts enrolled in the BRG Ph1/2 or pivotal Ph2 (ALTA) trials. Methods: Plasma samples were analyzed using the Resolution Bioscience ctDx Lung Panel v3.0. BRG activity was described using the confirmed objective response rate (cORR) (RECIST v1.1). Data are reported as of May 31, 2016 for the Ph1/2 (NCT01449461) and ALTA (NCT02094573) trials. Results: Of 291 CRZ-resistant ALK+ NSCLC pts enrolled in the Ph1/2 (N = 69) and ALTA (N = 222) trials, evaluable plasma samples were obtained from 67 pts at BL. cORR to BRG in these pts was 49% (33/67). An ALK fusion was detected in plasma in 45% (30/67) of these pts (cORR 57% [17/30]), of whom 33% (10/30) had secondary ALK mutations (cORR 50% [5/10]) and 67% (20/30) did not (cORR 60% [12/20]). Best responses in pts with secondary ALK mutations were: 2 CR (ALK amplification [Amp] copy number [CN] = 10; T1151M); 3 PR (L1196M; E1408V; Amp CN = 6); 4 SD (L1196M; E1419K; F1174C; C1156Y+S1206F+G1269A); 1 PD (T1151R+C1156Y+E1161D+F1174L). Of 67 pts with evaluable plasma at BL, 35 discontinued BRG therapy, of whom 20 had evaluable samples collected at EOT. No new mutations were detected at EOT in 75% (15/20) of pts. Complex mutation patterns were associated with resistance in the remaining 25% (5/20): High-level ALK-Amp (CN = 58); ALK-Amp (CN = 14)+MET-Amp (CN = 6); ALK-S1206F+S1206C+Amp (CN = 6); ALK-G1202R+L1196M+L1198Q; ALK-G1202R+BRAF-V600E+KRAS-G12D. Conclusions: ALK fusions were detected in plasma in < 50% of CRZ-resistant ALK+ NSCLC pts. BRG had substantial activity in ALK fusion–positive pts with a range of CRZ-resistance mutations. Neither primary nor secondary resistance to BRG was associated with any single plasma ALK mutation. The therapeutic implications of complex secondary resistance patterns associated with BRG require further exploration. Clinical trial information: NCT01449461, NCT02094573.