Activity of brigatinib (BRG) in crizotinib (CRZ) resistant patients (pts) according to ALK mutation status

Abstract

Background: BRG is an investigational, selective ALK inhibitor with potent preclinical activity against native ALK and a broad set of mutants associated with clinical resistance to CRZ. BRG has shown promising efficacy in ALK rearranged (+) NSCLC pts previously treated with CRZ in a phase (Ph) 1/2 trial. We examined the association between BRG efficacy and ALK mutation status using tumor specimens collected after CRZ and prior to BRG treatment (tx) (baseline [BL]), and after BRG tx (Post-BL) in pts enrolled in the Ph1/2 trial and a Ph2 trial of ALK+ NSCLC pts whose disease progressed on CRZ (ALTA). Methods: Samples analysis: FoundationOne next-generation sequencing (NGS) platform. BRG activity: best response (RECIST v1.1) from BL. Data reported: Jan, 2016 for sample analyses, Nov and Dec, 2015 for Ph1/2 and ALTA clinical results, respectively. Results: Of the 301 ALK+ NSCLC pts enrolled in the Ph1/2 (N = 79) and ALTA (N = 222) trials, evaluable tumor samples were obtained from 30 pts at BL. Confirmed overall response in these pts was 63% (19/30). Secondary ALK mutations were detected in 30% (9/30) of pts. Confirmed ORR in these pts was 67% (6/9); 6 confirmed partial responses (PRs) (3 F1174L, L1196M, S1206F, and G1269A); 1 PR (G1202R) awaiting confirmation; 1 stable disease (SD) (L1196M) in a pt with 1 cycle (C = 28 days) of tx; 1 progressive disease (PD) (F1245V). Secondary ALK mutations were not detected in 70% (21/30) of pts, including 4 who were ALK fusion (-) by NGS (but ALK+ locally). Confirmed ORR in these pts was 62% (13/21); 2 CR, 11 PR, 7 SD, and 1 PD; including 3 SD and 1 PD in ALK (-) pts. Post-BL samples were collected from 5 pts (all Ph1/2), 2 of whom also had BL samples. Secondary ALK mutations, and other genetic aberrations of interest, were detected in 4 pts: 1 with F1174L (at C13 [also present at BL]; PD at C13); 2 with G1202R (at C21 [not present at BL]; PD at C13; and at C35 [BRAF G469A also detected]; PD at C35); and 1 with D1203N, G1269A, and I1171H (at C9; PD at C7). Conclusions: BRG maintains activity in CRZ resistant ALK+ NSCLC independent of the presence of secondary ALK mutations. While 2 single mutants (F1174L and G1202R) have been detected after long term tx with BRG, responses were also observed when these mutants were present at BL. Clinical trial information: NCT01449461 and NCT02094573.