Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): First report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA).

9007 Background: We report the first results of a pivotal ph 2 trial of BRG in pts with ALK+ NSCLC. BRG, an investigational oral tyrosine kinase inhibitor (TKI) with preclinical activity against rearranged ALK and CRZ-resistant mutants, yielded promising clinical activity in CRZ-treated ALK+ NSCLC pts in a ph 1/2 study. As responses and AEs varied with starting BRG dose, two BRG regimens are being evaluated in this ongoing randomized study. Methods: Pts ≥18 y with advanced ALK+ NSCLC whose disease progressed on CRZ and who had received no other ALK TKI were eligible. Pts were stratified by presence of brain metastases at baseline and best response to prior CRZ and randomized 1:1 to receive oral BRG at 90 mg qd (arm A) or 90 mg qd for 7 d followed by 180 mg qd (arm B). Primary endpoint was investigator-assessed confirmed ORR per RECIST v1.1. Key secondary endpoints included PFS and IRC-assessed confirmed ORR and CNS response/PFS. Results: 222 pts were randomized (arm A/B, n=112/n=110; last pt enrolled 21 Sept 2015): median age was 51 y/57 y; 71%/67% had brain metastases. As of 7 Dec 2015, 63%/74% (A/B) were ongoing; median time on treatment was 25 wk/23 wk. Investigator-assessed ORR in A: 46% (95% CI 36–55%; 39 confirmed responses + 12 single responses awaiting confirmation), including 1 confirmed complete response (CR); ORR in B: 54% (95% CI 44–63%; 49 confirmed responses + 10 single responses awaiting confirmation), including 5 confirmed CRs. Median PFS in A/B: 8.8 mo/11.1 mo (events per arm [A/B]: 44/25). Most common grade ≥3 treatment-emergent AEs (A/B) included: increased CPK (3%/8%), hypertension (4%/5%), pneumonia (3%/5%), rash (1%/4%), increased lipase (3%/2%), and pneumonitis (2%/3%). Early-onset pulmonary events (within first 7 d) occurred in 6% of pts (3% grade ≥3); no such events occurred within 7 d of escalation to 180 mg in arm B. Discontinuations and dose reductions due to AEs (A/B) were 3%/6% and 7%/18%, respectively. Conclusions: In each arm, BRG yielded substantial responses and robust PFS, with an acceptable safety profile. A ph 3 study of BRG at 90 mg qd for 7 d followed by 180 mg qd vs CRZ in TKI-naive, advanced ALK+ NSCLC is planned. Clinical trial information: NCT02094573.

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