319O - ALTA-3: A randomized trial of brigatinib (BRG) vs alectinib (ALC) in crizotinib (CRZ)-refractory advanced ALK+ NSCLC

Background

In patients (pts) with ALK+ NSCLC, resistance to the first-generation ALK TKI CRZ eventually develops, with CNS progression and/or ALK-acquired resistance mutations. ALC and BRG are CNS-active, next-generation ALK TKIs with differing selectivity vs these mutations. Single-arm post-CRZ trials with ALC reported median PFS (mPFS) <12 mo, while BRG showed mPFS >16 mo (16.3–16.7). ALTA-3 (NCT03596866) was designed to test whether BRG efficacy is superior to ALC in ALK+ NSCLC that progressed on CRZ. We report results of the preplanned interim analysis (IA).

Methods

ALTA-3 was a phase 3 trial in pts with advanced ALK+ NSCLC who progressed on CRZ. Treatment with ≤2 systemic regimens for advanced NSCLC was allowed, excluding CRZ, but no other ALK TKI. Pts were randomized 1:1 to BRG 180 mg QD (7-day lead-in at 90 mg) or ALC 600 mg BID and stratified by baseline brain metastases (BL BM; yes/no) and best CRZ response (CR/PR vs other). Primary endpoint: BIRC-assessed PFS (RECIST v1.1); secondary endpoints included OS, ORR by BIRC, and safety. An IA for efficacy and futility was conducted, planned after ∼115 (∼70%) of 164 expected events occurred.

Results

From May 2019 to Jun 2021, 248 pts were randomized (BRG/ALC, n=125/123); median age: 54/53 yr; BL BM: 64%/61%; best response CR/PR to prior CRZ: 67%/69%. At IA data cutoff (11 Feb 2022), median follow-up (BRG/ALC) was 15.9/16.9 mo, with 107 (43%; 50/57) BIRC PFS events. BRG BIRC mPFS was 19.3 mo vs ALC 19.2 mo (HR 0.97 [95% CI: 0.66–1.42]; 2-sided log-rank P=0.867). The study met futility criteria (BIRC PFS P>0.6948) at IA and is being discontinued. OS was immature (41 events [16.5%]). BIRC-confirmed ORR (BRG/ALC), 52%/61% (OR: 0.70 [0.42‒1.15]); in pts with measurable BL BM, iORR was 73%/68% (OR: 1.31 [0.44–3.84]). Most common TEAEs: BRG, increased CPK (71%), AST (56%), ALT (43%); ALC, increased AST (40%) and ALT (38%); anemia (37%); grade 3/4: BRG, increased CPK (26%) and lipase (7%); ALC, increased ALT (6%) and AST (5%). TEAEs led to dose interruption (BRG/ALC): 54%/26%; discontinuation: 9%/6%.

Conclusions

At the IA, BIRC PFS was numerically similar between arms. No new safety findings were observed, with safety profiles consistent with known BRG and ALC profiles.

Clinical trial identification

NCT03596866.

Editorial acknowledgement

Professional medical writing assistance was provided by Lauren Gallagher, RPh, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by Millennium Pharmaceuticals, Inc.

Legal entity responsible for the study

Takeda Development Center Americas, Inc., Lexington, MA, USA.

Funding

Takeda Development Center Americas, Inc., Lexington, MA, USA.

Disclosure

J.C. Yang: Financial Interests, Personal, Other, Honoraria or advisory role: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Takeda, AstraZeneca, Hansoh Pharmaceuticals. G. Liu: Financial Interests, Personal, Other, Honoraria: Takeda, Amgen, AstraZeneca, Roche, Novartis, Merck, Pfizer, Jazz Pharmaceuticals; Financial Interests, Institutional, Research Grant: Takeda, AstraZeneca, Amgen, Boehringer Ingelheim. S. Lu: Financial Interests, Personal, Other, Grants or contracts: AstraZeneca, Hutchison, Bristol Myers Squibb, Heng Rui, BeiGene, Roche, Hansoh; Financial Interests, Personal, Other, Consulting fees: Roche/Genetech, Hutchison MediPharma, ZaiLab, Novartis, AstraZeneca, GenomiCare, Yuhan Corporation, Menarini, Mirati Therapeutics Inc., Roche; Financial Interests, Personal, Other, Honoraria: Roche/Genentech, Hansoh, BeiGene, AstraZeneca. M. Burotto: Financial Interests, Personal, Other, Consulting fees: Roche/Genentech, Bristol Myers Squibb, MSD Oncology, Novartis, AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche/Genentech, MSD Oncology, Bristol Myers Squib, AstraZeneca. S. Vincent, J. Yin, X. Ma: Financial Interests, Personal, Full or part-time Employment: Takeda. S. Popat: Other, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Janssen, Lily, Merk Serono, MSD, Novartis, Pfizer, Sanofi, Seattle Genetics, Takeda, Turning Point Therapeutics, X; Other, Personal, Invited Speaker: Medscape, Touch Medical, VJ Oncology; Other, Personal, Expert Testimony: Roche; Other, Personal, Other, Journal deputy editor: Elsevier; Financial Interests, Institutional, Other, Sub-investigator: Amgen, Blueprint, MSD, Seattle Genetics; Other, Personal, Other, Coordinating PI: Ariad, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Janssen, Lilly, Roche, Takeda, Turning Point Therapeutics; Other, Personal, Other, Local PI: AstraZeneca, GlaxoSmithKline, Roche, Trizel; Financial Interests, Institutional, Research Grant: Guardant Health; Other, Personal, Other, Advisory and leadership roles: ALK Positive UK, British Thoracic Oncology Group, European Society of Medical Oncology, European Thoracic Oncology Platform, International Association for the Study of Lung Cancer, Lung Cancer Europe, Mesothelioma Applied Research Foundation, Ruth Strauss. All other authors have declared no conflicts of interest.