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Brigatinib (BRG) vs crizotinib (CRZ) in the phase III ALTA-1L trial

2019; Elsevier BV; Volume: 30; Linguagem: Inglês

10.1093/annonc/mdz063.004

1569-8041

Raffaele Califano, Maximilian J. Hochmair, Cesare Gridelli, Angelo Delmonte, M.R. García Campelo, Alessandra Bearz, Frank Griesinger, Alessandro Morabito, Enriqueta Felip, Sunita Ghosh, Marcello Tiseo, J. Haney, David Kerstein, Sanjay Popat, D. Ross Camidge,

Cancer Genomics and Diagnostics

Background: We report results of the first interim analysis (IA) from the ALTA-1L study of BRG vs CRZ in anaplastic lymphoma kinase (ALK) inhibitor–naive, ALK-positive non–small cell lung cancer (ALK+ NSCLC; NCT02737501). Methods: This open-label, multicenter study enrolled patients (pts) with advanced ALK+ NSCLC. Eligible pts had ≤1 prior systemic therapy for advanced NSCLC. Asymptomatic central nervous system (CNS) metastases were allowed. Pts were randomized 1:1 to BRG 180 mg QD with 7-day lead-in at 90 mg or CRZ 250 mg BID. Primary endpoint was blinded independent review committee (BIRC)-assessed progression-free survival (PFS; RECIST v1.1); secondary efficacy endpoints included BIRC-assessed objective response rate (ORR), intracranial ORR (iORR), and intracranial PFS (iPFS). IAs were planned at 50% and 75% of 198 expected PFS events. Results: 275 pts were randomized (BRG/CRZ, n = 137/138); median age (years) 58/60. 26%/27% received prior chemotherapy for advanced disease, and 29%/30% had baseline brain metastases. At data cutoff (19 Feb 2018), with a median follow-up of 11.0/9.3 months (BRG/CRZ) and 99 PFS events, BRG met the prespecified threshold for statistical superiority vs CRZ in the primary endpoint of BIRC-assessed PFS (HR 0.49; 95% CI, 0.33–0.74; log-rank P = 0.0007); BRG median PFS was not reached (NR; 95% CI, NR) vs CRZ 9.8 months (95% CI, 9.0–12.9). Investigator-assessed PFS HR 0.45 (95% CI, 0.30–0.68); log-rank P = 0.0001. Table shows additional efficacy data. Most common grade ≥3 treatment-emergent adverse events (AEs): BRG: increased blood creatine phosphokinase (16.2%) and lipase (13.2%), hypertension (9.6%); CRZ: increased alanine aminotransferase (9.5%), aspartate aminotransferase (5.8%), and lipase (5.1%). Any grade interstitial lung disease/pneumonitis: BRG, 3.7%; CRZ, 2.2%. Discontinuations due to AE (BRG/CRZ): 11.8%/8.8%.Table106OBIRC-Assessed Endpoint, %BRG (n = 137)CRZ (n = 138)P ValueAll ptsORRaResponse, ≥1 assessment;76 (68–83b95% CI;)73 (65–80b95% CI;)Confirmed ORR71 (62–78b95% CI;)60 (51–68b95% CI;)0.0678With any intracranial CNS metastases(n = 43)(n = 47)iORRaResponse, ≥1 assessment;79 (64–90b95% CI;)23 (12–38b95% CI;)Confirmed iORR67 (51–81b95% CI;)17 (8–31b95% CI;)<0.0001Median iPFS, monthsNR (11–NRb95% CI;)6 (4–9b95% CI;)1-year iPFS67 (47–80b95% CI;)21 (6–42b95% CI;)HR0.27 (0.13–0.54)<0.0001cLog-rankWith measurable intracranial CNS metastases(n = 18)(n = 21)iORRaResponse, ≥1 assessment;83 (59–96b95% CI;)33 (15–57b95% CI;)Confirmed iORR78 (52–94b95% CI;)29 (11–52b95% CI;)0.0028a Response, ≥1 assessment;b 95% CI;c Log-rank Open table in a new tab Conclusions: BRG showed a statistically and clinically significant improvement in PFS vs CRZ in ALK inhibitor–naive ALK+ NSCLC. Clinical trial identification: NCT02737501. Editorial acknowledgement: Professional medical writing assistance was provided by Lauren Gallagher, PhD, (Peloton Advantage, Parsippany, NJ) and funded by Millennium Pharmaceuticals, Inc. Legal entity responsible for the study: ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Funding: ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Disclosure: R. Califano: Honoraria, consulting/advisory role: AstraZeneca, BMS, Roche, MSD, Boehringer Ingelheim, Takeda, Novartis, Pfizer, Lilly Oncology. C. Gridelli: Speakers bureau, advisory role: Pfizer, Roche. A. Delmonte: Consulting/advisory role: AstraZeneca, Boehringer Ingelheim. M.R. Garcia Campelo: Honoraria: ARIAD, AstraZeneca, Roche, Pfizer, BMS, Boehringer Ingelheim; Speakers bureau, advisory role: ARIAD, AstraZeneca, Roche, Pfizer, BMS, Boehringer Ingelheim. A. Bearz: Speakers bureau, advisory role: AstraZeneca, Pfizer, Eli Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Takeda. F. Griesinger: Research funding to institution: AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Siemens; Consulting or advisory role: ARIAD, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, ARIAD, AbbVie, Siemens. E. Felip: Consulting/advisory role: AbbVie, AstraZeneca, Blue Print Medicines, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Guardant Health, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda; Speakers bureau: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda. S. Popat: Research funding to institution: Boehringer Ingelheim, Epizyme, BMS, Clovis Oncology, Roche, Lilly, Takeda; Honoraria: Boehringer Ingelheim, AstraZeneca, Roche, Takeda, Chugai Pharma; Consulting or advisory role: Boehringer Ingelheim, Roche, Novartis, Pfizer, AstraZeneca, BMS, MSD, Guardant Health, AbbVie; Travel, accommodations, expenses: Boehringer Ingelheim, BMS, Merck Sharp & Dohme. A. Morabito: Honoraria: AstraZeneca, Roche, Boehringer Ingelheim, Pfizer, MSD, BMS. S. Ghosh: Honoraria/speakers bureau: Pfizer. M. Tiseo: Speakers bureau, advisory role: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Roche. J. Haney, D. Kerstein: Employment, stock and other ownership interests: Arîad. D.R. Camidge: Honoraria: AstraZeneca, Takeda, Arrys/Kyn, Genoptix, G1 Therapeutics (DSMB), Mersana Therapeutics, Roche/Genentech, Ignyta, Daichii Sankyo (ILD adjudication committee), Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med, Orion, Clovis, Celgene, Novartis); Research funding (ARIAD/Takeda). All other authors have declared no conflicts of interest.