Final PFS, updated OS and safety data from the randomised, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC

Background: We report mature PFS, updated OS and safety data from the global phase III ALEX study (NCT02075840) of ALC vs CRZ in patients (pts) with untreated ALK+ NSCLC after a further 12 months (m) of follow-up (cutoff date: 30 Nov 2018). Methods: Eligible pts had stage IIIB/IV ALK+ NSCLC (by central IHC), ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Asymptomatic CNS metastases (mets) were allowed. Pts were randomised 1:1 to twice-daily ALC 600mg (n = 152) or CRZ 250mg (n = 151). Primary endpoint: investigator (INV)-assessed PFS (RECIST v1.1), with q8w CNS imaging in all pts. Results: Mature, median INV-assessed PFS: 34.8 m (95% CI 17.7–NR) ALC vs 10.9 m (95% CI 9.1–12.9) CRZ (ITT stratified HR 0.43, 95% CI 0.32–0.58; p < 0.0001); pts with event, 53.3% ALC vs 80.8% CRZ. Median duration of follow-up: 37.8 m ALC vs 23.0 m CRZ. Median INV-assessed PFS was longer with ALC vs CRZ in pts with baseline (BL) CNS mets (25.4 m vs 7.4 m, respectively, HR 0.37, 95% CI 0.23–0.58) and in those without (38.6 m vs 14.8 m, respectively, HR 0.46, 95% CI 0.31–0.68). PFS event-free rate was higher with ALC vs CRZ regardless of BL CNS mets status, with 43.7% of ALC pts event-free at 4 years (Table). OS data remain immature (events: 32%; stratified HR 0.69, 95% CI 0.47–1.02). OS in pts with CNS mets at BL, HR 0.60 (95% CI 0.34–1.05) and in pts without CNS mets at BL, HR 0.77 (95% CI 0.45–1.32). The 4-year OS rate was 64.5% (95% CI 55.6–73.4) with ALC vs 52.2% (95% CI 42.6–64.8) with CRZ. Despite longer median treatment duration with ALC vs CRZ (27.7 m vs 10.8 m), the safety profile for ALC remains favourable; fewer ALC-treated pts experienced grade 3–5 AEs (48.7% vs 55.0% CRZ). Conclusions: This final updated PFS analysis confirms the superior efficacy and favourable tolerability of ALC compared with CRZ in pts with untreated ALK+ NSCLC. OS data remain immature (stratified HR 0.69, 95% CI 0.47–1.02), with a 4-year OS rate of 64.5% (95% CI 55.6–73.4) with ALC. [Table presented] Clinical trial identification: NCT02075840. Editorial acknowledgement: Nicola Griffin of Gardiner-Caldwell Communications; funded by F. Hoffmann-La Roche. Legal entity responsible for the study: F. Hoffmann-La Roche Ltd. Funding: F. Hoffmann-La Roche Ltd. Disclosure: T.S.K. Mok: Leadership role: Sanonics Ltd.; Honoraria (self), Advisory / Consultancy: ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chimed, Cirina, Fishawack Facilitate, Ignyta, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, SFJ Pharm; Research grant / Funding (self): AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, SFJ Pharmaceutical and XCovery. A.T. Shaw: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche Ltd, Genentech, Pfizer, Novartis, Ariad, Ignyta, Daiichi-Sankyo, Taiho, Blueprint medicines, LOXO, EMD Serono and Foundation medicine. R.D. Camidge: Honoraria (self), Advisory / Consultancy: AbbVie, Ariad, Array, Celgene, Clovis Oncology, Eli Lilly, Genoptix, G1 Therapeutics, Novartis, Orion, and F. Hoffmann-La Roche Ltd/Genentech. S.M. Gadgeel: Honoraria (self), Advisory / Consultancy: Ariad, AstraZeneca, Bristol-Myers Squibb, Pfizer and F. Hoffmann-La Roche Ltd/Genentech. R. Dziadziuszko: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche Ltd, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca and Tesaro. D. Kim: Travel / Accommodation / Expenses: F. Hoffmann-La Roche Ltd, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca and Tesaro; Travel / Accommodation / Expenses: Novartis Oncology; Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery and Yuhan. M. Perol: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche Ltd/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Sharp & Dohme, Chugai, Bristol-Myers Squibb, Amgen, Novartis, Pierre Fabre, AstraZeneca, Takeda; Research grant / Funding (institution): F. Hoffmann-La Roche Ltd, AstraZeneca, Chugai and Takeda. S. Ou: Honoraria (self): ARIAD, AstraZeneca, Pfizer, F. Hoffmann-La Roche Ltd/Genentech and TP Therapeutics; Speaker Bureau / Expert testimony: ARIAD, AstraZeneca and F. Hoffmann-La Roche Ltd/Genentech; Research grant / Funding (self): ARIAD, AstraZeneca, Daiichi Sankyo, Pfizer and F. Hoffmann-La Roche Ltd/Genentech; Shareholder / Stockholder / Stock options: TP Therapeutics. W. Bordogna: Full / Part-time employment: F. Hoffmann-La Roche Ltd. V. Smoljanović: Full / Part-time employment: F. Hoffmann-La Roche Ltd. M. Hilton: Full / Part-time employment: F. Hoffmann-La Roche Ltd. S. Peters: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche Ltd, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Nova. All other authors have declared no conflicts of interest.