Alectinib for the treatment of pretreated RET-rearranged advanced NSCLC: Results of the ETOP ALERT-lung trial.

BACKGROUND

Alectinib, a highly selective next generation ALK-inhibitor, has exhibited potent anti-tumour activity in RET-rearranged NSCLC in the preclinical stage.

METHODS

ALERT-lung is a single-arm, phase II trial evaluating the activity of alectinib for the treatment of pretreated RET-rearranged advanced NSCLC. Alectinib was administered orally, 600 mg, twice per day until progression, refusal or unacceptable toxicity (treatment could continue beyond progression, if patient was deriving clinical benefit). Patient recruitment closed prematurely due to discouraging results for alectinib in a phase I/II study in the same indication.

RESULTS

All 14 patients who enrolled until the premature accrual closure, received at lease one dose of alectinib. Among them, median age was 61 years, majority (71 %) was female, never smokers, of ECOG PS 1. No objective response (complete or partial response) was recorded. Of the 13 evaluable patients, three (23 %) achieved and maintained disease stabilisation for 24 weeks. Up to 31 March 2021 (median follow-up 15.9 months), 12 PFS-events (92 %) were observed, with median PFS of 3.7 months (95 % C.I.: 1.8 - 7.3 months). Overall, three deaths (23 %) were reported. Seven patients (50 %) experienced grade ≥ 3 adverse events, while three discontinued treatment due to erythema multiforme of grade 3, related to alectinib. No treatment-related serious adverse event was reported.

CONCLUSIONS

Accrual into our trial was terminated early in response to other reports of limited activity of alectinib in patients with RET-fusion NSCLC and the emergence of more potent selective RET-inhibitors. Also in our trial, alectinib did not show the expected potential for anti-tumour activity in NSCLC.

Informations de copyright

Copyright © 2022 Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Enriqueta Felip reports grants for oncology innovation (GOI) from Merck Healthcare KGAa and Fundación Merck Salud, consulting fees from Amgen, Astra Zeneca, Bristol Myers Squibb, Daichii Sankyo, Eli Lilly, F. Hoffmann-La Roche, Glaxo Smith Kline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Sanofi, and Takeda, payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Peervoice, Pfizer, Sanofi, Takeda, and Touch Oncology, she also reports to be an independent board member of GRÍFOLS. Urania Dafni reports a honorarium as Member of the Tumor Agnostic Evidence Generation working Group of Roche. Thierry Berghmans reports consulting fees from Inhatarget and reported participation on a Data Safety Monitoring Board or Advisory Board for BMS, Bayer, Merck, Janssen, and Roche. Francesco Passiglia reports consulting fees from Merck Sharp and Dohme, Astrazeneca, Janssen, Amgen, and Beigene, payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen, Amgen, Pfizer, and ThermoFisher Scientific, support for attending meetings and/or travel from Roche and Amgen, he also reports participation on a Data Safety Monitoring Board or Advisory Board for Amgen and Janssen. Anne-Marie C. Dingemans reports grants or contracts from Amgen, Dutch Cancer Society, and HANART, consulting fees from Amgen, Bayer, Boehringer Ingelheim, Sanofi, and Roche, payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen, Pfizer, AstraZeneca, Lilly, and Takeda, reports participation on a Data Safety Monitoring Board or Advisory Board for Takeda and Roche, leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as chair of EORTC LCG (unapaid). Santiago Viteri reports payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, BMS, TAKEDA, CURIO, and ROCHE, payments for expert testimony from REDDY PHARMA IBERIA, support for attending meetings and/or travel from OSE IMMUNOTHERAPEUTHICS, MSD, TAKEDA, and MERCK, reports participation on a data safety monitoring board or advisory board for MERCK, JANSSEN, PUMA, ASTRA ZENECA, BMS, TAKEDA, and ROCHE. Christian Britschgi reports consulting fees from Astra Zeneca, Pfizer, Roche, Takeda, Janssen-Cilag, Boehringer-Ingelheim, support for attending meetings and/or travel from AstraZeneca and Takeda. Sinead Cuffe reports support for attending meetings and/or travel from MSD, BMS, and Pfizer. Mariano Provencio reports grants or contracts from BMS, MSD, Lilly, AZ, and Takeda, consulting fees from BMS, MSD, Lilly, AZ, and Takeda, payments or honoraria for lectures from BMS, MSD, AZ, and Takeda, support for attending meetings from MSD and AZ. Sabine Merkelbach-Bruse reports payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, QuIP, Targos, Roche, Novartis, GSK, Molecular Health, Janssen, BMS, and MSD, support for attending meetings and/or travel from BMS, reports participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Roche, Novartis, GSK, Molecular Health, Janssen, Merck, Amgen, and Onkowissen. Solange Peters reports grants/research support from Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, GSK,Merck Sharp and Dohme, and Roche/Genentech, consulting fees from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen,Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, and Vaccibody, payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Mirati, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, and Takeda. Jürgen Wolf reports participation on advisory boards for Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, and Takeda, reports lecture fees from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, and Takeda, reports research support to institution from BMS, Janssen Pharmaceutica, Novartis, Pfizer. Rolf A. Stahel reports grants or contracts from AstraZeneca, BMS, Daiichi Sankyo, Celgene, Ipsen, Janssen, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, and Roche. Consulting fees from AstraZeneca, BMS, Boehringer Ingelheim, Janssen, Merck, MSD, Novartis, Novocure, Pfizer, and Roche, payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Blueprint, Boehringer Ingelheim, GSK, MSD, Roche, and Sandoz, he also reports participation on a data safety monitoring board or advisory board for Genentech/Roche, MSD, and Takeda. All other authors declare no conflicts of interest.