Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND

At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population.

METHODS

This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m

FINDINGS

Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause).

INTERPRETATION

The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation.

FUNDING

French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé.

TRANSLATION

For the French translation of the abstract see Supplementary Materials section.

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests JG has been an advisory board member for Bristol Myers Squibb, Hookipa Pharma, MSD, Merck, Nanobiotix, and Roche, outside the submitted work; reports support for attending meetings or travel, or both, from Merck and MSD; and received grant support, paid to his institution, from the GEMLUC (Groupement des Entreprises Monégasques dans la Lutte Contre le Cancer and GEFLUC (Groupement des Entreprises Françaises dans la Lutte contre le Cancer), and the French National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer, through the French programme PAIR-VADS. CE reports receiving consulting fees from Bristol Myers Squibb, Elevar, F-star Therapeutics, Innate Pharma, Merck Serono, MSD, and Novartis outside the submitted work; and support for attending meetings or travel, or both, from MSD and Merck Serono. PDe reports personal fees from LEO Pharma and Pfizer, and support for attending meetings or travel, or both, from Pfizer, outside the submitted work. JF reports personal fees from MSD, Merck, Sanofi, Bristol Myers Squibb, Roche, AstraZeneca, Seagen, Hookipa, and Elevar; has been an advisory board member for Roche, Seagen, and Elevar; and reports support for attending meetings or travel, or both, from MSD and Merck, outside the submitted work. ESB reports personal fees from MSD and Merck Serono, and support for attending meetings or travel, or both, from MSD and Merck Serono, outside the submitted work. PDa reports personal fees from Gilead Science and support for attending meetings or travel from Lilly, or both, and has been an advisory board member for Pfizer, outside the submitted work. CF reports personal fees from Astellas Pharma, AstraZeneca, Biogaran, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology, Eisai, GSK, Leo Pharma, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Seagen, and Viatris; and non-financial support from AstraZeneca, Janssen Oncology, Đeo Pharma, and Pierre Fabre, outside the submitted work. JB reports support for attending meetings from Bristol Myers Squibb, Merck, Nanobiotix, and MSD; participated on advisory boards for Merck, MSD, Bristol Myers Squibb, Nanobiotix, and Roche; and reports consulting fees from Bristol Myers Squibb, Merck, Nanobiotix, MSD, and Roche, outside the submitted work. AA has been an advisory member for MSD, outside the submitted work; and received grant support, paid to their institution, from the French National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer for a study grant through the French programme PAIR-VADS. All other authors declare no competing interests.