Randomized phase II study of preoperative afatinib in untreated head and neck cancers: predictive and pharmacodynamic biomarkers of activity

Grégoire Marret (1, 2) , Stéphane Temam (3, 4, 5) , Maud Kamal (1, 2) , Caroline Even (3, 4, 5) , Jean-Pierre Delord (6, 7) , Caroline Hoffmann (8) , Gilles Dolivet (9, 10) , Olivier Malard (11) , Jérôme Fayette (12, 13) , Olivier Capitain (14) , Sébastien Vergez (6) , Lionel Geoffrois (9) , Frédéric Rolland (15) , Philippe Zrounba (12, 13) , Laurent Laccourreye (16) , Esma Saada-Bouzid (17, 18, 19, 20) , Nicolas Aide (21) , Valérie Bénavent (22) , Jerzy Klijianenko (8) , Constance Lamy (1, 2) , Elodie Girard (23) , Sophie Vacher (1) , Julien Masliah-Planchon (1) , Leanne de Koning (1) , Vincent Puard (1) , Edith Borcoman (1) , Marta Jimenez (22) , Ivan Bièche (1) , Jocelyn Gal (18) , Christophe Le Tourneau (23)

1 Institut Curie [Paris]
2 Département de radiothérapie [Gustave Roussy]
3 Cancer Campus
4 CCF - Département de cancérologie cervico-faciale [Gustave Roussy]
5 Département de médecine oncologique [Gustave Roussy]
6 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
7 ICR - Institut Claudius Regaud
8 U932 - Immunité et cancer
9 UNICANCER/ICL - Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy]
10 CRAN - Centre de Recherche en Automatique de Nancy
11 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
12 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
13 Centre Léon Bérard [Lyon]
14 UNICANCER/ICO - Institut de Cancérologie de l'Ouest [Angers/Nantes]
15 CRLCC René Gauducheau
16 Cytokines : structure, signalisation et prolifération tumorale
17 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
18 UNICANCER/CAL - Centre de Lutte contre le Cancer Antoine Lacassagne [Nice]
19 LIA ROPSE - Laboratoire International Associé Réponse des Organismes et Populations face au Stress Environnemental - Université Côte d’Azur - Centre Scientifique de Monaco
20 CSM - Centre Scientifique de Monaco
21 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
22 UNICANCER
23 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe

There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and pharmacodynamic biomarkers of efficacy of afatinib, a pan-HER tyrosine kinase inhibitor, in a window-of-opportunity trial (NCT01415674). Multi-omics analyses were carried out on pre-treatment biopsy and surgical specimen for biological assessment of afatinib activity. Sixty-one treatment-naïve and operable HNSCC patients were randomised to afatinib 40 mg/day for 21–28 days versus no treatment. Afatinib produced a high rate of metabolic response. Responders had a higher expression of pERK1/2 ( P = 0.02) and lower expressions of pHER4 ( P = 0.03) and pRB1 ( P = 0.002) in pre-treatment biopsy compared to non-responders. At the cellular level, responders displayed an enrichment of tumor-infiltrating B cells under afatinib ( P = 0.02). At the molecular level, NF-kappa B signaling was over-represented among upregulated genes in non-responders ( P < 0.001; FDR = 0.01). Although exploratory, phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy.

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Pharmacologie; Santé publique et épidémiologie

Grégoire Marret, Stéphane Temam, Maud Kamal, Caroline Even, Jean-Pierre Delord, et al.. Randomized phase II study of preoperative afatinib in untreated head and neck cancers: predictive and pharmacodynamic biomarkers of activity. Scientific Reports, 2023, 13, pp.22524. ⟨10.1038/s41598-023-49887-4⟩. ⟨hal-04543900⟩