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

Author:

Marret Grégoire1,Temam Stéphane2,Kamal Maud1,Even Caroline3,Delord Jean-Pierre4,Hoffmann Caroline1,Dolivet Gilles5,Malard Olivier6,Fayette Jérôme7,Capitain Olivier8,Vergez Sébastien9,Geoffrois Lionel5,Rolland Frédéric10,Zrounba Philippe7,Laccourreye Laurent11,Saada-Bouzid Esma12,Aide Nicolas13,Bénavent Valérie14,Klijianienko Jerzy15,Lamy Constance1,Girard Elodie16,Vacher Sophie1,Masliah-Planchon Julien1,de Koning Leanne17,Puard Vincent1,Borcoman Edith1,Jimenez Marta14,Bièche Ivan1,Gal Jocelyn18,Tourneau Christophe Le1

Affiliation:

1. Institut Curie

2. Institut Gustave Roussy

3. Gustave Roussy

4. Institut Universitaire du Cancer de Toulouse

5. Institut de Cancérologie de Lorraine

6. Centre Hospitalier Universitaire Nantes

7. Centre Leon Berard

8. Centre Paul Papin

9. Institut Claudius Regaud

10. Centre René Gauducheau

11. Centre hospitalier universitaire d'Angers

12. Centre Antoine Lacassagne Cancer Institute

13. Centre François Baclesse

14. UNICANCER

15. Institut Curie, PSL University, Pathology Department

16. Institut Curie, PSL University

17. Institut Curie, PSL Research University, Translational Research Department, F -75005, Paris

18. Centre Antoine Lacassagne

Abstract

Abstract 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.

Publisher

Research Square Platform LLC

Reference59 articles.

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