Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial

Kunitoshi Yoshino , Koji Matsumoto , Shunji Takahashi , Kazuto Matsuura , Miguel Angel Alvarez Avitia , Hector Jorge Gonzalez Riestra , E. Van Meerten , J. Buter , A. J. Gelderblom , Andrzej Kawecki , Wojciech Golusinski , Rui Dinis , Leonor Ribeiro , Regina Silva , Helder Mansinho , Irina Selezneva , Mikhail Biakhov , Rinat Galiulin , Adel Izmailov , Vladimir Vladimirov , Valery Vinogradov , Fagim Mufazalov , Neus Baste , Josep Ma Del Campo , Ricard Mesia Nin , Antonio Lopez Pousa , Juan Jose Grau De Castro , Oscar Reig , Ruth Vera , Josemanuel Trigo , Lara Iglesias , Javier Martinez Trufero , Sergio Vazquez , Belen Rubio , Jose Enrique Ales , Esther Villar , Jordi Rubio , Yolanda Escobar , Ainara Soria , Mauel Chaves , Gun Wickart Johansson , Signe Friesland , Roger Tell , Jan Nyman , Sacha Rothschild , Alfred Zippelius , Nurguel Usluoglu , Inna Gogunska , Dmytro Zabolotniy , Yuriy Vinnyk , Oleksandr Burian , Andrew Sykes , David Peel , James Lester , Martin Robinson , Devraj Srinivasan , Ioanna Fragkandrea-Nixon , Elizabeth Junor , Simon Gollins , Mererid Evans , Kate Newbold , David Hwang , Stefano Schipani , Mohammed Rizwanullah , Omar Atiq , Konstantinos Arnaoutakis , Jessica Bauman , Ranee Mehra , Hyunseok Kang , Christine Chung , Thomas Davis , Antonio Jimeno , Roger Keresztes , Chaitali Nangia , Sai-Hong Ignatius , Yungpo Bernard Su , Lindsay Carol Overton , Mitchell A. Garrison , Woondong Jeong , Ahmad Wehbe , Athanassios Argiris , Anne Chiang , Daniel Morgensztern , Missak Haigentz , Danko Martincic , Mercedes Porosnicu , Barbara Burtness , Robert Haddad , Jose Dinis , Jose Trigo , Ilya Romanov , Jan Vermorken , Jean Bourhis , Amanda Psyrri , Irina Vasilevskaya , Chaitali Singh Nangia , Manuel Chaves-Conde , Josep Maria del Campo , Daniel Rauch , Bushi Wang , Neil Gibson , Eva Ehrnrooth , Kevin Harrington , Ezra E. W. Cohen , Raul Eduardo Giglio , Cesar Raul Blajman , Jose Mario Freue , Norma Graciela Pilnik , Felipe Salvador Palazzo , Margaret Mcgrath , Thorsten Fureder , Gabriela Kornek , Angelika Pichler , Thomas Bauernhofer , Christoph Tinchon , Richard Greil , Martin Burian , Heinz Kienzer , Pol Specenier , Brieuc Sautois , Philip Debruyne , Marie-Pascale Graas , Annelies Maes , Christophe Lonchay , Jean-Francois Daisne , Christel Fontaine , Gilberto Castro Junior , Frias De Oliveira , Rodrigo Perez Pereira , Pedro Rafael Martins de Marchi , Luciano de Souza Viana , Jose Getulio Martins Segalla , Ulisses Ribaldo Nicolau , Nicolas Silva Lazaretti , Swati Kulkarni , Yasmin Alam , Cheryl Ho , George Shenouda , Denis Soulieres , Khalil Sultanem , Simron Singh , Pablo Gonzalez Mella , Jose Antonio Solis Campos , Petra Holeckova , Jana Prausova , Radka Obermannova , Jeppe Friborg , Lena Specht , Amr Abdelaziz Elsaid , Heikki Minn , Laurent Martin , Frederic Rolland , Philippe Ceruse , Gilles Calais , Caroline Even , Joe Guigay , Charles Ferte , Frederic Peyrade , Florence Duffaud , Elise Champeaux-Orange , Alexandre Coutte (1) , Florian Clatot , Pierre Fournel , Laurence Bozec Le Moal , Andreas Dietz , Viktor Gruenwald , Thomas Gauler , Orlando Guntinas-Lichius , Guido Hildebrandt , Thomas Kuhnt , Horst-Juergen Schmidt , Michael Henke , Anja Rueckert , Wolfram Brugger , Nicole Rotter , Rolf Mahlberg , Vasilios Karavasilis , Georgios Fountzilas , Diamanto Psyrri , Istvan Lang , Andras Boer , Judit Kocsis , Gabor Pajkos , Laszlo Tamas , A. L. Anand , Murali Voona , Ananda Selvakumar Pandy , Kirushna Kumar , Raj Kumar Poovna Nathan , Venkatesan Srinivasan , Bhooshan Zade , Minish Jain , B. J. Srinivasa , Radheshyam Naik , B. K. Mohanty , Nirav Asarawala , Tomer Charas , Salem Billan , Aron Popovtzer , Lisa Licitra , Daris Ferrari , Paolo Fao , Marco Merlano , Maria Cossu Rocca , Akihiro Homma , Hirofumi Fujii , Makoto Tahara , Syujiro Minami , Masato Fujii , Tomoya Yokota , Shigenori Kadowaki , Kei Muro , Naomi Kiyota , Kenji Okami , Toshinari Yagi

1 CHIMERE - CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516

ImportanceLocoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC. ObjectiveTo assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC. Design, Setting, and ParticipantsThis multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population. InterventionsPatients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal. Main Outcomes and MeasuresThe primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life. ResultsA total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P=.48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group). Conclusions and RelevanceThis study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended. Trial RegistrationClinicalTrials.gov identifier: NCT01345669

Domaines: Sciences du Vivant [q-bio]

Kunitoshi Yoshino, Koji Matsumoto, Shunji Takahashi, Kazuto Matsuura, Miguel Angel Alvarez Avitia, et al.. Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial. JAMA oncology, 2019, 5 (8), pp.1170-1180. ⟨10.1001/jamaoncol.2019.1146⟩. ⟨hal-03600495⟩