Barbara Burtness1, Robert Haddad2, José Dinis3, José Trigo4, Tomoya Yokota5, Luciano de Souza Viana6, Ilya Romanov7, Jan Vermorken8, Jean Bourhis9, Makoto Tahara10, José Getulio Martins Segalla11, Amanda Psyrri12, Irina Vasilevskaya13, Chaitali Singh Nangia14, Manuel Chaves-Conde15, Naomi Kiyota16, Akihiro Homma17, Petra Holeckova18, Josep Maria Del Campo19, Nirav Asarawala20, Ulisses Ribaldo Nicolau21, Daniel Rauch22, Caroline Even23, Bushi Wang24, Neil Gibson25, Eva Ehrnrooth26, Kevin Harrington27, Ezra E W Cohen28. 1. Department of Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 3. Instituto Português de Oncologia, Porto, Portugal. 4. Department of Medical Oncology, Hospital Virgen de la Victoria, IBIMA, Malaga, Spain. 5. Division of Gastrointestinal Oncology, Shizuoka Cancer Centre, Shizuoka, Japan. 6. Department of Medical Oncology, Hospital Marcio Cunha, Ipatinga, Brazil. 7. Russian Oncological Research Centre, Moscow, Russia. 8. Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium. 9. Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 10. Department of Head and Neck Medical Oncology, National Cancer Centre Hospital East, Kashiwa, Japan. 11. Department of Clinical Oncology, Hospital Amaral Carvalho, Jau, Brazil. 12. Department of Internal Medicine, National Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece. 13. Oncology Centre of Moskovskiy, St Petersburg, Russia. 14. Comprehensive Cancer Centre, University of California at Irvine, Orange. 15. Department of Oncology, Hospital Virgen del Rocio, Sevilla, Spain. 16. Department of Medical Oncology and Hematology, Kobe University Hospital Cancer Center, Kobe, Japan. 17. Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan. 18. Department of Oncology and Radiotherapy, Hospital Na Bulovce and 1st Medical Faculty of Charles University, Prague, Czech Republic. 19. Department of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. 20. Shree Krishna Hospital and Medical Research Centre, Gujarat, India. 21. Department of Clinical Oncology, AC Camargo Cancer Center, São Paulo, Brazil. 22. Inselspital, University Hospital Bern, Bern, Switzerland. 23. Department of Head and Neck Cancer, Gustave Roussy, Villejuif, France. 24. Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut. 25. Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. 26. Boehringer Ingelheim, Danmark A/S, Denmark. 27. Division of Radiotherapy and Imaging, The Royal Marsden Hospital/The Institute of Cancer Research, National Institute for Health Research Biomedical Research Centre, London, United Kingdom. 28. Department of Translational Science, Moores Cancer Centre, University of California at San Diego, La Jolla.
Abstract
IMPORTANCE: Locoregionally 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. OBJECTIVE: To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC. DESIGN, SETTING, AND PARTICIPANTS: This 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. INTERVENTIONS: Patients 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 MEASURES: The 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. RESULTS: A 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 RELEVANCE: This 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 REGISTRATION: ClinicalTrials.gov identifier: NCT01345669.
IMPORTANCE: Locoregionally 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. OBJECTIVE: To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC. DESIGN, SETTING, AND PARTICIPANTS: This 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. INTERVENTIONS: Patients 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 MEASURES: The 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. RESULTS: A 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 RELEVANCE: This 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 REGISTRATION: ClinicalTrials.gov identifier: NCT01345669.
Authors: Salvatore Alfieri; Andrea Carenzo; Francesca Platini; Mara S Serafini; Federica Perrone; Donata Galbiati; Andrea P Sponghini; Roberta Depenni; Andrea Vingiani; Pasquale Quattrone; Edoardo Marchesi; Maria F Iannó; Arianna Micali; Elisa Mancinelli; Ester Orlandi; Sara Marceglia; Laura D Locati; Lisa Licitra; Paolo Bossi; Loris De Cecco Journal: Cancers (Basel) Date: 2020-04-09 Impact factor: 6.639