Nancy Y Lee1, Robert L Ferris2, Amanda Psyrri3, Robert I Haddad4, Makoto Tahara5, Jean Bourhis6, Kevin Harrington7, Peter Mu-Hsin Chang8, Jin-Ching Lin9, Mohammad Abdul Razaq10, Maria Margarida Teixeira11, József Lövey12, Jerome Chamois13, Antonio Rueda14, Chaosu Hu15, Lara A Dunn16, Mikhail Vladimirovich Dvorkin17, Steven De Beukelaer18, Dmitri Pavlov19, Holger Thurm19, Ezra Cohen20. 1. Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: leen2@mskcc.org. 2. UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 3. Attikon University Hospital, National Kapodistrian University of Athens, Athens, Greece. 4. Dana-Farber Cancer Institute, Boston, MA, USA. 5. National Cancer Center Hospital East, Kashiwa, Japan. 6. Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland. 7. The Royal Marsden Hospital-The Institute of Cancer Research National Institute for Health Research Biomedical Research Centre, London, UK. 8. Taipei Veterans General Hospital, National Yang Ming University, Taipei, Taiwan. 9. Department of Radiation Oncology, Changhua Christian Hospital, Changhua, Taiwan. 10. Stephenson Cancer Center, University of Oklahoma, Oklahoma, OK, USA. 11. Instituto Português de Oncologia de Coimbra Francisco Gentil, EPE, Coimbra, Portugal. 12. Országos Onkológiai Intézet, Sugárterápiás Osztály Semmelweis Egyetem, Onkológiai Tanszék, Budapest, Hungary. 13. Centre Hospitalier Prive Saint Gregoire, Saint Gregoire, France. 14. Medical Oncology, Costa del Sol Sanitary Agency and Regional University Hospital, IBIMA, Málaga, Spain. 15. Fudan University Cancer Hospital, Xuhui, Shanghai, China. 16. Memorial Sloan Kettering Cancer Center, New York, NY, USA. 17. Budgetary Institution of Healthcare of the Omsk Region, Clinical Oncology Dispensary, Omsk, Russia. 18. Pfizer, Zürich, Switzerland. 19. Pfizer, La Jolla, CA, USA. 20. Moores Cancer Center, UC San Diego Health, La Jolla, CA, USA.
Abstract
BACKGROUND: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. FINDINGS: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). INTERPRETATION: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.
BACKGROUND: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. FINDINGS: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). INTERPRETATION: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.
Authors: Thomas E Bickett; Michael Knitz; Laurel B Darragh; Shilpa Bhatia; Benjamin Van Court; Jacob Gadwa; Shiv Bhuvane; Miles Piper; Diemmy Nguyen; Hua Tu; Laurel Lenz; Eric T Clambey; Kevin Barry; Sana D Karam Journal: Clin Cancer Res Date: 2021-09-13 Impact factor: 12.531
Authors: Pierre Blanchard; Anne W M Lee; Alexandra Carmel; Ng Wai Tong; Jun Ma; Anthony T C Chan; Ruey Long Hong; Ming-Yuan Chen; Lei Chen; Wen-Fei Li; Pei-Yu Huang; Dora L W Kwong; Sharon S X Poh; Roger Ngan; Hai-Qiang Mai; Camille Ollivier; George Fountzilas; Li Zhang; Jean Bourhis; Anne Aupérin; Benjamin Lacas; Jean-Pierre Pignon Journal: Clin Transl Radiat Oncol Date: 2021-11-26
Authors: Steven H Lin; Henning Willers; Sunil Krishnan; Jann N Sarkaria; Michael Baumann; Theodore S Lawrence Journal: Int J Radiat Oncol Biol Phys Date: 2021-08-25 Impact factor: 8.013