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Cited by 661Head and Neck Cancer StudiesCancer Immunotherapy and BiomarkersColorectal and Anal Carcinomas

Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Lee, Nancy Y, Ferris, Robert L, Psyrri, Amanda, Haddad, Robert I, Tahara, Makoto, Bourhis, Jean, Harrington, Kevin, Chang, Peter Mu-Hsin +13 more·2021·The Lancet Oncology
DOI 10.1016/s1470-2045(20)30737-3
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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/m 2 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.

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  • In phase 3 NCT02952586, avelumab plus standard-of-care chemoradiotherapy in HNSCC did not meet the primary endpoint (PFS).

    “Furthermore, in the phase 3 study NCT02952586 exploring the efficacy of avelumab plus standard-of-care chemoradiotherapy in HNSCC, it did not meet the primary endpoint (PFS) [86].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [86]

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Authors
Lee, N. Y., Ferris, R. L., Psyrri, A., Haddad, R. I., Tahara, M., Bourhis, J., Harrington, K., Chang, P. M.-H., Lin, J.-C., Razaq, M. A., Teixeira, M. M., Lövey, J., Chamois, J., Rueda, A., Hu, C., Dunn, L. A., Dvorkin, M. V., De Beukelaer, S., Pavlov, D., Thurm, H., & Cohen, E.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • UPMC Hillman Cancer Center (US)
  • National and Kapodistrian University of Athens (GR)
  • Dana-Farber Cancer Institute (US)
  • National Cancer Center Hospital East (JP)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • Institute of Cancer Research (GB)
  • Taipei Veterans General Hospital (TW)
  • Changhua Christian Hospital (TW)
  • OU Health Stephenson Cancer Center (US)
  • Instituto Português de Oncologia de Coimbra Francisco Gentil (PT)
  • Semmelweis University (HU)
  • Centre Hospitalier privé Saint Grégoire (FR)
  • Instituto de Investigación Biomédica de Málaga (ES)
  • Fudan University (CN)
  • Budgetary Health Care Institution of the Omsk Region "Clinical Oncology Center" (RU)
  • Pfizer (United States) (US)
  • UC San Diego Health System (US)
Corresponding author
Lee, Nancy Y
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2021-04
Volume
22
Issue
4
Pages
450-462
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(20)30737-3
OpenAlex
W3147500389
Cited by
661
References
26
Citations by year
2026: 112 · 2025: 148 · 2024: 121 · 2023: 137 · 2022: 100 · 2021: 43
FWCI
87.84
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • Merck KGaA
  • Pfizer
  • Merck
Topics
  • Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Surgery › Colorectal and Anal Carcinomas
Keywords
PD-L1 blockade, head and neck squamous cell carcinoma, locally advanced cancer, chemoradiotherapy, cisplatin, intensity-modulated radiotherapy, progression-free survival, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, oral cancer, maintenance therapy, immune checkpoint inhibitors, treatment discontinuation, adverse events
MeSH terms
Squamous Cell Carcinoma of Head and Neck, Progression-Free Survival, Adult, Aged, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Cisplatin, Double-Blind Method, Female, Germany, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Placebos, Standard of Care, Chemoradiotherapy, B7-H1 Antigen, Antibodies, Monoclonal, Humanized

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