No Progression-Free Survival Benefit With First-Line Avelumab Plus Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck

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As reported in The Lancet Oncology by Nancy Y. Lee, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, the phase III JAVELIN Head and Neck 100 trial has shown no improvement in progression-free survival with the addition of the PD-L1 inhibitor avelumab to chemoradiotherapy in patients with previously untreated locally advanced squamous cell carcinoma of the head and neck.1

The investigators noted that the trial is the first report of a phase III study of an immune checkpoint inhibitor combined with chemoradiotherapy and the first report of a phase III trial of an immune checkpoint inhibitor in locally advanced squamous cell carcinoma of the head and neck.

Nancy Y. Lee, MD

Nancy Y. Lee, MD

Study Details

In the double-blind trial, 697 patients unselected for PD-L1 status with disease of the oropharynx, hypopharynx, larynx, or oral cavity from sites in 13 countries were randomly assigned between December 2016 and January 2019 to receive intravenous avelumab at 10 mg/kg (n = 350) or placebo (n = 347) every 2 weeks throughout chemoradiotherapy and up to 12 months after chemoradiotherapy. The 9-week chemoradiotherapy phase consisted of cisplatin at 100 mg/m2 on days 1, 22, and 43 plus intensity-modulated radiotherapy with standard fractionation of 70 Gy in 35 fractions over 7 weeks. Patients also received a single 10-mg/kg avelumab or placebo lead-in dose, given 7 days prior to the chemotherapy phase. Randomization was stratified by human papillomavirus (HPV) status, tumor stage, and nodal stage. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population.

The avelumab vs placebo chemoradiotherapy groups were well balanced. The median patient age was 60 years (interquartile range [IQR] = 54–65 years, 29% ≥ 65 years) vs 59 years (IQR = 54–65 years, 29% ≥ 65 years), 83% vs 82% were male, 64% vs 66% were White, and 29% vs 25% were Asian. Eastern Cooperative Oncology Group performance status was 0 (55% vs 62%) or 1 in all patients. Geographic region was North America for 23% vs 27%, Western Europe for 30% vs 33%, Eastern Europe for 15% vs 13%, and Asia for 29% vs 24%. HPV status was positive in 35% vs 34% and negative in 65% vs 66%. Tumor stage was < T4 in 57% vs 56% and T4 in 43% vs 44%, nodal stage was N0–N2b in 53% vs 52% and N2c–N3 in 47% vs 48%, and the site of the primary tumor was the oral cavity in 13% vs 14%, oropharynx in 45% vs 49%, larynx in 17% vs 19%, and hypopharynx in 25% vs 18%.

Progression-Free Survival

The trial was terminated in March 2020 on the basis of futility, determined at preplanned interim analysis after 224 progression-free survival events had been observed. Patient study treatment was stopped, and follow-up for progression-free survival and overall survival was discontinued.

Median follow-up for progression-free survival was 14.6 months (IQR = 8.5–19.6 months) in the avelumab group and 14.8 months (IQR = 11.6–18.8 months) in the placebo group. Median progression-free survival was not reached (118 events; 95% confidence interval [CI] = 16.9 months to not estimable) in the avelumab group vs not reached (106 events; 95% CI = 23.0 months to not estimable) in the placebo group (stratified hazard ratio [HR] = 1.21, 95% CI = 0.93–1.57, P = .92). Estimated 2-year progression-free survival was 53% vs 57%.

Subgroup analyses were consistent with the primary analysis, with hazard ratios favoring the placebo group in most subgroups. For stratification factors, hazard ratios were 1.26 (95% CI = 0.74–2.15) for HPV-positive status and 1.16 (95% CI = 0.86–1.57) for HPV-negative status, 1.17 (95% CI = 0.80–1.71) for stage < T4 and 1.22 (95% CI = 0.85–1.75) for stage T4, and 1.09 (95% CI = 0.74–1.60) for nodal stage N0–N2b and 1.33 (95% CI = 0.93–1.91) for nodal stage N2c–N3. Hazard ratios were 1.37 (95% CI = 1.00–1.88) among 249 vs 237 patients with PD-L1 expression < 25% and 0.59 (95% CI = 0.28–1.22) among 50 vs 73 with PD-L1 expression ≥ 25%. Though a very small subset, there is a hint of benefit with the addition of avelumab among patients with PD-L1 expression ≥ 25%.

Median follow-up for overall survival was 16.7 months (IQR = 12.8–21.2 months) in the avelumab group and 16.8 months (IQR = 13.1–20.8 months) in the placebo group. Overall survival was not formally tested, per study protocol, since the study did not meet the primary endpoint of progression-free survival. Median overall survival was not reached in the avelumab group or the placebo group (95% CI = not estimable to not estimable for both), with a stratified hazard ratio of 1.31 (95% CI = 0.93–1.85, P = .94). An objective response was observed in 74% vs 75% of patients, with a complete response in 48% vs 51%. Median duration of response was not reached in either group.


  • The trial was stopped due to futility.
  • Median progression-free survival was not reached in either group, with a nonsignificant hazard ratio for progression-free survival favoring the placebo vs avelumab group.

Adverse Events

Grade ≥ 3 adverse events occurred in 88% of patients in the avelumab group vs 82% of the placebo group and were considered related to treatment in 80% vs 74%; the most common treatment-related events in the avelumab group were neutropenia (16% vs 15% of the placebo group), mucosal inflammation (14% vs 13%), dysphagia (14% vs 14%), and anemia (12% vs 13%). Infusion-related reactions occurred in 22% (grade 3 in 2%) vs 3% (grade 3 in < 1%) of patients. 

Potential immune-related adverse events occurred in 35% (grade ≥ 3 in 5%) vs 26% (grade ≥ 3 in 2%), with the most common in the avelumab group being thyroid disorders (25% vs 17%). Serious treatment-related adverse events occurred in 36% vs 32%. Death related to treatment occurred in two patients (1%) in the avelumab group (due to general disorders/site conditions and vascular rupture) and one patient (< 1%) in the placebo group (due to acute respiratory failure).

The investigators concluded: “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 [chemoradiotherapy].” 

DISCLOSURE: The study was funded by Pfizer and Merck KGaA. Dr. Lee has served as a consultant or advisor to Merck, Merck Serono, Pfizer, and Sanofi; has received research funding from AstraZeneca; and has received institutional research funding from Pfizer.


1. Lee NY, Ferris RL, Psyrri A, et al: 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. Lancet Oncol 22:450-462, 2021.


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