As reported in The Lancet Oncology by Nancy Y. Lee, MD, and colleagues, the phase III JAVELIN Head and Neck 100 trial showed 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.

The investigators noted that the trial is the first report of a phase III study of an immune checkpoint inhibitor combined with chemoradiotherapy, as well as 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

Study Details

The double-blind trial included 697 patients unselected for PD-L1 status with disease of the oropharynx, hypopharynx, larynx, or oral cavity from sites in 13 countries. They 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 for up to 12 months, both in addition to 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 received a single 10-mg/kg lead-in dose of avelumab or placebo given 7 days prior to the chemotherapy phase. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population.

Progression-Free Survival

The trial was terminated in March 2020 on the basis of futility determined at preplanned interim analysis after 224 events were 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 (interquartile range [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–not estimable) in the avelumab group vs not reached (106 events; 95% CI = 23.0 months–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. Hazard ratios were 1.37 (95% CI = 1.00–1.88) among 249 vs 237 patients with PD-L1 expression < 25% (estimated 2-year rates of 52% vs 59%) and 0.59 (95% CI = 0.28–1.22) among 50 vs 73 with expression ≥ 25% (estimated 2-year rates of 72% vs 52%).

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–not estimable for both), with a stratified hazard ratio of 1.31 (95% CI = 0.93–1.85, P = .94). Objective response was observed in 74% vs 75% of patients, with complete response in 48% vs 51%. Median duration of response was not reached in either 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%, with the most common treatment-related events in the avelumab group being 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%).

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.”

Dr. Lee, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Pfizer and Merck KGaA. For full disclosures of the study authors, visit thelancet.com.