As reported in The Lancet Oncology by Jean-Pascal Machiels, MD, and colleagues, the phase III KEYNOTE-412 trial showed no significant improvement in event-free survival with the addition of pembrolizumab to concurrent chemoradiotherapy in newly diagnosed patients with high-risk locally advanced head and neck squamous cell carcinoma (HNSCC).
Jean-Pascal Machiels, MD
Study Details
In the double-blind trial, 804 patients from 133 sites globally were randomly assigned between April 2017 and May 2019 to receive pembrolizumab at 200 mg (n = 402) or placebo (n = 402) plus chemoradiotherapy. Pembrolizumab and placebo were given every 3 weeks for up to 17 doses (1 before chemoradiotherapy, 2 during chemoradiotherapy, and 14 as maintenance therapy). Chemoradiotherapy consisted of cisplatin at 100 mg/m2 every 3 weeks for two or three doses and physician’s choice of accelerated (6 fractions per week) or standard (5 fractions per week) fractionation radiotherapy at 70 Gy in 35 fractions. About 82% of patients in the trial were male, and 77% were White. The primary endpoint was event-free survival in the intention-to-treat population.
Event-Free Survival
Median follow-up was 47.7 months (interquartile range = 42.1–52.3 months). Median event-free survival was not reached (95% confidence interval [CI] = 44.7 months to not reached) in the pembrolizumab group vs 46.6 months (95% CI = 27.5 months to not reached) in the control group (hazard ratio [HR] = 0.83, 95% CI = 0.68–1.03, P = .043, which did not reach the predetermined significance threshold of P ≤ .024). Event-free survival at 2 years was 63% vs 56% (HR = 0.83, 95% CI = 0.68–1.03).
In the prespecified subgroup analysis among patients with a PD-L1 combined positive score ≥ 1, median event-free survival was not reached (95% CI = 50.2 months to not reached) in 339 patients in the pembrolizumab group vs 45.2 months (95% CI = 26.8 months to not reached) in 356 control group patients (HR = 0.80, 95% CI = 0.64–1.00); 24-month event-free survival was 64% vs 56%.
At 24 months, rates of loss of locoregional control were 12% vs 15% (HR = 0.83, 95% CI = 0.58–1.19) and distant metastasis–free survival was 71% vs 66% (HR = 0.84, 95% CI = 0.67–1.05). At 3 years, estimated overall survival was 72% vs 70% (HR = 0.90, 95% CI = 0.71–1.15).
Adverse Events
Grade ≥ 3 adverse events occurred in 92% of patients in the pembrolizumab/chemoradiation group vs 88% of the placebo/chemoradiation group, most commonly decreased neutrophils (27% vs 25%), stomatitis (20% vs 17%), anemia (20% vs 15%), dysphagia (19% vs 16%), and decreased lymphocytes (19% vs 20%). Serious adverse events occurred in 62% vs 49% of patients, most commonly pneumonia (11% vs 6%), acute kidney injury (8% vs 8%), and febrile neutropenia (6% vs 2%). Treatment-related adverse events led to death in four patients in the pembrolizumab group (due to aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis in one patient each) and six patients in the control group (due to pharyngeal hemorrhage in three and mouth hemorrhage, postprocedural hemorrhage, and sepsis in one each).
The investigators concluded, “Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches.”
Dr. Machiels, of Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Experimentale, UCLouvain, Brussels, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit thelancet.com.
