The aim of the KEYNOTE-412 study is to determine the efficacy and safety of combining pembrolizumab with chemoradiation (CRT) in patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC). The primary hypothesis is that pembrolizumab in combination with CRT is superior to CRT alone regarding event-free survival (EFS).1
Despite advancements in multimodal therapy, the 5-year overall survival rate for LA HNSCC remains approximately 50%. In response to this persistent challenge, the KEYNOTE-412 phase III trial investigated the potential benefits of adding pembrolizumab to concurrent chemoradiotherapy for LA HNSCC patients.2
Methods
In the randomised, double-blind, phase III KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected LA HNSCC from 130 global medical centres were randomly assigned (1:1) to receive pembrolizumab (200 mg) plus CRT or placebo plus CRT. Pembrolizumab and placebo were administered intravenously once every three weeks for up to seventeen doses (one before CRT, two during CRT, and fourteen as maintenance therapy). CRT included cisplatin (100 mg/m2) administered intravenously once every three weeks for two/three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was EFS analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment.
Findings
In total, 804 participants were randomly assigned to the pembrolizumab (n=402) or the placebo groups (n=402). The results did not reveal any significant differences in EFS between the arms (HR[95%CI]: 0.83[0.68–1.03]; p=0.043 [significance threshold, p≤0.024]). Median EFS was not reached in the pembrolizumab group and stood at 46.6 months in the placebo group. Grade ≥3 adverse events (AEs) were reported in 92% vs. 88% of patients treated in the pembrolizumab and placebo arms, respectively. The most common grade ≥3 AEs were decreased neutrophil count (27% vs. 25% of patients in the pembrolizumab and placebo groups, respectively) stomatitis (20% vs. 17%), anaemia (20% vs. 15%), dysphagia (19% vs. 16%), and decreased lymphocyte count (19% vs. 20%). Serious AEs 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 AEs led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis).
Conclusions
Pembrolizumab plus CRT did not significantly improve EFS compared with CRT alone in a molecularly unselected LA HNSCC population. No new safety signals were observed. LA HNSCC remains a challenging disease, which requires better treatment approaches.2
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