Pembrolizumab failed to improve outcomes of patients with locally advanced squamous cell carcinoma of the head and neck undergoing chemoradiotherapy

Results of the KEYNOTE-412 study have been just published online in Lancet Oncology. This randomized, double-blind, phase 3 trial recruited 804 patients with newly diagnosed, high-risk, unresected locally advanced HNSCC. Patients were randomly assigned (1:1) to pembrolizumab plus standard chemoradiotherapy (70 Gy delivered in 35 fractions combined with cisplatin 100 mg/m2 q3w) or placebo plus chemoradiotherapy (CHRT). Pembrolizumab and placebo were administered once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, and 14 as maintenance therapy).

After a median follow-up of 47.7 months, median event-free survival (EFS – primary endpoint) was not reached in the pembrolizumab+CHRT and 46.6 months in the placebo+CHRT, which translated into a nonsignificantly decreased relative risk of relapse or death by 27% (HR=0.83; 95%CI 0.68-1.03). Subgroup analyses of the impact of PD-L1 expression demonstrated a complete lack of benefit from added pembrolizumab in CPS<1 – (HR=1.09; 95%CI 0.56-2.11) and marginal albeit still insignificant benefit in CPS≥1 (HR=0.80; 95%CI 0.64-1.00).

Surprisingly, unlike in squamous cell cervical cancer patients, where pembrolizumab combined with cisplatin-based chemoradiotherapy significantly improved outcomes (ENGOT-cx11/GOG-3047/KEYNOTE-A18), the efficacy of this checkpoint inhibitor combined with chemoradiotherapy failed to improve EFS in patients with HNSCC in KEYNOTE-412 study. Whether it is related to the chemotherapy regimen – high-dose, immune-ablative cisplatin once every three weeks in HNSCC versus weekly, metronomically dosed cisplatin, or any other factors like HPV status, performance status, etc. – the question is still out.

https://doi.org/10.1016/S1470-2045(24)00100-1