Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 (ClinicalTrials.gov).

Orexin Receptor Antagonism in Painful Diabetic Neuropathy: A Phase 2 Trial With Filorexant.

OBJECTIVES: To evaluate whether orexin receptor antagonism with filorexant provides pain relief in patients with painful diabetic neuropathy (PDN). METHODS: In this double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal proof-of-concept study, patients with PDN (aged 18 to 75 y) entered a 2-week, single-blind active run-in period with filorexant 10 mg nightly, before randomization 1:1 to placebo or filorexant in a 2-week, double-blind treatment period. The primary efficacy endpoint was time to efficacy failure among "primary responders" (≥30% decrease in evening pain intensity during the run-in). Secondary endpoints were time to efficacy failure among "all responders" (≥20% decrease in evening pain intensity during the run-in) and mean change from baseline in evening pain intensity throughout last 3 days of the double-blind period. RESULTS: Of the 182 patients treated during the run-in, 170 were randomized in the double-blind period, including 65 primary responders and 88 responders. There was no significant difference in proportion of patients with efficacy failure during the double-blind period with filorexant versus placebo among primary (24.3% vs. 32.1% [P=0.411]) or all (34.0% vs. 43.9% [nominal P=0.302]) responders or in mean change from baseline in evening pain intensity scores (estimated treatment difference: -0.587 [P=0.269], primary; -0.687 [P=0.108], all). Adverse events were reported by 24.7% of patients during the run-in. A higher proportion of patients treated with filorexant versus placebo reported adverse events during the double-blind period (23.9% vs. 13.4%). DISCUSSION: These data do not provide evidence for the efficacy of nightly filorexant for the treatment of PDN.