Pembrolizumab (pembro) vs standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase 3 KEYNOTE-040 trial

Abstract

Background: Pembro showed antitumor activity and manageable toxicity in R/M HNSCC in an extended phase 1b study. KEYNOTE-040 (NCT02252042) was a global, open-label, phase 3 study of pembro vs SOC for R/M HNSCC. Methods: Eligible pts with SCC of the oral cavity, oropharynx, hypopharynx, or larynx who had recurrence or PD after a platinum-containing regimen were randomized 1:1 to pembro 200 mg Q3W for 24 mo or investigator choice of standard doses of methotrexate (M), docetaxel (D), or cetuximab (C). Randomization was stratified by ECOG PS (0 vs 1), HPV status (p16 positive vs negative), and PD-L1 tumor proportion score (TPS) (>=50% vs<50%). Treatment was given until confirmed PD or intolerable toxicity. Primary end point was OS in the ITT population. Key secondary end points were OS in pts with PD-L1 combined positive score (CPS) >=1% and PFS and ORR in the ITT and CPS>=1% populations. Prespecified efficacy boundary for OS in the ITT population was one-sided P=.0175. Results: 495 pts enrolled: 247 were assigned to pembro, 248 to SOC (65 M, 110 D, 73 C). After median follow-up of 7.3mo, 8.9% of pts remained on pembro, 0.9% on SOC. Pembro prolonged OS in the ITT population, but the difference did not achieve statistical significance (HR 0.81, one-sided P=.0204; Table). There was no difference in PFS (Table). ORR was higher with pembro (Table). Pembro outcomes were improved in pts with PD-L1-expressing tumors (Table). 12.5% of pts in the SOC arm received subsequent immunotherapy, potentially impacting OS. Grade 3-5 drug-related AE incidence was 13.4% with pembro and 36.3% with SOC; 1.6% and 0.9%, respectively, died of drug-related AEs. Conclusions: Pembro provided an 19% reduction in the risk of death over SOC in pts with R/M HNSCC, although the prespecified efficacy boundary was not reached; subsequent immunotherapy in the SOC arm may have confounded OS analysis. Greater differences in OS, PFS, and ORR favoring pembro were seen in patients with PD-L1 expressing tumors. (Table Presented).