Background
Phase III, open-label RCT (KEYNOTE-040) of 495 patients with squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx with recurrent disease or progression 3-6mo after multimodal platinum-based therapy, or progression after platinum for R/M HNSCC; up to 2 prior lines for R/M disease; known p16 status for oropharyngeal disease.
Interventions and follow up
Arm A: pembrolizumab 200 mg IV q3wk until disease progression
Arm B: investigator's choice – methotrexate 40 mg/m2 weekly (escalable to 60 mg/m2), docetaxel 75 mg/m2 q3wk, or cetuximab 400 mg/m2 loading then 250 mg/m2 weekly, until progression
Primary endpoint: OS in the intention-to-treat population
Secondary endpoints: OS in PD-L1-positive subgroups, PFS, ORR, DoR, safety, tolerability
mFollow up: 7.6 months
Arm B: investigator's choice – methotrexate 40 mg/m2 weekly (escalable to 60 mg/m2), docetaxel 75 mg/m2 q3wk, or cetuximab 400 mg/m2 loading then 250 mg/m2 weekly, until progression
Primary endpoint: OS in the intention-to-treat population
Secondary endpoints: OS in PD-L1-positive subgroups, PFS, ORR, DoR, safety, tolerability
mFollow up: 7.6 months
Results
mOS (ITT): 8.4mo vs 6.9mo; HR 0.80, 95% CI 0.65-0.98; P=.0161
mOS (CPS ≥1%): 8.7mo vs 7.1mo; HR 0.74, 95% CI 0.58-0.93; P=.0049
mOS (CPS ≥50%): 11.6mo vs 7.9mo; HR 0.53, 95% CI 0.35-0.81; nominal P=.0014
mPFS (ITT): 2.1mo vs 2.3mo; P=.3037 (favoring SOC)
mPFS (CPS ≥1%): 2.2mo vs 2.3mo; P=.1526
mPFS (CPS ≥50%): 3.5mo vs 2.2mo; P=.0034 (favoring pembrolizumab)
mOS (CPS ≥1%): 8.7mo vs 7.1mo; HR 0.74, 95% CI 0.58-0.93; P=.0049
mOS (CPS ≥50%): 11.6mo vs 7.9mo; HR 0.53, 95% CI 0.35-0.81; nominal P=.0014
mPFS (ITT): 2.1mo vs 2.3mo; P=.3037 (favoring SOC)
mPFS (CPS ≥1%): 2.2mo vs 2.3mo; P=.1526
mPFS (CPS ≥50%): 3.5mo vs 2.2mo; P=.0034 (favoring pembrolizumab)
Adverse events
Grade 3-5 treatment-related (arm A vs B): 13.4% vs 36.3%
Treatment-related deaths: 1.6% vs 0.9%
Most common immune-mediated events with pembrolizumab: hypothyroidism and pneumonitis; chemotherapy arm showed more myelosuppression and mucositis
Treatment-related deaths: 1.6% vs 0.9%
Most common immune-mediated events with pembrolizumab: hypothyroidism and pneumonitis; chemotherapy arm showed more myelosuppression and mucositis
Conclusions
Pembrolizumab prolonged overall survival versus standard-of-care chemotherapy in platinum-pretreated recurrent or metastatic HNSCC, with greater benefit in PD-L1-enriched subgroups and a more favorable safety profile.
Key Limitations
Open-label; the ITT OS benefit narrowly missed the prespecified significance threshold; heterogeneous comparator; no PFS benefit except in CPS ≥50%. Short median follow-up.
Clinical Context
KEYNOTE-040 supported the FDA and EMA approval and use of pembrolizumab in platinum-pretreated R/M HNSCC, complementing CheckMate 141. ESMO guidelines recommend anti-PD-1 therapy for platinum-refractory recurrent/metastatic HNSCC.