Background
Phase III RCT (KEYNOTE-048) of 882 patients with previously untreated recurrent or metastatic HNSCC (oropharynx, oral cavity, hypopharynx, or larynx), randomized to one of three arms and stratified by PD-L1 combined positive score (CPS).
Interventions and follow up
Arm A: pembrolizumab 200 mg IV q3wk monotherapy
Arm B: pembrolizumab 200 mg q3wk + carboplatin AUC 5 q3wk or cisplatin 100 mg/m2 q3wk + 5-FU 1000 mg/m2/d x4 days q3wk for 6 cycles, then pembrolizumab monotherapy q3wk for up to 35 cycles
Arm C: cetuximab 250 mg/m2 weekly + carboplatin AUC 5 q3wk or cisplatin 100 mg/m2 q3wk + 5-FU 1000 mg/m2/d x4 days q3wk for 6 cycles, then cetuximab maintenance (EXTREME regimen)
Primary endpoints: OS and PFS
mFollow up: 11.1 months
Arm B: pembrolizumab 200 mg q3wk + carboplatin AUC 5 q3wk or cisplatin 100 mg/m2 q3wk + 5-FU 1000 mg/m2/d x4 days q3wk for 6 cycles, then pembrolizumab monotherapy q3wk for up to 35 cycles
Arm C: cetuximab 250 mg/m2 weekly + carboplatin AUC 5 q3wk or cisplatin 100 mg/m2 q3wk + 5-FU 1000 mg/m2/d x4 days q3wk for 6 cycles, then cetuximab maintenance (EXTREME regimen)
Primary endpoints: OS and PFS
mFollow up: 11.1 months
Results
mOS (total, arm B vs C): 13.0mo vs 11.7mo; HR 0.77, 95% CI 0.63-0.93; P=.0034
mOS CPS ≥1 (arm A vs C): 12.3mo vs 10.3mo; HR 0.78, 95% CI 0.64-0.96; P=.0086
mOS CPS ≥1 (arm B vs C): 14.7mo vs 11.0mo; HR 0.60, 95% CI 0.45-0.82; P=.0004
mOS CPS ≥20 (arm A vs C): 14.9mo vs 10.7mo; HR 0.61, 95% CI 0.45-0.83; P=.0007
mOS CPS ≥20 (arm B vs C): 13.6mo vs 10.4mo; HR 0.65, 95% CI 0.53-0.80; P<.0001
PFS: neither pembrolizumab monotherapy nor pembrolizumab plus chemotherapy improved PFS versus EXTREME
mOS CPS ≥1 (arm A vs C): 12.3mo vs 10.3mo; HR 0.78, 95% CI 0.64-0.96; P=.0086
mOS CPS ≥1 (arm B vs C): 14.7mo vs 11.0mo; HR 0.60, 95% CI 0.45-0.82; P=.0004
mOS CPS ≥20 (arm A vs C): 14.9mo vs 10.7mo; HR 0.61, 95% CI 0.45-0.83; P=.0007
mOS CPS ≥20 (arm B vs C): 13.6mo vs 10.4mo; HR 0.65, 95% CI 0.53-0.80; P<.0001
PFS: neither pembrolizumab monotherapy nor pembrolizumab plus chemotherapy improved PFS versus EXTREME
Adverse events
Grade ≥3 all-cause (arm A vs B vs C): 55% vs 85% vs 83%
AEs leading to death (arm A vs B vs C): 8% vs 12% vs 10%
AEs leading to death (arm A vs B vs C): 8% vs 12% vs 10%
Conclusions
Pembrolizumab plus platinum and 5-FU significantly improved overall survival in the total population, and pembrolizumab monotherapy improved OS in PD-L1 CPS-positive disease, versus the EXTREME regimen in first-line recurrent or metastatic HNSCC, with monotherapy showing favorable safety.
Key Limitations
Open-label; pembrolizumab monotherapy not superior in unselected patients (benefit limited to CPS-positive disease); no PFS benefit, with early crossing of survival curves raising concern for patients with rapidly progressive, high-burden disease for whom chemotherapy combinations may be preferred.
Clinical Context
KEYNOTE-048 led to FDA and EMA approval of first-line pembrolizumab (monotherapy for CPS ≥1, or with chemotherapy regardless of CPS) for R/M HNSCC, displacing EXTREME as the preferred first-line standard. ESMO guidelines recommend pembrolizumab-based first-line therapy guided by PD-L1 CPS.