- What was studied:
- Design:
- International, randomized, open-label phase 3 trial (n=714)
- Adults with resectable stage III to IVA larynx, hypopharynx, or oral cavity SCC, or oropharynx SCC (stage III to IVA p16-negative, or stage III T4 N0 to N2 p16-positive)
- Randomized 1:1 to standard surgery → pathology-directed adjuvant RT ± high-dose cisplatin with or without perioperative pembrolizumab
- Regimen (pembro arm):
- 200 mg q3 weeks × 2 neoadjuvant cycles → surgery → 3 cycles concurrent with postoperative RT ± cisplatin → 15 additional adjuvant cycles (total 17 including neoadjuvant)
- Primary endpoint:
- Event-free survival (EFS) with hierarchical testing in PD-L1 CPS ≥10, then CPS ≥1, then ITT
- Key secondary endpoints included:
- Major pathologic response (mPR) and overall survival (OS)
- Design:
- Key efficacy results:
- EFS benefit (first interim analysis; median follow-up 38.3 mo):
- CPS ≥ 10:
- 36-mo EFS 59.8% vs 45.9%; HR 0.66 (95% CI 0.49–0.88; p=0.004)
- CPS ≥ 1:
- 36-mo EFS 58.2% vs 44.9%; HR 0.70 (0.55–0.89; p=0.003)
- All patients (ITT):
- 36-mo EFS 57.6% vs 46.4%; HR 0.73 (0.58–0.92; p=0.008).
- Reported median EFS (ITT):
- 51.8 vs 30.4 months, favoring perioperative pembrolizumab
- Distant metastasis control:
- DMFS improved:
- Median 51.8 vs 35.7 months, HR 0.71, 95% CI 0.56–0.90
- 36-mo DMFS 59.1% vs 49.9%
- DMFS improved:
- Locoregional control difference:
- Was modest (HR 0.92, 95% CI 0.61–1.41)
- Pathologic response:
- mPR rates were higher with pembrolizumab:
- In CPS ≥ 10, mPR increased by ~13.7% pre-op
- mPR rates were higher with pembrolizumab:
- CPS ≥ 10:
- EFS benefit (first interim analysis; median follow-up 38.3 mo):
- Surgical feasibility and downstream treatment:
- Surgery completion was similar:
- 88% in both arms
- Neoadjuvant pembrolizumab did not reduce operability
- Surgery completion was similar:
- Neoadjuvant / adjuvant pembrolizumab:
- Was associated with:
- Fewer high-risk pathologic features (32.5% vs 44.4%)
- Lower proportion requiring adjuvant high-dose cisplatin (38.9% vs 50.5%)
- Was associated with:
- Safety:
- Grade ≥ 3 treatment-related AEs:
- 44.6% (pembrolizumab) vs 42.9% (SOC)
- Treatment-related deaths:
- 1.1% vs 0.3%
- Grade ≥ 3 immune-mediated AEs ~ 10%:
- One grade 5 pneumonitis reported across sources
- No new safety signals
- Grade ≥ 3 treatment-related AEs:
- Regulatory status and who qualifies (U.S.):
- FDA approval (June 13, 2025):
- Pembrolizumab is approved for resectable, locally advanced HNSCC with PD-L1 CPS ≥1:
- As neoadjuvant single-agent, continued with postoperative RT ± cisplatin, then continued as adjuvant single-agent:
- PD-L1 testing is required
- As neoadjuvant single-agent, continued with postoperative RT ± cisplatin, then continued as adjuvant single-agent:
- Pembrolizumab is approved for resectable, locally advanced HNSCC with PD-L1 CPS ≥1:
- FDA approval (June 13, 2025):
- How to apply in practice (surgeon’s lens):
- Patient selection:
- Resectable stage III to IVA HNSCC candidates (non-nasopharynx) with PD-L1 CPS ≥ 1
- Discuss benefits particularly strong in CPS ≥ 10:
- But benefit observed across CPS ≥ 1 and ITT
- Workflow:
- Two neoadjuvant pembrolizumab cycles → timely surgery (completion comparable to SOC) → risk-adapted RT ± cisplatin with concurrent pembrolizumab → complete remaining adjuvant cycles
- Coordinate closely with rad oncology /medical oncology for start dates and toxicity monitoring
- Counseling:
- Emphasize EFS / DMFS gains and potential reduction in need for high-dose cisplatin due to fewer high-risk pathologic features, balanced against immune-related toxicities (pneumonitis, endocrinopathies, colitis, etc.)
- OS:
- Data currently immature; trend favorable but not yet statistically significant
- Continue guideline-concordant surveillance
- Patient selection:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 