Background
Phase III double-blind RCT (KEYNOTE-716), N=976 completely resected stage IIB/IIC cutaneous melanoma (AJCC 8th ed; T3b-T4b N0 M0). High-risk primary features (≥2.0 mm + ulceration or ≥4.0 mm), pathologically node-negative. Stratified by T-stage (T3b vs T4a vs T4b) and region. Enrolled 2019-2020 across 160 sites.
Interventions and follow up
Arm A: Pembrolizumab 200 mg q3wk × up to 17 cycles (~1 year)
Arm B: Placebo × up to 17 cycles
Primary endpoint: Recurrence-free survival (RFS)
mFollow up: 14.3 months (primary RFS analysis)
Arm B: Placebo × up to 17 cycles
Primary endpoint: Recurrence-free survival (RFS)
mFollow up: 14.3 months (primary RFS analysis)
Results
12-month RFS: 90.5% vs 83.1%, HR 0.65, 95% CI 0.46-0.92, P=.0132
DMFS: HR 0.64, 95% CI 0.43-0.95 (exploratory)
OS: immature at primary analysis
DMFS: HR 0.64, 95% CI 0.43-0.95 (exploratory)
OS: immature at primary analysis
Adverse events
Grade ≥3 AEs: 16.1% vs 6.0%
Immune-mediated AEs any grade: 37.4% vs 8.2%; Grade ≥3 7.4% vs 0.8%
Most common immune AEs: hypothyroidism 20.7%, rash 8.6%, diarrhea/colitis 5.5%
Discontinuation due to AE: 9.3% vs 1.2%
Immune-mediated AEs any grade: 37.4% vs 8.2%; Grade ≥3 7.4% vs 0.8%
Most common immune AEs: hypothyroidism 20.7%, rash 8.6%, diarrhea/colitis 5.5%
Discontinuation due to AE: 9.3% vs 1.2%
Conclusions
Adjuvant pembrolizumab significantly reduced recurrence risk vs placebo in resected stage IIB/IIC melanoma (HR 0.65, P=.0132), establishing adjuvant PD-1 inhibition as a standard option in this higher-risk early-stage population previously managed with observation alone.
Key Limitations
Short follow-up (14.3 months median); OS immature, and whether RFS benefit translates to OS is undetermined. Stage IIB/IIC patients have ~80-85% 5-year survival with surgery alone, so over-treatment of non-recurrers is a concern. PD-L1 and BRAF status not validated predictive biomarkers. Longer follow-up needed for DMFS/OS. CheckMate 76K (nivolumab) showed similar HR 0.58 without direct comparison.
Clinical Context
FDA approved pembrolizumab (Keytruda) for adjuvant stage IIB/IIC melanoma (December 2021) based on KEYNOTE-716, the first IO approval in stage II (node-negative) melanoma, extending adjuvant immunotherapy to high-risk node-negative disease. Nivolumab (CheckMate 76K) subsequently received similar approval. ESMO lists pembrolizumab and nivolumab as preferred options for resected stage IIB/IIC. The decision is individualized given most patients (80-85%) survive long-term without adjuvant therapy.