Skip to content

Luke JJ, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Long-term follow-up, crossover, and rechallenge with pembrolizumab in the phase III KEYNOTE-716 study. European journal of cancer (Oxford, England : 1990). 2025;220:115381. PMID 40198940

One-paragraph summary

KEYNOTE-716 randomised 976 patients aged 12 years or older with completely resected stage IIB (T3b/T4a) or IIC (T4b) melanoma and a negative sentinel node, across 160 centres in 16 countries, 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 17 cycles. Patients who recurred after placebo or after 17 cycles of pembrolizumab could cross over to, or be rechallenged with, pembrolizumab in a second part of the trial. Recurrence-free survival was the primary endpoint and distant metastasis-free survival a secondary endpoint. At a median follow-up of 52.8 months (range 39.4–64.8), both favoured pembrolizumab; the trial also reports progression-free survival on next-line therapy (PRFS2) and outcomes in the crossover and rechallenge populations (NCT03553836).

Key findings

  • Recurrence-free survival HR 0.62 (95% CI 0.50–0.78); 48-month RFS 71.3% (pembrolizumab) vs 58.3% (placebo).
  • Distant metastasis-free survival HR 0.59 (0.45–0.77); 48-month DMFS 81.0% vs 70.1%.
  • PRFS2 HR 0.75 (95% CI 0.56–1.01); 48-month PRFS2 82.5% vs 76.7% — the endpoint that incorporates what happens after recurrence.
  • In the crossover population (median follow-up 36.9 months), median recurrence-free survival was not reached in patients with resectable disease (n = 41; 48-month RFS 50.6%), and median progression-free survival was 22.0 months in patients with unresectable disease (n = 30).
  • Earlier analyses: first interim HR 0.65 (0.46–0.92, P = .0066) at median 14.4 months (Luke 2022, PMID 35367007); second interim HR 0.61 (0.45–0.82) at 20.9 months.

Limitations

  • No overall-survival result. Trial-level surrogacy of recurrence-free survival for overall survival in adjuvant melanoma is only moderate (R² = 0.59, 95% CI 0.08–1.00) even though patient-level association is strong (Coart 2020, PMID 32777716).
  • The PRFS2 confidence interval crosses 1.0, so once patients who recur on placebo receive pembrolizumab at recurrence, much of the advantage narrows. Whether adjuvant therapy in stage IIB/IIC produces durable benefit or mostly moves treatment earlier is unresolved.
  • The harm side is not reported in the same units: chronic immune-related adverse events persisted beyond 12 weeks after cessation in 43.2% of adjuvant anti-PD-1 recipients in an independent cohort, mostly grade 1–2 and mostly unresolved (Patrinely 2021, PMID 33764387).
  • 90% of participants were White; the trial does not inform practice in the populations with the worst melanoma outcomes.
  • The comparator is placebo, not deferred treatment at recurrence, so the trial does not directly answer the question its PRFS2 result raises.

Why it matters

KEYNOTE-716 and CheckMate 76K (Kirkwood 2023, PMID 37845511) together moved adjuvant systemic therapy into node-negative melanoma — a setting with no systemic therapy at all before 2022 — and the justification is the stage IIC/IIIA inversion: node-negative stage IIC disease has worse survival than node-positive stage IIIA disease in every validation cohort examined (Kanaki 2019, PMID 31401470). The trial is also the clearest available illustration of the surrogate-endpoint problem that runs through the whole adjuvant literature: a strong recurrence-free-survival result, a strong distant-metastasis-free-survival result, and a PRFS2 result whose confidence interval includes no benefit. A published critique argues that adjuvant anti-PD-1 for resected stage IIB–IV melanoma is "non-personalized medicine with no overall survival benefit" (Ochenduszko 2024, PMID 39025250); the disagreement is live and belongs in the record.

Cited by wiki pages

  • adjuvant therapy
  • staging
  • immune-related adverse events
  • neoadjuvant therapy
  • overview
  • clinical trials landscape