Adjuvant pembrolizumab in resected stage IIB / IIC melanoma
KEYNOTE-716; adjuvant anti-PD-1 stage IIB / IIC; Keytruda adjuvant
Adjuvant pembrolizumab for completely resected stage IIB / IIC melanoma is UK-funded through NICE TA837 (2022), supported by the KEYNOTE-716 phase 3 trial (Luke et al., Lancet 2022). High-risk node-negative melanoma — pT3b (Breslow > 2.0–4.0 mm with ulceration), pT4a (> 4.0 mm, no ulceration) and pT4b (> 4.0 mm with ulceration), all N0 — carries meaningful recurrence risk, comparable to lower-stage III disease. Adjuvant pembrolizumab 200 mg every 3 weeks (or 400 mg every 6 weeks) for one year reduces recurrence (HR ~ 0.65) at the cost of irAEs in approximately one third of patients. The decision balances absolute recurrence-risk reduction against irAE burden and patient preference.
Indication
- People aged 12 years and over with completely resected stage IIB or IIC melanoma — pT3b, pT4a or pT4b, all N0, M0.
- Indication based on AJCC 8 pathological staging after wide local excision and (where indicated) negative sentinel lymph-node biopsy.
- Surgery and SLNB must have been completed before initiating pembrolizumab.
- NICE TA837 (2022) recommends pembrolizumab as adjuvant treatment for completely resected stage IIB / IIC melanoma.
KEYNOTE-716 evidence
- Luke et al., Lancet 2022 — 976 patients with resected stage IIB / IIC melanoma randomised to pembrolizumab 200 mg q3w (or 400 mg q6w) for ≤ 1 year vs placebo.
- Recurrence-free survival HR 0.65 (95% CI 0.46–0.92); 12-month RFS 91% vs 83%, 36-month RFS 76% vs 64%.
- Distant metastasis-free survival HR 0.59 — significant.
- Overall survival data immature at first analysis; ongoing follow-up.
- Magnitude of benefit comparable to KEYNOTE-054 in resected stage III disease.
- Adverse events — treatment-related Grade ≥ 3 in 17% pembrolizumab vs 5% placebo. Discontinuation for AE in 15%.
Dosing
- Pembrolizumab 200 mg IV every 3 weeks, or 400 mg IV every 6 weeks, for up to 17 cycles or ~ 1 year — whichever first.
- Continue unless disease recurrence or unacceptable toxicity.
- If recurrence during adjuvant — switch to advanced-disease management pathway.
Toxicities — see cutaneous irAEs
- Immune-related adverse events affect 30–50% of patients on anti-PD-1 monotherapy:
- Cutaneous — pruritus, rash, lichenoid, psoriasiform, vitiligo — see cutaneous irAEs.
- Endocrine — thyroid dysfunction (commonest), hypophysitis, T1DM, adrenal insufficiency.
- Gastrointestinal — colitis, hepatitis.
- Pulmonary — pneumonitis.
- Rare but severe — myocarditis, neurological irAEs (Guillain-Barré, myasthenia), encephalitis.
- Permanent discontinuation in 15%; most events manageable with steroid taper.
- Patient education on irAE recognition essential — early reporting of symptoms.
Decision considerations
- Absolute risk reduction at 36 months ~ 12% (76% RFS vs 64% in placebo) — substantial.
- Number-needed-to-treat to prevent one recurrence at 3 years ~ 8.
- OS benefit not yet demonstrated but trend favourable; awaiting mature data.
- irAE risk — patient preference and pre-existing autoimmune disease relevant.
- Discuss with patient at MDT — many opt for adjuvant therapy given the substantial risk reduction; others prefer surveillance given OS uncertainty.
- Active surveillance imaging schedule remains the same regardless of adjuvant choice (NG14 §1.9.15).
References
- Luke JJ et al. Adjuvant pembrolizumab versus placebo in resected stage IIB or IIC melanoma (KEYNOTE-716): an interim analysis of a multicentre, randomised, double-blind, phase 3 trial. Lancet; 2022;399:1718–29.
- NICE TA837. Pembrolizumab for adjuvant treatment of resected stage 2B or 2C melanoma. London: NICE; 2022.
- Luke JJ et al. KEYNOTE-716 — 36-month analysis. J Clin Oncol; 2024.
Spot a correction?
If any clinical statement, citation or link on this page needs updating, please email admin@skinoncology.net with the page name, the proposed correction and the supporting source.