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Adjuvant therapy for resected melanoma

TL;DR — Adjuvant checkpoint blockade and adjuvant BRAF/MEK inhibition both reduce recurrence substantially in resected stage III melanoma, and adjuvant therapy has now been extended to node-negative stage IIB/IIC disease on the strength of recurrence-free survival alone. The overall-survival evidence is thinner than the recurrence evidence: only EORTC 18071 (ipilimumab) has shown a statistically significant OS benefit (HR 0.73, 95% CI 0.60–0.89, P = .002; 8.7% absolute difference at 7 years) (Eggermont 2019, PMID 31400634), while COMBI-AD's final analysis after a median 8.33 years found OS favouring dabrafenib–trametinib without reaching significance (HR 0.80, 0.62–1.01, P = .06) (Long 2024, PMID 38899716). In stage IIB/IIC, KEYNOTE-716 gave 48-month recurrence-free survival 71.3% versus 58.3% (HR 0.62, 0.50–0.78) and DMFS 81.0% versus 70.1% (HR 0.59, 0.45–0.77) (Luke 2025, PMID 40198940), and CheckMate 76K gave 12-month RFS 89.0% versus 79.4% (HR 0.42, 0.30–0.59, P < .0001) (Kirkwood 2023, PMID 37845511) — an indirect comparison finds no significant difference between the two agents (RFS HR 0.97, 0.69–1.35) (Andreikos 2026, PMID 42101794). The unresolved question is whether recurrence-free survival is an adequate surrogate: patient-level association with OS is strong (ρ = 0.84, 0.82–0.87) but trial-level association is only moderate (R² = 0.59, 0.08–1.00) (Coart 2020, PMID 32777716).

Stage III: the registrational trials

Trial Population Intervention Key results
EORTC 18071 (Eggermont 2015/2019, PMID 25840693; PMID 31400634) 951 patients, stage III cutaneous melanoma (excluding ≤1 mm nodal or in-transit metastasis), 99 sites Ipilimumab 10 mg/kg vs placebo Median OS follow-up 6.9 years: RFS HR 0.75 (0.63–0.88), P < .001; DMFS HR 0.76 (0.64–0.90), P = .002; OS HR 0.73 (0.60–0.89), P = .002, absolute difference 8.7% at 7 years
CheckMate 238 (Weber 2017, PMID 28891423; Larkin 2023, PMID 37058595) 906 patients, resected stage IIIB/C or IV Nivolumab 3 mg/kg vs ipilimumab 10 mg/kg, 1 year 12-month RFS 70.5% vs 60.8% (HR 0.65, 97.56% CI 0.51–0.83, P < .001). At minimum 62 months: RFS HR 0.72 (0.60–0.86), 5-year rates 50% vs 39%; 5-year DMFS 58% vs 51%; 5-year OS 76% vs 72% (75% data maturity). Grade 3/4 treatment-related AEs 14.4% (nivolumab) vs 45.9% (ipilimumab)
KEYNOTE-054 / EORTC 1325 (Eggermont 2021, PMID 33857412) 1,019 patients, resected AJCC-7 stage IIIA (>1 mm nodal), IIIB or IIIC, 123 centres, 23 countries Pembrolizumab 200 mg vs placebo, up to 18 doses Median follow-up 42.3 months: 3.5-year DMFS 65.3% (60.9–69.5) vs 49.4% (44.8–53.8), HR 0.60 (0.49–0.73), P < .0001; 3.5-year RFS 59.8% vs 41.4%, HR 0.59 (0.49–0.70). PD-L1-positive subgroup (n = 853): DMFS HR 0.61 (0.49–0.76)
COMBI-AD (Long 2017, PMID 28891408; Long 2024, PMID 38899716) 870 patients, resected stage III BRAF V600-mutant melanoma Dabrafenib 150 mg bd + trametinib 2 mg od, 12 months, vs double placebo Final analysis at median 8.33 years: OS HR 0.80 (0.62–1.01), P = .06 (not significant); BRAF V600E subgroup (n = 792) HR 0.75 (0.58–0.96); RFS HR 0.52 (0.43–0.63)

Two things the table makes explicit. First, the only unambiguous overall-survival win in adjuvant melanoma belongs to ipilimumab, a drug largely displaced from this setting by anti-PD-1 on toxicity grounds. Second, COMBI-AD — the trial with the longest follow-up of any modern adjuvant regimen — misses statistical significance for OS at P = .06 despite a halving of relapse risk. Adjuvant therapy in melanoma is established on recurrence endpoints, not on demonstrated survival gain, with the single historical exception.

Estimated cure fractions

Mixture-cure models applied to patient-level RFS data estimated cure rates of 48.3% (95% CI 41.8–54.9) with nivolumab and 38.2% (32.7–44.1) with ipilimumab in CheckMate 238, and 38.0% (32.1–44.2) with ipilimumab versus 29.2% (24.4–34.6) with placebo in EORTC 18071; the indirect cross-trial comparison gave odds of cure significantly higher with nivolumab than placebo (OR 2.33, 1.49–3.65) (Weber 2025, PMID 39378385). These are modelled quantities resting on the assumption that "cured" patients have general-population mortality, and they are an indirect comparison across two trials with different populations.

Stage IIB/IIC: extending adjuvant therapy into node-negative disease

The rationale is the stage IIC/IIIA inversion described in staging: node-negative stage IIB/C patients have recurrence risk similar to resected stage IIIA/B (PMID 37845511).

Trial Design Results
KEYNOTE-716 (Luke 2022, PMID 35367007; Long 2022, PMID 36265502; Luke 2024, PMID 38452313; Luke 2025, PMID 40198940) 976 patients ≥12 years with completely resected stage IIB (T3b/T4a) or IIC (T4b) melanoma and negative sentinel node, 160 centres, 16 countries; pembrolizumab 200 mg vs placebo ×17 cycles, with crossover/rechallenge First interim (median 14.4 months): first recurrence or death 11% vs 17%, HR 0.65 (0.46–0.92), P = .0066. Second interim (20.9 months): 15% vs 24%, HR 0.61 (0.45–0.82). At median 52.8 months: RFS HR 0.62 (0.50–0.78), 48-month RFS 71.3% vs 58.3%; DMFS HR 0.59 (0.45–0.77), 48-month DMFS 81.0% vs 70.1%; PRFS2 HR 0.75 (0.56–1.01), 48-month rates 82.5% vs 76.7%
CheckMate 76K (Kirkwood 2023, PMID 37845511; NCT04099251) 790 patients, resected stage IIB/C, randomised 2:1 to nivolumab 480 mg vs placebo every 4 weeks for 12 months At minimum 7.8 months: RFS HR 0.42 (0.30–0.59), P < .0001; 12-month RFS 89.0% vs 79.4%; DMFS HR 0.47 (0.30–0.72). Grade 3/4 treatment-related AEs 10.3% vs 2.3%; one treatment-related death (0.2%)
Indirect comparison (Andreikos 2026, PMID 42101794) Anchored Bucher indirect comparison of KEYNOTE-716 and CheckMate 76K No significant difference: RFS HR 0.97 (0.69–1.35), DMFS HR 0.81 (0.54–1.21); subgroup RFS all non-significant (stage IIB 0.97, IIC 1.00, age <65 1.20, age ≥65 0.77)

The PRFS2 result is the most important number on this page and the least quoted. Progression-free survival on next-line therapy (PRFS2) in KEYNOTE-716 gave HR 0.75 (0.56–1.01) with 48-month rates 82.5% versus 76.7% (PMID 40198940) — i.e. 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, and that is exactly what the surrogate-endpoint question below is about. Recent secondary analyses examine outcomes by histopathological subgroup (Schadendorf 2024, PMID 38485189) and by primary tumour location (Yoon 2025, PMID 39893343), and a further secondary analysis appeared in 2026 (PMID 41701495).

Stage IIIA: where the indication is weakest

The German validation cohort concluded that the indication for adjuvant therapy in AJCC-8 stage IIIA is questionable, since its 5-year melanoma-specific survival (89%) exceeds that of stage IIB (80%) and IIC (67%) (Kanaki 2019, PMID 31401470). Retrospective multicentre data across 34 centres in Australia, Europe and the US in 628 stage IIIA patients found 2-year recurrence-free survival of 79.3% (74.1–84.8) with anti-PD-1, 98.6% (96.0–100) with dabrafenib–trametinib and 84.3% with observation — with poor prognostic variables significantly more frequent in the anti-PD-1 group, so the comparison is confounded by indication (Grover 2025, PMID 40204154).

Adjuvant radiotherapy to the nodal basin

Adjuvant nodal radiotherapy predates the systemic era and addresses a different endpoint. In a prospective phase 2 study of 234 patients with node-involved melanoma receiving 48 Gy in 20 fractions to the nodal basin, regional in-field relapse as first site occurred in 16 of 234 (6.8%); 5-year overall survival was 36%, progression-free survival 27% and regional control 91%, and treatment was well tolerated (Burmeister 2006, PMID 17064803). Loco-regional control after postoperative radiotherapy for regional nodal metastases has been reported separately (PMID 19828412), and radiotherapy for cutaneous cancers reviewed (PMID 34955421).

Regional control is not survival. The pattern matches completion lymph-node dissection (PMID 28591523): an intervention that improves nodal control at the cost of morbidity, without a demonstrated survival effect. Adjuvant nodal radiotherapy is not part of the current European treatment recommendations, which are framed around systemic therapy (Garbe 2025, PMID 39709737).

The surrogate-endpoint problem

Every modern adjuvant approval in melanoma rests on recurrence-free or distant-metastasis-free survival.

  • Patient-level association between RFS and OS is strong (ρ = 0.84, 95% CI 0.82–0.87) using EORTC 18071 individual patient data at median 5.3 years; trial-level association is only moderate (R² = 0.59, 95% CI 0.08–1.00) — a confidence interval so wide that it is compatible with almost no trial-level surrogacy (Coart 2020, PMID 32777716).
  • Earlier work evaluated relapse-free survival as a surrogate for overall survival specifically in stage II–III melanoma adjuvant therapy (Suciu 2018, PMID 28922786).
  • The interferon era is the cautionary comparator: individual-patient-data meta-analysis of 15 trials found event-free survival HR 0.86 (0.81–0.91, P < .00001) and OS HR 0.90 (0.85–0.97, P = .003), but absolute differences of only 3.5% (EFS) and 3.0% (OS) at 5 years and 2.7%/2.8% at 10 years, with benefit apparently confined to patients with ulcerated tumours (heterogeneity P = .04 EFS, P = .002 OS) (Ives 2017, PMID 28692949). A statistically significant hazard ratio with a 3% absolute effect defined standard of care for a decade.
  • What happens after recurrence matters and is under-reported: CheckMate 238 published outcomes with post-recurrence systemic therapy following adjuvant checkpoint blockade (Weber 2024, PMID 39102624).

Harms, quality of life and the absolute-benefit calculation

Regimen Grade 3/4 treatment-related AEs Source
Nivolumab (stage III/IV) 14.4% PMID 28891423
Ipilimumab 10 mg/kg (stage III/IV) 45.9% PMID 28891423
Nivolumab (stage IIB/C) 10.3% (vs 2.3% placebo) PMID 37845511

Health-related quality of life was a prespecified exploratory endpoint in KEYNOTE-054, assessed with EORTC QLQ-C30 every 6 months in patients alive at 108 weeks from randomisation — the long-term HRQOL analysis is the most detailed available for adjuvant melanoma therapy (Bührer 2024, PMID 39146951). EORTC 18071 reported HRQOL as a secondary outcome for adjuvant ipilimumab (Coens 2017, PMID 28162999), and CheckMate 76K reported patient-reported outcomes for stage IIB/C nivolumab (PMID 40680468). Permanent endocrine toxicity is the specific harm that dominates the risk side of the stage II calculation — see immune-related adverse events.

Cost-effectiveness has been modelled for adjuvant pembrolizumab in stage IIB/IIC in the US (Zhang 2023, PMID 37191852) and for adjuvant nivolumab in the same population (PMID 42033368).

Real-world effectiveness and treatment duration

Question Evidence
Does stopping early harm outcomes? In 620 patients completing adjuvant nivolumab or pembrolizumab for AJCC-8 stage III/IV resected melanoma in the prospective multicentre German ADOREG registry, recurrence-free and overall survival were compared between patients completing a regular 52 ± 4-week course without recurrence during therapy (n = 229) and those with premature termination before 48 weeks (n = 214). Early termination did not negatively affect outcomes (Tomsitz 2025, PMID 40119686)
Do older patients tolerate it? 885 patients aged ≥65 (280 aged ≥75) in the Dutch Melanoma Treatment Registry 2018–2022: grade ≥3 immune-related events in 15.5% (65–74) and 13.9% (≥75) with no significant age association; comorbidity count was associated (OR 1.83, 0.99–3.40); 1-year recurrence-free survival 80.0%, matching registration trials (Özkan 2024, PMID 39368226)
What happens after adjuvant failure? CheckMate 238 reported outcomes with post-recurrence systemic therapy following adjuvant checkpoint blockade (Weber 2024, PMID 39102624); a Spanish registry substudy of 1,316 advanced melanoma patients describes chemotherapy outcomes after immunotherapy, including 12 patients treated after adjuvant immunotherapy (Berciano-Guerrero 2026, PMID 42411543)
Real-world advanced-disease outcomes generally Single-centre tertiary data from Switzerland (PMID 38473216)

The early-termination finding matters for the harm–benefit calculation. If a full 52-week course is not required for benefit, the chronic-toxicity exposure that dominates the stage IIB/IIC decision may be reducible without loss — but ADOREG is a registry comparison, not a randomised duration trial, and patients who stop early differ systematically from those who complete.

Biomarkers

At 5 years in CheckMate 238, higher tumour mutational burden, higher tumour PD-L1, higher intratumoral CD8⁺ T cells, higher IFN-γ-associated gene expression signature and lower peripheral serum C-reactive protein were each associated with improved RFS and OS with both nivolumab and ipilimumab (Larkin 2023, PMID 37058595). These are prognostic across both arms rather than predictive of differential benefit, which is the distinction that matters for treatment selection. ctDNA is being evaluated as an adjuvant biomarker: droplet digital PCR assays for BRAF-V600-mutant circulating tumour DNA have been clinically validated as a prognostic biomarker in resected stage III melanoma receiving adjuvant therapy (Syeda 2025, PMID 40250457) — see surveillance and survivorship.

Interpretation rules for this page

  • Separate RFS, DMFS and OS. Only EORTC 18071 shows a significant OS benefit; COMBI-AD misses at P = .06 with 8.33 years of follow-up (PMID 31400634; PMID 38899716).
  • Report absolute differences, not just hazard ratios. Interferon's HR 0.90 for OS corresponded to a 3.0% absolute difference at 5 years (PMID 28692949).
  • CheckMate 238 has no placebo arm. Its comparator is ipilimumab, so "adjuvant nivolumab versus no treatment" is an indirect estimate (PMID 28891423; PMID 39378385).
  • Cure fractions are modelled, not observed (PMID 39378385).
  • Trial-level surrogacy of RFS for OS is weak (R² = 0.59, CI 0.08–1.00) even where patient-level association is strong (PMID 32777716).
  • PRFS2 narrows the stage II benefit substantially and must be reported alongside RFS (PMID 40198940).
  • Stage III trial populations used AJCC 7 in KEYNOTE-054 and predate AJCC 8 subgrouping, so eligibility does not map cleanly onto current stage definitions (PMID 33857412; PMID 35964471).

Open questions

  • Does adjuvant anti-PD-1 improve overall survival in stage IIB/IIC, or does it mainly advance the timing of a treatment that works at recurrence (PMID 40198940)?
  • Is adjuvant therapy justified in stage IIIA, whose survival exceeds that of stage IIB and IIC (PMID 31401470; PMID 40204154)?
  • Should the neoadjuvant approach replace adjuvant therapy in resectable stage III disease (PMID 36856617; PMID 38828984)? See neoadjuvant therapy.
  • Can ctDNA select patients who need adjuvant therapy, sparing the rest (PMID 40250457)?
  • Is there a predictive — not merely prognostic — biomarker for adjuvant benefit (PMID 37058595)?
  • What is the absolute benefit of adjuvant therapy in stage IIB/IIC set against permanent endocrine toxicity, per 100 patients treated (PMID 37845511; PMID 40198940)?
  • Should adjuvant BRAF/MEK or anti-PD-1 be preferred in BRAF-mutant stage III disease? No head-to-head trial exists (PMID 38899716; PMID 33857412).

References

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