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Immunotherapy for advanced melanoma

TL;DR — Melanoma is the disease in which checkpoint blockade first produced durable long-term survival, and CheckMate 067 now has ten-year data: median overall survival 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab and 19.9 months with ipilimumab, with hazard ratios for death of 0.53 (95% CI 0.44–0.65) and 0.63 (0.52–0.76) against ipilimumab. Median melanoma-specific survival exceeded 120 months in the combination arm (not reached, 37% alive at trial end), and among patients alive and progression-free at three years, ten-year melanoma-specific survival was 96%, 97% and 88% across the three arms (Wolchok 2025, PMID 39282897). Anti-PD-1 monotherapy beat ipilimumab in KEYNOTE-006 (24-month OS 55% vs 43%; HR 0.68 for both pembrolizumab schedules) (Schachter 2017, PMID 28822576). The newest first-line option, nivolumab plus relatlimab (anti-LAG-3), improved progression-free survival over nivolumab (median 10.1 vs 4.6 months, HR 0.75, 0.62–0.92, P = .006) at roughly half the grade 3/4 toxicity of ipilimumab-containing combinations, with 4-year OS 52.0% vs 42.8% (Tawbi 2022, PMID 34986285; Lipson 2025, PMID 40513285). The unresolved clinical question is not whether checkpoint blockade works but which combination, in which patient, and for how long.

The long-term outcome data

Trial / analysis Regimen Result
CheckMate 067, 10-year final (Wolchok 2025, PMID 39282897; NCT01844505) Nivolumab 1 mg/kg + ipilimumab 3 mg/kg ×4 then nivolumab 3 mg/kg vs nivolumab vs ipilimumab, 1:1:1 Median OS 71.9 / 36.9 / 19.9 months; HR for death 0.53 (0.44–0.65) combination vs ipilimumab, 0.63 (0.52–0.76) nivolumab vs ipilimumab. Median melanoma-specific survival >120 months (not reached) / 49.4 / 21.9 months. Among those alive and progression-free at 3 years, 10-year MSS 96% / 97% / 88%
CheckMate 067, 6.5-year (Wolchok 2022, PMID 34818112) Same, n = 314 / 316 / 315 Median OS 72.1 / 36.9 / 19.9 months
KEYNOTE-006 final OS (Schachter 2017, PMID 28822576) Pembrolizumab q2w vs q3w vs ipilimumab; 834 randomised, 811 treated, 87 institutions, 16 countries Median follow-up 22.9 months, 383 deaths. Median OS not reached in either pembrolizumab group vs 16.0 months with ipilimumab; HR 0.68 (0.53–0.87) q2w and 0.68 (0.53–0.86) q3w. 24-month OS 55% / 55% / 43%
Ipilimumab pooled analysis (Schadendorf 2015, PMID 25667295) 1,861 patients from 10 prospective and 2 retrospective studies; secondary analysis n = 4,846 including expanded access Median OS 11.4 months (10.7–12.1). Survival curve plateaus around year 3 at 22% (all), 26% (treatment-naive), 20% (previously treated); 21% plateau in the expanded analysis. Plateau independent of prior therapy and of ipilimumab dose
RELATIVITY-047 (Tawbi 2022, PMID 34986285; NCT03470922) Nivolumab 480 mg + relatlimab 160 mg fixed dose vs nivolumab 480 mg, q4w, phase 2–3, double-blind Median PFS 10.1 months (6.4–15.7) vs 4.6 (3.4–5.6), HR 0.75 (0.62–0.92), P = .006; 12-month PFS 47.7% vs 36.0%. Grade 3/4 treatment-related AEs 18.9% vs 9.7%
RELATIVITY-047 4-year update (Lipson 2025, PMID 40513285) Same, minimum follow-up 45.3 months 4-year PFS 30.6% (25.4–35.9) vs 23.6% (18.9–28.5); 4-year OS 52.0% (46.6–57.1) vs 42.8% (37.5–47.9); ORR 43.9% vs 33.4%; 4-year melanoma-specific survival 59.7% (54.1–64.8) vs 49.6% (44.0–54.9)

The ipilimumab plateau is the historically important observation. Schadendorf's pooled analysis showed a survival curve that flattens at ~20–22% around year three and stays flat with follow-up to ten years, independent of prior therapy or dose (PMID 25667295). That plateau — not the median survival — is what made melanoma the reference disease for durable immunotherapy benefit, and CheckMate 067's ten-year melanoma-specific survival of 96–97% among three-year progression-free patients is its modern restatement (PMID 39282897).

Combination versus monotherapy: the toxicity-for-efficacy trade

CheckMate 067 was not powered for a formal combination-versus-monotherapy comparison; that comparison is descriptive (PMID 34818112). What can be said:

Nivolumab + ipilimumab Nivolumab Nivolumab + relatlimab
Median OS 71.9 months (PMID 39282897) 36.9 months (PMID 39282897) not reached at 4 years; 4-year OS 52.0% (PMID 40513285)
Grade 3/4 treatment-related AEs High (see immune-related adverse events) Lower 18.9% vs 9.7% for nivolumab (PMID 34986285)
Treatment-free survival at 60 months 39% of patients surviving treatment-free 24% — (PMID 34799400)

The relatlimab combination's own authors frame its value as "durable benefit… at a lower toxicity cost compared with other immuno-oncology combinations" (PMID 40513285) — a positioning claim rather than a head-to-head result. No randomised trial compares nivolumab–relatlimab against nivolumab–ipilimumab. The only registered study containing both combination arms was non-randomised and terminated after enrolling two participants (NCT03724968); Harmony instead compares fianlimab–cemiplimab against relatlimab–nivolumab (NCT06246916).

Treatment-free survival: the endpoint that fits the biology

Conventional endpoints do not capture the distinctive feature of checkpoint blockade — that many responders stop treatment and stay well. Treatment-free survival was developed for this and is defined as the area between the Kaplan–Meier curve for time to protocol therapy cessation and the curve for time to subsequent systemic therapy or death (Regan 2019, PMID 31498030).

  • CheckMate 067 at 60 months: 39%, 24% and 11% of patients assigned nivolumab plus ipilimumab, nivolumab and ipilimumab respectively had survived treatment-free, with the measure partitioned into time with and without persistent or late-onset grade ≥2 select treatment-related adverse events (Regan 2021, PMID 34799400).
  • RELATIVITY-047 at 48 months: OS 52% vs 43%, with 38% and 33% of patients respectively free of treatment, partitioned by time with and without grade ≥3 treatment-related adverse events, with subgroup analysis by BRAF status and PD-L1 (Regan 2025, PMID 40940136).
  • Real-world: in 316 patients receiving first-line nivolumab, pembrolizumab or nivolumab–ipilimumab in Alberta 2013–2020, treatment-free survival was estimated as the difference in 36-month restricted mean survival times between two conventional endpoints (Gupta 2023, PMID 37351883).
  • Treatment-free survival is sensitive to subgroup definitions, which limits cross-trial comparison (Mantia 2022, PMID 34855329).

Sequencing against targeted therapy

DREAMseq (ECOG-ACRIN EA6134) is the only randomised trial of sequence in BRAF V600-mutant metastatic melanoma: 265 treatment-naive patients randomised to nivolumab–ipilimumab (arm A) or dabrafenib–trametinib (arm B), crossing over at progression to the alternate therapy (arms C and D). Two-year OS was 71.8% (95% CI 62.5–79.1) starting with immunotherapy versus 51.5% (41.7–60.4) starting with targeted therapy (log-rank P = .010); the trial was stopped early by the DSMC. Objective response rates were 46.0% (A), 43.0% (B), 47.8% (C) and 29.6% (D) — note the drop to 29.6% for immunotherapy given after targeted therapy. Median duration of response was not reached for arm A and was 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented progression, and grade ≥3 toxicities were of similar frequency between arms (Atkins 2023, PMID 36166727). Start with immunotherapy in BRAF-mutant disease is the one sequencing question in melanoma with a randomised answer — see targeted therapy.

After progression

  • Rechallenge in prior responders. In 85 patients across 12 French centres who had achieved disease control on a first course of checkpoint inhibition that was subsequently interrupted, rechallenge used pembrolizumab (52%), nivolumab (41%), ipilimumab (2%) or ipilimumab plus nivolumab (5%) (Nardin 2023, PMID 37509227).
  • Broader rechallenge evidence. Retreatment, rechallenge and escalation with subsequent checkpoint inhibitors after initial failure has been analysed across cancers (PMID 41202502), with meta-analyses of rechallenge efficacy and safety in solid tumours (PMID 39726701; PMID 33032816) and of safety after prior immune therapy (PMID 35727369). Outcomes after retreatment with MAPK inhibitors and checkpoint inhibitors specifically in melanoma have been reported (PMID 34254534).
  • Options after double-checkpoint failure are limited; comparisons of pembrolizumab–lenvatinib against conventional chemotherapy after PD-1/CTLA-4 failure exist only as retrospective series (PMID 39435288), and the state of the art after progression has been reviewed (PMID 34009481). Cellular therapy is the main evidence-based option — see cellular therapy and resistance.

Response patterns are not chemotherapy response patterns

Immunotherapy generated its own response-assessment problem. Pseudoprogression — a response occurring after apparent progression — was first reported in melanoma patients treated with ipilimumab and led to immune-specific criteria (irRC, irRECIST, iRECIST) permitting continued treatment beyond progression; the rate has never exceeded 10% of patients across tumour types. Rapid progression after immunotherapy ("hyperprogression") has been described in the opposite direction (Borcoman 2018, PMID 30231380). Imaging assessment of response under immunotherapy has been reviewed (PMID 36387133), including FDG-PET/CT-based monitoring (PMID 34768681).

Two consequences follow for reading this page's tables. First, objective response rate under checkpoint blockade is not directly comparable with objective response rate under chemotherapy or targeted therapy, because the criteria and the biology of the endpoint differ. Second, the phenomenon has a limit: at under 10% of patients, pseudoprogression does not justify treating progression as uninformative. Tebentafusp in uveal melanoma is the more extreme case, where survival benefit extended to patients whose best RECIST response was progression with >20% target growth (Piperno-Neumann 2026, PMID 42162665) — see uveal melanoma.

Predictors of benefit

No validated predictive biomarker selects checkpoint therapy in advanced melanoma. What exists is prognostic or correlative:

  • IFN-γ signalling and T-cell infiltration. In baseline and on-therapy biopsies from 101 advanced melanoma patients on nivolumab ± ipilimumab, T-cell infiltration and IFN-γ signatures corresponded most strongly with response, with reciprocal decreases in cell-cycle and WNT pathways (Grasso 2020, PMID 32916126). A T-cell-inflamed gene expression profile developed across pembrolizumab studies contains IFN-γ-responsive genes covering antigen presentation, chemokines, cytotoxicity and adaptive resistance, and is necessary but not always sufficient for benefit (Ayers 2017, PMID 28650338).
  • Tertiary lymphoid structures. Co-occurrence of CD8⁺ T cells and CD20⁺ B cells was associated with improved survival independently of other clinical variables, and a derived TLS signature predicted outcomes in checkpoint-treated cohorts (Cabrita 2020, PMID 31942071).
  • Tumour mutational burden. High TMB associated with better outcomes in the adjuvant CheckMate 238 biomarker analysis (Larkin 2023, PMID 37058595), but a pan-cancer analysis found high TMB fails to predict checkpoint response across all cancer types (McGrail 2021, PMID 33736924).
  • Automated TIL quantification was evaluated in 1,202 advanced melanoma patients on first-line anti-PD-1 ± anti-CTLA-4 across 11 Dutch centres, with objective response rate as the primary outcome (Schuiveling 2025, PMID 41100131).
  • Relatlimab-specific biology has been analysed through biomarker work in RELATIVITY-047 (Lipson 2025b, PMID 40607902).

Where checkpoint blockade underperforms

Setting Status
Uveal melanoma Checkpoint blockade does not reproduce the cutaneous result; tebentafusp is the first-line agent (Piulats 2024, PMID 38048850) — see uveal melanoma
Acral and mucosal melanoma Lower response rates and under-representation in registrational trials — see acral and mucosal melanoma
Active brain metastases CheckMate 204 established intracranial activity of the combination — see brain metastases (Tawbi 2021, PMID 34774225)
Primary and acquired resistance Antigen loss, MHC disruption and immune exclusion via PTEN loss are the three dominant programmes (Lim 2023, PMID 36934113)

Prognostic factors within the advanced population

Factor Evidence
Liver metastases and number of metastatic sites In a multicentre retrospective cohort of 759 patients treated with single-agent anti-PD-(L)1 across solid tumours (71% NSCLC, 19% melanoma, 10% urologic) enrolled 2012–2018, 22% had liver metastases and 49% had more than one metastatic site; liver metastasis was associated with worse progression-free and overall survival (Maugeais 2022, PMID 36672591)
Composite risk stratification In 398 patients with metastatic melanoma treated with checkpoint inhibitors, lactate dehydrogenase, neutrophil-to-lymphocyte ratio, performance status, prior therapies, liver metastases and lung metastases were associated with overall survival; 205 died, with mortality of 34%, 47% and 73% across low-, medium- and high-risk groups. Higher-risk patients were more likely to receive checkpoint inhibitors within 14, 30 and 90 days of death, with no association between risk group and hospice referral or location of death (Grad 2023, PMID 37543031)
Baseline S100B and LDH Independent predictors alongside M1c and M1d stage and pT4b primary category in 200 patients on anti-PD-1 (Janka 2023, PMID 37664072)
Bone metastases Systematic review of 29 studies: bone metastasis-free interval ranged 4–72 months and incidence varied 2–49% across 14 studies; 24% of studies focused solely on spinal metastases (Shimizu 2024, PMID 38765703)
Kinetics In 126 stage IV patients, kinetic index of progression predicted overall survival better than LDH or tumour load, with median survival 459, 388 and 183 days across ascending terciles (Gaudy-Marqueste 2014, PMID 24440089)

The end-of-life finding deserves emphasis. Patients at highest predicted risk of death were the most likely to receive checkpoint inhibitors in their final 14, 30 and 90 days (PMID 37543031). The durable-response plateau that defines this class creates a hope that is hard to time-limit, which is the clinical expression of the prognostic-uncertainty theme in patient experience and advocacy.

Interpretation rules for this page

  • CheckMate 067's combination-versus-monotherapy comparison is descriptive, not powered (PMID 34818112).
  • Report the plateau, not only the median. The clinically decisive quantity in melanoma immunotherapy is the fraction alive years out (PMID 25667295; PMID 39282897).
  • Melanoma-specific survival and overall survival diverge at ten years because competing mortality accumulates (PMID 39282897).
  • Treatment-free survival is a derived quantity sensitive to subgroup definition (PMID 34855329).
  • Response rate is sequence-dependent: immunotherapy after targeted therapy had ORR 29.6% versus 46.0% first-line in the same trial (PMID 36166727).
  • No head-to-head trial compares nivolumab–relatlimab with nivolumab–ipilimumab; cross-trial toxicity comparisons are indirect (PMID 40513285).

Open questions

  • Is nivolumab–relatlimab or nivolumab–ipilimumab preferable first-line, and in which subgroups? No randomised comparison exists; the non-randomised direct-combination study terminated at n = 2 (PMID 34986285; PMID 39282897; NCT03724968).
  • How long should checkpoint therapy continue in a responder, and can stopping rules be defined prospectively (PMID 34799400; PMID 37509227)?
  • Why does the ipilimumab plateau sit at ~21% while combination therapy reaches far higher long-term survival — is it the same biological phenomenon at a different level (PMID 25667295; PMID 39282897)?
  • What is standard of care after failure of both PD-1 and CTLA-4 blockade (PMID 34009481; PMID 39435288)?
  • Can the IFN-γ/TMB biomarker combination that predicts neoadjuvant pathological response select first-line therapy in advanced disease (PMID 33558721)?
  • Does treatment-free survival predict anything the conventional endpoints do not, or is it a re-expression of them (PMID 31498030; PMID 34855329)?

References

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