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Melanoma clinical trials landscape

TL;DR — Every NCT identifier below was retrieved from the ClinicalTrials.gov v2 API on 2026-09-01; status, enrolment and primary-completion dates are as recorded that day. This is a selected phase 3 efficacy and practice-changing landscape, excluding legacy trials with completed primary endpoints, biosimilar/pharmacokinetic studies and tumour-agnostic baskets. Its centres of gravity are: (i) new checkpoint partners and direct LAG-3 comparison — fianlimab plus cemiplimab, relatlimab plus nivolumab and Harmony Head-to-Head; (ii) cellular therapy and vaccines moving earlier — lifileucel, IMA203, intismeran autogene and IO102–IO103; (iii) de-escalation and duration — reduced-frequency or shortened checkpoint therapy, MelMarT-II, NORMA 2 and an older-patient trial; and (iv) dedicated subtype trials — uveal, acral and NRAS-mutant melanoma. The most conspicuous gap remains that no trial compares modern neoadjuvant against modern adjuvant therapy with overall survival as the primary endpoint — see neoadjuvant therapy.

Active phase 3 trials by setting

Advanced and metastatic disease, first line

NCT Trial Design n Status / primary completion
NCT05352672 Fianlimab (anti-LAG-3) + cemiplimab vs pembrolizumab, previously untreated unresectable/metastatic melanoma, adolescents and adults Randomised phase 3 1,546 Active, not recruiting; PCD 2026-03-12
NCT06112314 PRISM-MEL-301: IMC-F106C (PRAME-directed ImmTAC) regimen vs nivolumab regimens, previously untreated advanced melanoma Randomised phase 3 680 Recruiting; PCD 2027-10-16
NCT05727904 Lifileucel (TIL) regimen + pembrolizumab vs pembrolizumab alone, untreated advanced melanoma Randomised phase 3 670 Recruiting; PCD 2028-03-01
NCT06697301 EIK1001 + pembrolizumab vs placebo + pembrolizumab, first line advanced melanoma Randomised phase 2/3 740 Recruiting; PCD 2035-12
NCT04657991 Encorafenib + binimetinib + pembrolizumab, advanced/metastatic melanoma Phase 3 257 Active, not recruiting; PCD 2026-01-12
NCT05732805 BCD-217 (nurulimab + prolgolimab) followed by anti-PD-1 vs anti-PD-1 monotherapy, first line Randomised phase 3 270 Active, not recruiting; PCD 2024-06-20
NCT04674683 HBI-8000 + nivolumab vs placebo + nivolumab, advanced melanoma Randomised phase 3 450 Active, not recruiting; PCD 2026-07
NCT05155254 IO102–IO103 vaccine + pembrolizumab vs pembrolizumab, advanced melanoma Randomised phase 3 407 Active, not recruiting; PCD 2025-05-30
NCT05625399 Subcutaneous vs intravenous nivolumab–relatlimab fixed-dose combination Randomised phase 3 579 Active, not recruiting; PCD 2025-08-04
NCT06246916 Harmony Head-to-Head: fianlimab–cemiplimab vs relatlimab–nivolumab Randomised phase 3 560 Recruiting; PCD 2027-03-22

Advanced disease after checkpoint failure

NCT Trial n Status / PCD
NCT06743126 SUPRAME: ACTengine IMA203 (TCR-engineered T cells) vs investigator's choice, previously treated unresectable/metastatic cutaneous melanoma 360 Recruiting; PCD 2028-01
NCT05549297 TEBE-AM: tebentafusp regimen vs investigator's choice, previously treated advanced melanoma 540 Recruiting; PCD 2028-03
NCT06264180 IGNYTE-3: oncolytic virus + nivolumab vs physician's choice, advanced melanoma progressing on anti-PD-1 and anti-CTLA-4 400 Recruiting; PCD 2030-09-30
NCT05868707 OH2 oncolytic injection in melanoma 340 Recruiting; PCD 2026-03

Two things stand out. Tebentafusp — developed for and licensed in uveal melanoma — is being tested in cutaneous melanoma after checkpoint failure (NCT05549297), and PRAME-directed ImmTAC is being tested against nivolumab first line (NCT06112314). The ImmTAC platform is the main structural innovation in melanoma therapy since checkpoint blockade, and its evidence in uveal disease is described in uveal melanoma.

Adjuvant and neoadjuvant

NCT Trial n Status / PCD
NCT05608291 Fianlimab + cemiplimab vs pembrolizumab, adjuvant, for preventing or delaying recurrence 1,564 Active, not recruiting; PCD 2026-07-27
NCT05933577 V940-001: intismeran autogene (mRNA-4157) + pembrolizumab vs pembrolizumab, high-risk resected melanoma 1,089 Active, not recruiting; PCD 2029-10-26
NCT05270044 COLUMBUS-AD: adjuvant encorafenib + binimetinib in high-risk stage II BRAF-mutant melanoma 815 Active, not recruiting; PCD 2027-03-31
NCT04309409 Adjuvant nivolumab in stage IIA/IIB/IIC high-risk melanoma 374 Active, not recruiting; PCD 2027-09
NCT04949113 NADINA: neoadjuvant ipilimumab + nivolumab vs standard adjuvant nivolumab, macroscopic stage III 423 Active, not recruiting; PCD 2024-01-12
NCT06794775 SWE-NEO: neoadjuvant monotherapy vs combination immunotherapy, resectable stage III 128 Recruiting; PCD 2032-04-15
NCT03567889 Neoadjuvant intratumoral Daromun, clinical stage IIIB/C/D 186 Recruiting; PCD 2027-12
NCT06754904 Omitting therapeutic lymph-node dissection after major pathological response in the index node 213 Recruiting; PCD 2027-04-01
NCT03553836 KEYNOTE-716: adjuvant pembrolizumab vs placebo, resected stage IIB/IIC 976 Active, not recruiting; PCD 2021-06-21
NCT04099251 CheckMate 76K: adjuvant nivolumab vs placebo, resected stage IIB/C 790 Active, not recruiting; PCD 2022-06-28
NCT02362594 KEYNOTE-054: adjuvant pembrolizumab vs placebo, resected high-risk stage III 1,019 Active, not recruiting; PCD 2018-01-08
NCT05751928 Neoadjuvant BCD-217 (nurulimab + prolgolimab), resectable stage III 411 Active, not recruiting; PCD 2027-01
NCT06488482 Six vs twelve months of perioperative/adjuvant checkpoint therapy 1,792 Recruiting; PCD 2030-09

Stage II is now the most crowded setting in melanoma, with two completed placebo-controlled adjuvant trials (NCT03553836, NCT04099251), a third ongoing (NCT04309409), a BRAF-targeted adjuvant trial (NCT05270044) and a margins trial (NCT03860883) all enrolling node-negative patients — a setting that had no systemic therapy at all before 2022. See adjuvant therapy.

De-escalation, duration and surgical questions

NCT Question n Status / PCD
NCT03860883 MelMarT-II: 1 cm vs 2 cm excision margins, AJCC stage II primary cutaneous melanoma 2,998 Recruiting; PCD 2029-12-31
NCT02821013 Duration of anti-PD-1 therapy in metastatic melanoma 614 Recruiting; PCD 2027-12-31
NCT07068074 Management of treatment-naive primary melanoma in elderly patients 428 Not yet recruiting; PCD 2031-01-01
NCT06754904 Omission of therapeutic lymph-node dissection after major pathological response 213 Recruiting; PCD 2027-04-01
NCT06500455 Longer-duration versus usual radiation therapy for metastatic disease to the brain 269 Recruiting; PCD 2028-06-30
NCT05078047 Standard-frequency checkpoint therapy vs dosing every 3 months after response 646 Active, not recruiting; PCD 2029-05-07
NCT07530887 NORMA 2: re-excision (1–2 cm) vs no re-excision after a ≥1 mm clear diagnostic excision, pT1b–pT4b melanoma 1,749 Recruiting; PCD 2033-11
NCT07552597 MagMen-II: magnetic vs technetium/blue-dye sentinel-node localisation 254 Not yet recruiting; PCD 2029-12-31

The duration trial (NCT02821013) is the direct test of the treatment-free-survival observation described in immunotherapy in advanced disease, and MelMarT-II is the direct test of the unresolved margin question in surgical management and margins.

Subtype-specific phase 3 trials

Subtype NCT Trial n Status / PCD
Uveal, metastatic NCT05987332 Darovasertib (IDE196) + crizotinib first line 420 Active, not recruiting; PCD 2027-01-15
Uveal, primary NCT07015190 Neoadjuvant darovasertib in primary uveal melanoma 520 Recruiting; PCD 2030-10
Uveal, adjuvant NCT06246149 Adjuvant tebentafusp in high-risk ocular melanoma 290 Recruiting; PCD 2032-11
Uveal, primary tumour NCT06007690 Belzupacap sarotalocan (AU-011), masked randomised controlled trial 108 Active, not recruiting; PCD 2027-11-15
Uveal, hepatic NCT05022901 Melphalan/hepatic delivery system expanded access, hepatic-dominant ocular melanoma 30 Active, not recruiting; PCD 2024-03-01
Uveal, liver-directed NCT04283890 CHOPIN: percutaneous hepatic perfusion ± ipilimumab + nivolumab — Reported 2026 (van den Hoek 2026, PMID 41785896)
Uveal, adjuvant NCT05502900 Melatonin vs observation after primary-tumour treatment 100 Recruiting; PCD 2031-01-01
Uveal, metastatic NCT06581406 RP2 oncolytic virus + nivolumab vs ipilimumab + nivolumab 280 Recruiting phase 2/3; PCD 2030-01
Acral NCT05789043 Camrelizumab + apatinib + temozolomide, first line advanced acral melanoma 140 Recruiting; PCD 2026-08-15
NRAS-mutant NCT06008106 Tunlametinib vs combination chemotherapy, advanced NRAS-mutant melanoma 165 Recruiting; PCD 2027-09-22
NRAS-mutant NCT06346067 SEACRAFT-2: naporafenib + trametinib, NRAS-mutant melanoma 78 Active, not recruiting; PCD 2028-04

Uveal melanoma now has six active phase 3 or phase 2/3 efficacy trials spanning primary tumour, neoadjuvant, adjuvant and metastatic settings, plus an active expanded-access hepatic-delivery study — a transformation from a disease with essentially no phase 3 pipeline a decade ago (compare the flat survival curve in uveal melanoma). NRAS-mutant melanoma, by contrast, still has no approved targeted agent and two modest phase 3 trials (n = 165 and n = 78).

Landmark completed trials and their registrations

Trial NCT Publication
CheckMate 067 NCT01844505 Wolchok 2025, PMID 39282897
RELATIVITY-047 NCT03470922 Tawbi 2022, PMID 34986285; Lipson 2025, PMID 40513285
SWOG S1801 NCT03698019 Patel 2023, PMID 36856617
NADINA NCT04949113 Blank 2024, PMID 38828984
OpACIN-neo / PRADO NCT02977052 Rozeman 2019, PMID 31160251; Reijers 2022, PMID 35661157
Neoadjuvant nivolumab + relatlimab NCT02519322 Amaria 2022, PMID 36289334; Burton 2025, PMID 40638872
NeoCombi NCT01972347 Long 2019, PMID 31171444; Menzies 2024, PMID 38754780
KEYNOTE-716 NCT03553836 Luke 2022, PMID 35367007; Luke 2025, PMID 40198940
CheckMate 76K NCT04099251 Kirkwood 2023, PMID 37845511
KEYNOTE-942 NCT03897881 Weber 2024, PMID 38246194; Khattak 2026, PMID 42223134
MSLT-II NCT00297895 Faries 2017, PMID 28591523; Crystal 2022, PMID 35921122
CheckMate 204 NCT02320058 Tawbi 2021, PMID 34774225
MelMarT (feasibility) NCT02385214 Moncrieff 2018, PMID 29850955
ONTRAC (nicotinamide) — Chen 2015, PMID 26488693

What is not being tested

  • Neoadjuvant versus adjuvant with overall survival as the primary endpoint. NADINA's primary endpoint is event-free survival at a median 9.9 months' follow-up (PMID 38828984); no successor trial in the active phase 3 list above uses overall survival as primary for that comparison.
  • Population melanoma screening. No randomised trial of screening has ever been conducted, and none appears in the active phase 3 registry (PMID 37071089).
  • Completed margin evidence in T1 melanoma or melanoma in situ. MelMarT-II is restricted to AJCC stage II (NCT03860883), but the recruiting phase 3 NORMA 2 trial now includes pT1b–pT4b invasive melanoma and tests re-excision against no re-excision after a ≥1 mm clear diagnostic excision (NCT07530887). No randomised melanoma-in-situ-specific margin trial was found in the 2026-09-01 registry search.
  • Head-to-head comparison of nivolumab–relatlimab against nivolumab–ipilimumab. Both are licensed first-line options with no randomised comparison (PMID 34986285; PMID 39282897). A non-randomised phase 2 study containing both combination arms terminated after enrolling two participants (NCT03724968); Harmony instead compares the two anti-LAG-3 combinations (NCT06246916).
  • Prospective validation of any predictive biomarker for checkpoint selection. The IFN-γ/TMB combination that separates neoadjuvant pathological response rates from 39% to 100% has not been tested as a selection tool (Rozeman 2021, PMID 33558721).
  • ctDNA-guided outcome utility. CAcTUS randomised 21 patients and established the feasibility of a ctDNA-triggered treatment switch, but not an outcome benefit (Lee 2026, PMID 42168180; NCT03808441). A separate randomised adaptive BRAF/MEK study is registered but not yet recruiting (NCT06470880) — see surveillance and survivorship.
  • Trials designed for skin-of-colour and East Asian populations. The acral trial (NCT05789043) is Chinese-led and is the exception that demonstrates the rule (see acral and mucosal melanoma).

Interpretation rules for this page

  • Every identifier here was verified live on 2026-09-01; status and dates change and should be re-verified at each sweep.
  • Primary completion date is not publication date. Several trials listed as "active, not recruiting" have primary completion dates years in the past with results already published.
  • Enrolment figures are planned or actual as recorded in the registry, not always as analysed in publications.
  • Registry phase labels are self-reported. Several entries carry combined phase 2/3 designations.
  • Absence from this list is not absence of a trial — this is a phase 3-focused snapshot, and the phase 1–2 pipeline is far larger.

Open questions

  • Will a trial ever compare neoadjuvant against adjuvant therapy with overall survival as primary (PMID 38828984)?
  • Do the two fianlimab phase 3 trials (NCT05352672, NCT05608291) establish LAG-3 blockade as a first-line and adjuvant standard, and how will they be compared with relatlimab?
  • Does moving TIL therapy to first line (NCT05727904) improve outcomes over sequencing it after checkpoint failure (PMID 36477031)?
  • Will darovasertib change uveal melanoma survival, which has been flat for five decades (NCT05987332; PMID 40225965)?
  • What is the optimal duration of anti-PD-1 therapy (NCT02821013)?
  • Can margin de-escalation to 1 cm be established for stage II disease (NCT03860883)?

References

  1. van den Hoek L, et al. Percutaneous hepatic perfusion combined with ipilimumab and nivolumab for metastatic uveal melanoma (CHOPIN): a single-centre, open-label, randomised, phase 2 trial. The Lancet. Oncology. 2026;27:372-382. PMID 41785896
  2. Wolchok JD, et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. The New England journal of medicine. 2025;392:11-22. PMID 39282897
  3. Tawbi HA, et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. The New England journal of medicine. 2022;386:24-34. PMID 34986285
  4. Lipson EJ, et al. Nivolumab plus relatlimab in advanced melanoma: RELATIVITY-047 4-year update. European journal of cancer (Oxford, England : 1990). 2025;225:115547. PMID 40513285
  5. Patel SP, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. The New England journal of medicine. 2023;388:813-823. PMID 36856617
  6. Blank CU, et al. Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. The New England journal of medicine. 2024;391:1696-1708. PMID 38828984
  7. Rozeman EA, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. The Lancet. Oncology. 2019;20:948-960. PMID 31160251
  8. Reijers ILM, et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nature medicine. 2022;28:1178-1188. PMID 35661157
  9. Amaria RN, et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature. 2022;611:155-160. PMID 36289334
  10. Burton EM, et al. Long-Term Survival and Biomarker Analysis Evaluating Neoadjuvant Plus Adjuvant Relatlimab (anti-LAG3) and Nivolumab (anti-PD1) in Patients With Resectable Melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2025;43:2856-2862. PMID 40638872
  11. Long GV, et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF(V600) mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. The Lancet. Oncology. 2019;20:961-971. PMID 31171444
  12. Menzies AM, et al. Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma. Annals of oncology : official journal of the European Society for Medical Oncology. 2024;35:739-746. PMID 38754780
  13. Luke JJ, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet (London, England). 2022;399:1718-1729. PMID 35367007
  14. 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
  15. Kirkwood JM, et al. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nature medicine. 2023;29:2835-2843. PMID 37845511
  16. Weber JS, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet (London, England). 2024;403:632-644. PMID 38246194
  17. Khattak A, et al. Intismeran Autogene Plus Pembrolizumab Versus Pembrolizumab Alone in High-Risk Resected Melanoma: 5-Year Update of the Randomized Phase IIb KEYNOTE-942 Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2026;:JCO2600835. PMID 42223134
  18. Faries MB, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. The New England journal of medicine. 2017;376:2211-2222. PMID 28591523
  19. Crystal JS, et al. Therapeutic Value of Sentinel Lymph Node Biopsy in Patients With Melanoma: A Randomized Clinical Trial. JAMA surgery. 2022;157:835-842. PMID 35921122
  20. Tawbi HA, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. The Lancet. Oncology. 2021;22:1692-1704. PMID 34774225
  21. Moncrieff MD, et al. 1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study. Annals of surgical oncology. 2018;25:2541-2549. PMID 29850955
  22. Chen AC, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. The New England journal of medicine. 2015;373:1618-26. PMID 26488693
  23. Mangione CM, et al. Screening for Skin Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2023;329:1290-1295. PMID 37071089
  24. Rozeman EA, et al. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nature medicine. 2021;27:256-263. PMID 33558721
  25. Rohaan MW, et al. Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. The New England journal of medicine. 2022;387:2113-2125. PMID 36477031
  26. Weinberger Y, et al. Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival (SEER 1975-2020). Ocular oncology and pathology. 2025;11:30-36. PMID 40225965
  27. Lee R, et al. Use of circulating tumour DNA to prospectively guide a switch from targeted to immune therapy in BRAF mutant advanced melanoma: the randomised phase II CAcTUS trial. Nature communications. 2026;17:6850. PMID 42168180