Clinical Trial Results &Evidence Summary:Metastatic Uveal Melanoma
Uveal melanoma arises in the eye (the uveal tract) and is biologically distinct from cutaneous melanoma, the skin form of the disease. "Ocular melanoma" is a broader term that can include other eye structures; this page addresses metastatic uveal melanoma.
This page organizes published clinical-trial evidence in metastatic uveal melanoma, connecting therapies, biomarker eligibility, trial populations, comparators, and reported outcomes. It supports educational and research exploration, with links to original sources.
Tebentafusp's FDA-approved indication is for HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma. Its pivotal randomized trial enrolled previously untreated HLA-A*02:01-positive patients with metastatic disease.
These are two related but distinct statements: the approved indication describes which patients the drug is approved to treat, while the trial population describes who was studied in the pivotal trial (previously untreated patients only). Outcomes reported below apply to the studied population.
FDA Drug Trials Snapshots: KIMMTRAKPublished Clinical-Trial Evidence
The table below summarizes verified original publications and trial-registry records. Results from different studies are not directly comparable: they differ in study design, populations, comparators, endpoints, and follow-up.
Scroll horizontally to view the full table.
| Therapy or approach | Biomarker eligibility and study population | Trial identifier and phase | Study design and comparator | Key reported outcomes | Evidence limitations | Original-source link and publication year |
|---|---|---|---|---|---|---|
| Tebentafusp (bispecific gp100 TCR–anti-CD3 fusion protein) | Previously untreated, HLA-A*02:01-positive, metastatic uveal melanoma. n = 378 (252 tebentafusp / 126 control). | NCT03070392 (IMCgp100-202), Phase III. | Randomized 2:1, open-label. Comparator: investigator's choice of pembrolizumab, ipilimumab, or dacarbazine (82% received pembrolizumab, per the 5-year follow-up report). | Overall survival: 1-year OS 73% vs 59%; hazard ratio for death 0.51 (95% CI, 0.37-0.71; P<0.001). Median OS 21.7 vs 16.0 months (per FDA Drug Trials Snapshot). Progression-free survival: 6-month PFS 31% vs 19%; HR 0.73 (95% CI, 0.58-0.94; P=0.01). Objective response: low response rates were reported in the pivotal publication (see section below). Safety: rash 83%, pyrexia 76%, pruritus 69% (all grades); discontinuation due to adverse events 2%; no treatment-related deaths reported. | Open-label design; heterogeneous investigator's-choice comparator; single phase 3 trial; survival benefit observed despite low radiographic response rates. | Pivotal publication (PMID 34551229), 2021. FDA summary: FDA Drug Trials Snapshot. |
| Anti-PD-1 / anti-PD-L1 monotherapy | Patients with metastatic uveal melanoma treated with PD-1/PD-L1 antibodies across centers. n = 56 eligible patients. No biomarker eligibility for HLA-A*02:01 required. | No trial identifier; retrospective observational study. | Retrospective multicenter cohort. No randomized comparator. | Objective response: 2 of 56 patients (3.6%). Progression-free survival: median 2.6 months (95% CI, 2.4-2.8). Overall survival: median 7.6 months (95% CI, 0.7-14.6). Safety: not separately verified from the source for this summary. | Retrospective; small; no comparator; cannot establish comparative survival benefit; includes mixed treatment lines. | PubMed 27533448, 2016. |
| Nivolumab + ipilimumab combination | Metastatic uveal melanoma, any number of prior treatments permitted. n = 35 enrolled; 33 evaluable for efficacy. No biomarker eligibility for HLA-A*02:01 required. | NCT01585194, Phase II. | Single-arm phase 2 study. No comparator arm. | Objective response: 18% (1 complete, 5 partial responses among 33 evaluable). Progression-free survival: median 5.5 months (95% CI, 3.4-9.5). Overall survival: median 19.1 months (95% CI, 9.6-NR); 1-year OS 56% (95% CI, 38-71%). Safety: 40% grade 3-4 treatment-related adverse events. | Single-arm, small; no comparator; survival estimates are single-arm and cannot be interpreted as comparative benefit. | PubMed 33125309, 2021. |
| HEPZATO KIT (melphalan with hepatic delivery system) — liver-directed treatment | FDA-approved population: adults with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver, with no extrahepatic disease or extrahepatic disease limited to bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. No HLA-A*02:01 positivity requirement. Not every patient with liver metastases qualifies. | NCT02678572 (FOCUS), Phase III. | Single-arm, multicenter, open-label phase 3 study. The FDA approval efficacy analysis was based on 91 treated patients; there was no randomized comparator in that analysis. | Objective response: 36.3% (95% CI, 26.4-47.0), including 7.7% complete response. Duration of response: median 14 months (95% CI, 8.3-17.7). Applies to responders; it is not overall survival. Overall survival (single-arm, per publication): median 20.5 months; 1-year OS 80% — single-arm estimates, not comparative. Safety: FDA boxed warnings for severe peri-procedural complications (hemorrhage, hepatocellular injury, thromboembolic events) and myelosuppression with resulting severe infection, bleeding, or symptomatic anemia; available only through the HEPZATO KIT REMS. | Selected patient population; no randomized comparator in the approval efficacy analysis; duration of response applies to responders and is not overall survival; response results must not be compared directly with tebentafusp's survival results. | FOCUS publication (PMID 38704501), 2024. FDA approval: FDA announcement. |
Reading the table: overall survival, progression-free survival, objective response, and safety are separate endpoints and are labeled separately above. Median overall survival in the tebentafusp trial (21.7 months) and the single-arm nivolumab-ipilimumab study (19.1 months) were measured in different studies, populations, and designs, and must not be read as a head-to-head comparison. The HEPZATO KIT row reports response and duration-of-response results from a single-arm study; these are separate endpoints and must not be compared directly with tebentafusp's survival results.
Tebentafusp Evidence: The Pivotal Trial and Its Follow-Up
The three publications below report the same phase 3 trial (NCT03070392) and its follow-up analyses. They are not three independent trials: the 2021 publication reports the primary analysis, and the 2023 and 2026 publications report longer follow-up of the same randomized cohort.
Pivotal randomized trial (2021)
Primary analysis. Randomized 2:1 to tebentafusp (n=252) versus investigator's choice of pembrolizumab, ipilimumab, or dacarbazine (n=126). Primary endpoint overall survival: 1-year OS 73% vs 59% (HR 0.51; 95% CI, 0.37-0.71; P<0.001). This is the initial, shortest follow-up of the trial.
Three-year follow-up (2023)
Same trial, longer follow-up. At a minimum follow-up of 36 months, median OS was 21.6 vs 16.9 months; 3-year OS 27% vs 18% (HR 0.68; 95% CI, 0.54-0.87). Summary based on the published abstract.
Five-year follow-up (2026)
Final survival follow-up of the same trial, published in 2026. Median OS 21.6 vs 16.9 months (stratified HR 0.67; 95% CI, 0.54-0.85); 5-year OS 16% (95% CI, 11-21%) vs 8% (95% CI, 4-14%). A post hoc analysis reported that patients treated with tebentafusp beyond radiographic progression had longer overall survival than those who discontinued treatment. This post hoc association does not establish that continuing treatment caused longer survival; patient selection and other confounding factors may influence the result. Summary based on the published abstract.
Survival benefit and radiographic response in this evidence
In the tebentafusp trial, the improvement in overall survival was observed alongside low objective response rates on standard radiographic assessment. In other words, the survival benefit in this trial was not proportional to the rate of tumor shrinkage, and later follow-up reported post hoc associations between treatment beyond progression and longer post-progression survival. This relationship is specific to the tebentafusp evidence summarized above and its mechanism; it does not demonstrate that low response rates imply survival benefit for other therapies in other trials.
Source-access limitation
The summaries of the 2023 and 2026 publications on this page are based on their published abstracts, as accessed on this page's verification date. Full-text details beyond the abstracts were not independently reviewed here.
HEPZATO KIT — Liver-Directed Treatment
HEPZATO KIT delivers melphalan through a hepatic delivery system. The FDA approved it on August 14, 2023, for selected adults with uveal melanoma metastatic to the liver.
Its approved population includes patients with unresectable liver metastases affecting less than 50% of the liver, with either no disease outside the liver or extrahepatic disease limited to bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.
Unlike tebentafusp, its approved indication does not require HLA-A*02:01 positivity. Eligibility instead depends on disease distribution and other clinical requirements.
Supporting study and approval analysis (verified)
The registry record for the FOCUS study (NCT02678572) lists a single-arm, multicenter, open-label phase 3 design with an overall status of Completed (identifier and design verified in the registry record on October 8, 2026). The FDA approval efficacy analysis was based on 91 treated patients in this single-arm study.
Reported outcomes in the approval analysis: objective response rate 36.3% (95% CI, 26.4-47.0); median duration of response 14 months (95% CI, 8.3-17.7). Duration of response applies to responders; it is not overall survival. These findings come from a selected patient population, and there was no randomized comparator in the approval efficacy analysis; the response results must not be compared directly with tebentafusp's survival results.
Safety: the FDA prescribing information carries boxed warnings for severe peri-procedural complications (including hemorrhage, hepatocellular injury, and thromboembolic events) and for myelosuppression with resulting severe infection, bleeding, or symptomatic anemia. HEPZATO KIT is available only through a restricted program, the HEPZATO KIT REMS. View FDA prescribing information.
Relationship to tebentafusp
These approaches address different eligibility factors: tebentafusp connects HLA-A*02:01 status to systemic therapy, while HEPZATO KIT connects liver-dominant disease distribution to liver-directed treatment. Their studies report different endpoints and do not establish a head-to-head comparison or a treatment sequence.
Regulatory and Guideline Context
Jurisdiction: United States. The FDA approved tebentafusp (KIMMTRAK) on January 25, 2022, for HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma. This is a regulatory approval, not a clinical-practice guideline recommendation.
FDA Drug Trials Snapshots: KIMMTRAK (approval date January 25, 2022)No formal clinical-practice guideline recommendation for metastatic uveal melanoma has been verified on this page, so no guideline is cited here. Regulatory approval and guideline recommendation are distinct: a drug approval describes a permitted use, while a guideline recommendation reflects an organized assessment of evidence. NCI educational summaries are educational summaries of published evidence, not formal clinical-practice guidelines, and are not presented as such on this page.
Jurisdiction: United States. The FDA approved HEPZATO KIT (melphalan with a hepatic delivery system) on August 14, 2023, as a liver-directed treatment for adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. This is a regulatory approval, not a clinical-practice guideline recommendation. Approval or availability in other jurisdictions has not been verified on this page and is not implied.
FDA approval announcement (August 14, 2023)Research Directions and Trial Status
This section covers investigational approaches, trial-status information, and follow-up research on established therapies.
Checkpoint combinations
Example: a phase 2 study of nivolumab plus relatlimab (anti-LAG-3) in metastatic uveal melanoma, registry record NCT04552223. Current trial status and results availability have not been independently verified on this page. Consult the linked ClinicalTrials.gov record.
Longer-term follow-up of randomized evidence
Extended survival follow-up of the tebentafusp trial continues to be published (2021, 2023, and 2026 reports above), informing how randomized results in this disease are interpreted over time.
Other investigational areas
Areas such as other liver-directed regional approaches and biomarker-driven trial design appear in the uveal melanoma literature, but specific current trials are not described here because their registry status has not been checked for this page. Note: liver-directed melphalan with the hepatic delivery system (HEPZATO KIT) is FDA-approved and is covered in its own sections above. The evidence and regulatory status of other liver-directed approaches are not assessed on this page.
Trial status changes. Any recruiting or ongoing status should be confirmed directly in the linked registry record, and identifiers and status-check dates are included above for that purpose.
References
Source verification: the HEPZATO KIT sources below (the FDA approval announcement, the FOCUS publication, and the NCT02678572 registry record) were accessed and checked directly during this addition, on October 8, 2026. The sources for the tebentafusp, anti-PD-1, and nivolumab-ipilimumab entries were accessed and checked during the page's earlier revision (October 8, 2026); the 2023 and 2026 follow-up summaries are based on their published abstracts, as noted above. This addition has not re-verified those earlier entries. The NCT04552223 registry record could not be retrieved during the earlier check, so its listed status has not been independently verified here; confirm it in the linked registry record.
New England Journal of Medicine, 2021. Randomized, open-label phase 3 trial (IMCgp100-202).
Trial identifier: NCT03070392
New England Journal of Medicine, 2023;389:2256-2266. Follow-up analysis of the same phase 3 trial (IMCgp100-202).
Trial identifier: NCT03070392
Annals of Oncology, 2026;37(9). Final survival follow-up of the same phase 3 trial (IMCgp100-202).
Trial identifier: NCT03070392
U.S. Food and Drug Administration, 2022. Approval date January 25, 2022.
Cancer, 2016;122(21):3344-3353. Retrospective multicenter cohort study (56 eligible patients).
Journal of Clinical Oncology, 2021;39(6):599-607. Single-arm phase 2 trial.
Trial identifier: NCT01585194
ClinicalTrials.gov registry record (University of Miami), phase 2. Current trial status and results availability have not been independently verified on this page. Consult the linked ClinicalTrials.gov record.
Trial identifier: NCT04552223
Annals of Surgical Oncology, 2024. FOCUS trial publication (treated population n = 91). A correction to this article is indexed at PMID 39026142.
Trial identifier: NCT02678572
ClinicalTrials.gov registry record, phase 3, single-arm, multicenter, open-label. Overall status: Completed; identifier and design verified in the registry record, October 8, 2026.
Trial identifier: NCT02678572
U.S. Food and Drug Administration, August 14, 2023. Approval announcement for HEPZATO KIT (melphalan for Injection/Hepatic Delivery System).
This page organizes public-source evidence for educational and research use. It does not provide medical advice, treatment recommendations, or predictions of individual outcomes.