Abstract Background: Metastatic uveal melanoma (mUM) has a very poor prognosis with a historical survival rate of <10% at 5 yrs. Tebentafusp, a first in class ImmTAC bispecific (gp100 x CD3), is approved for adult HLA-A*02:01+ patients with unresectable or mUM based on a phase 3 study demonstrating improved overall survival (OS) compared to investigator’s choice (IC) (HR 0.51; IMCgp100-202; NCT03070392). This benefit was maintained at the 3-yr follow-up (HR 0.68), with a 3-yr OS rate of 27% for tebentafusp and 18% for IC. Molecular response assessed by ctDNA reduction was a better indicator of OS benefit than traditional RECISTv1.1 measurements. Here we report updated analyses of OS after a minimum follow-up of 5 yrs. Methods: In this randomized, open-label, Phase 3 trial, first line HLA-A*02:01+ mUM patients were randomized 2:1 to receive tebentafusp or IC of single-agent pembrolizumab, ipilimumab or dacarbazine, stratified by lactate dehydrogenase. Primary endpoint was OS. ctDNA reduction was an exploratory endpoint. OS was estimated using Kaplan-Meier methods and treatment effects compared using Cox proportional hazards model. A Cox model, adjusted for baseline and time-varying covariates at progression, compared post-progression survival in tebentafusp patients with versus without treatment beyond radiographic progression (TBP). Results: 378 patients were randomized to tebentafusp (252) or IC (126; 82% pembrolizumab). With extended follow-up, the OS continued to favor tebentafusp, with a stratified hazard ratio of 0.67 (95% CI, 0.54-0.85). The 5-year OS rate for tebentafusp was 16% (95% CI, 11-21) vs 8% (95% CI, 4-14) for IC. The OS benefit was evident even in patients with known poor prognostic factors, including those with large tumors ≥ 10 cm. OS benefit was also seen in patients who did not have radiographic response including those with best response of progressive disease (PD) or those with a best change of tumor growth (>20%). Notably, in the tebentafusp arm, TBP was associated with better OS compared to no TBP, even after adjusting for covariates (HR 0.61; 95% CI, 0.44-0.83). In tebentafusp-treated patients, longer OS was associated with undetectable ctDNA at baseline or ctDNA reductions ≥50% by week 9. Among 21 ctDNA-evaluable patients who survived ≥ 5 years, 15 had undetectable baseline ctDNA and the remaining 6 had ctDNA clearance. Deep reductions in ctDNA were seen in patients regardless of baseline tumor burden and across all RECIST categories. Conclusions: Tebentafusp demonstrates durable, long-term OS benefit in first line HLA-A*02:01+ patients, which at 5 years is the longest OS follow-up in a randomized trial in mUM. OS benefit is evident in those with poor prognostic factors and remains independent of radiographic response, with ctDNA levels proving to be a better indicator of activity. This is the first report of long-term OS benefit in a solid tumor treated with an ImmTAC therapy. Citation Format: Paul Nathan, Sophie Piperno-Neumann, Jessica C. Hassel, Marcus O. Butler, Max Schlaak, Ryan J. Sullivan, Reinhard Dummer, John M. Kirkwood, Joseph J. Sacco, Alexander N. Shoushtari, Josep M. Piulats, April KS Salama, Marlana Orloff, Anthony M. Joshua, Sebastian Ochsenreither, Lauris Gastaud, Brendan Curti, Lev Demidov, Mohammed Milhem, Bartosz Chmielowski, Kari Kendra, Paolo Antonio Ascierto, Eric H. Bernicker, Richard D. Carvajal, Omid Hamid, Laura Collins, Sarah Lockwood, Jaymin M. Patel, Jean-Francois Baurain, Piotr Rutkowski. Five-year survival with tebentafusp in previously untreated metastatic uveal melanoma in a phase 3 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT029.

Background: Treatment options are limited, and outcomes remain poor for patients with metastatic uveal melanoma (MUM). We conducted an investigator-initiated, prospective, single-arm, single-institution, phase II study evaluating the combination of an FAK inhibitor (defactinib) with a RAF/MEK inhibitor (avutometinib) for the treatment of MUM. Methods: From February 2021 through January 2023, 12 patients with MUM were treated with the combination of defactinib and avutometinib. Defactinib was given 200 mg twice daily, and avutometinib was given 3.2 mg twice a week. Both drugs were given for 3 weeks on and 1 week off (28-day cycle). Disease control rate was the primary endpoint of this study. Results: Median lines of prior therapies for the patients were two. After two cycles, six patients achieved stable disease while six patients developed progressive disease (disease control rate of 50%). With a median follow-up of 20.0 months, the median progression-free survival was 3.0 months and the median overall survival was 20.0 months. The combination was quite tolerable for patients, with no patients requiring dose reduction or discontinuation. Trial enrollment was stopped early by study sponsors before the anticipated accrual of 18 patients due to no patients having a significant reduction in disease. Conclusions: This is the first study reporting on the use of an FAK inhibitor combination in MUM. Further research should seek to elucidate an optimal combination treatment strategy for MUM, such as FAK and PKC inhibitors, for improved blockade of the signaling pathways downstream of GNAQ/GNA11 driver mutations.

Background: Uveal melanoma (UM) is a rare subtype of melanoma with distinct clinical and molecular features compared to other melanoma subtypes. UM tumors are frequently detected with mutations in GNA11, GNAQ, EIF1AX, BAP1, and SF3B1 instead of the typical mutations associated with cutaneous melanoma. Although hereditary UM is rare, germline BAP1 loss predisposes patients to UM and various other cancers. The CHEK2 (Checkpoint kinase 2) gene that encodes the protein CHK2, a serine-threonine kinase, is a cell cycle checkpoint regulator that acts as a tumor suppressor. CHK2 is involved in DNA repair, cell cycle arrest, or apoptosis in response to DNA damage. CHEK2 mutations have been linked to various cancers. While there is no strong evidence that CHEK2 mutations increase the risk of melanoma, two cases of germline CHEK2 mutations in UM patients have been reported. However, the incidence of CHEK2 variants in metastatic UM (MUM) has not been investigated. Thus, we conducted a retrospective analysis of patients with MUM and CHEK2 variants to understand this link better. Methods: We collected MUM cases from 2016 to 2024 from institutional databases. Tissues underwent analyses of molecular and genomic features, including tumor mutational burden, and were performed by a Clinically Certified Laboratory. Next-generation sequencing and variant calling were conducted to identify CHEK2 variants. Results: In this study, we reported ten patients with CHEK2 variants among 740 metastatic UM patients (1.4%) and four primary UM patients with CHEK2 germline mutations. Conclusions: Although rare, UM patients with an abnormal ATM–CHEK2 axis might receive clinical benefits from medications that target DNA repair mechanisms.

BACKGROUND:Tebentafusp has significantly improved overall survival in HLA-A*02:01+ metastatic uveal melanoma (mUM) patients even in those with a best objective response of progressive disease. Thus, strategies to maintain tebentafusp therapy are critical. Here, we examine the efficacy and safety of adding concurrent local therapy (CLT) to tebentafusp upon radiological progression with tebentafusp alone. PATIENTS AND METHODS:This multicenter retrospective study included mUM patients treated with tebentafusp and CLT, consisting of extrahepatic soft tissue irradiation and liver-directed therapies (LDTs). Efficacy of target and nontarget sites were assessed per RECIST version 1.1. PFS with tebentafusp alone (PFS1) was compared to that after adding CLTs to tebentafusp upon progression (PFS1+PFS2). ctDNA responses were explored. RESULTS:Of the 30 eligible patients, 21 (70%) received concurrent LDT, 7 (23%) had extrahepatic irradiation, and 2 (7%) had both. The objective response rate (ORR) was 12% (95% CI, 3-32) for tebentafusp alone and 28% (95% CI, 14-47) after adding CLTs. The disease-control rate with tebentafusp alone was 44% (95% CI, 25-65) vs 63% (95% CI, 44-78) after CLT. Median PFS1 was 5.8 months (95% CI, 2.8-13.4), while median PFS1+PFS2 was 14.8 months (95% CI, 9.2-NA). CLT thereby allowed treatment beyond progression with tebentafusp for approximately 9 months. Two patients (66%) had decreased ctDNA with tebentafusp alone, while 4 (100%) had decreased ctDNA after CLT. There were no treatment discontinuations due to toxicities from tebentafusp with CLT. CONCLUSIONS:CLT with tebentafusp was well-tolerated, extending the duration of tebentafusp benefit in a highly selected mUM population. This merits further studies to assess clinical utility.

Tebentafusp is a gp100xCD3 bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage specific antigen gp100 on HLA-A*02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions, yet the mechanisms are unknown. Here we analysed clinical data from the randomised phase 3 trial (NCT03070392) of tebentafusp (n=252) versus investigator’s choice (n=126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced and expression of melanocytic genes decreased, while gene expression related to immunity and cytokine signalling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival compared to patients without a rash in the phase 3 randomized trial IMCgp100-202 (HR 0.84; 95% CI 0.53-1.32). In summary, skin rash is an off-tumour, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.

e21532 Background: Approximately 50% of patients with uveal melanoma (UM) develop metastases with the liver being the primary site of disease in > 90% of cases. Control of hepatic tumors is critical to prolonging overall survival for patients with metastatic uveal melanoma (MUM). We report our initial single institution experience with commercially available PHP with melphalan (HEPZATO, Delcath, Queensbury, NY) for the treatment of UM hepatic metastases. Methods: MUM patients with < 50% hepatic tumor burden underwent commercially available PHP at 6 to 8-week intervals. Best radiographic response was assessed with contrast-enhanced MRI using RECIST 1.1 criteria. CTCAE v5.0 was used to assess adverse events. Results: Sixteen patients (6 men; median age, 60; range, 31–73) including 7 patients with extrahepatic metastasis, underwent PHP (n = 43 procedures) from March 2024 to January 2025. All patients had at least one prior liver-directed therapy (LDT), and 6 out of 7 patients failed prior systemic treatment. Patients underwent a median of 2 PHPs (range 1-5), and 14 patients had ≥ 2 procedures. Median follow-up was 4.8 months (range, 0.5 – 10.4). Fifteen patients are still alive after initial PHP [median, 4.4 months (range 0.5-10.4)]. Of the 12 patients who underwent follow-up MRI, 5 had stable disease (SD) and 3 demonstrated a partial response (67% disease control rate). Three patients with progression of disease (PD) after PHP underwent repeat treatment; one achieved SD while two have not yet undergone follow-up imaging. One patient stopped treatment due to intrahepatic and extrahepatic tumor progression. Twelve patients required transfusions following one (n = 8), two (n = 2), three (n = 1) or five (n = 1) PHPs. One patient developed grade 4 sinusoidal obstruction syndrome prohibiting additional LDT and died 5.9 months post PHP due to PD. One patient was hospitalized 2 weeks following PHP due to grade 4 thrombocytopenia and leukopenia requiring transfusions, antibiotics, and supportive care. Two patients developed grade 3 neutropenia requiring cancellation of subsequent procedures. Two patients experienced strokes precluding additional PHP treatments: one occurred 2 weeks post-treatment of unclear etiology but was diagnosed with a patent foramen ovale and echogenic material in the left atrium by trans-esophageal ECHO; the other occurred post-procedurally with near-complete symptom resolution on discharge. Another patient required intubation for 27 hours post procedure due to sustained metabolic acidosis. Conclusions: PHP remains a promising treatment for MUM patients. The durability of disease control is uncertain based on this early commercial experience, and it is unclear how PHP compares to other LDT for this disease. However, in our experience, procedural complications seem to be more significant, and treatment-limiting compared to alternative LDT.

Metastatic uveal melanoma (mUM) has a poor prognosis, with liver metastases typically presenting a therapeutic challenge. Melphalan/Hepatic Delivery System (Melphalan/HDS) is a drug/medical device combination used for liver-directed treatment of unresectable mUM patients. This study assessed efficacy and safety of Melphalan/HDS versus best alternative care (BAC). Eligible patients with unresectable mUM were randomized (1:1) to receive Melphalan/HDS (3 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of 6 cycles or BAC. Due to slow enrollment and patient reluctance to receive BAC treatment, the study design was amended to a single-arm Melphalan/HDS study, and all efficacy analyses of the randomized study were treated as exploratory. The study enrolled 85 patients. Eligible patients were randomized to receive Melphalan/HDS (n = 43) or BAC (n = 42), and 72 patients received study treatment (Melphalan/HDS [n = 40]; BAC [n = 32]). Exploratory analyses of efficacy endpoints showed numerical differences consistently favoring the Melphalan/HDS arm versus BAC (median overall survival: 18.5 vs. 14.5 months; median progression-free survival: 9.1 vs. 3.3 months; objective response rate: 27.5% vs. 9.4%; and disease control rate: 80.0% vs. 46.9%). Serious adverse events (SAEs) occurred in 51.2% of Melphalan/HDS and in 21.9% of BAC patients. The most common (>5%) SAEs included thrombocytopenia (19.5%), neutropenia (9.8%), leukopenia (9.8%) and febrile neutropenia (7.3%) in Melphalan/HDS patients and cholecystitis, nausea and vomiting (6.3% each) in BAC patients. No treatment-related deaths were observed. Treatment with Melphalan/HDS shows clinically meaningful efficacy and demonstrates a favorable benefit-risk profile in patients with unresectable mUM as compared to BAC.

BACKGROUND/OBJECTIVES:Uveal melanoma is a rare but aggressive intraocular malignancy that metastasizes in up to half of patients, most commonly to the liver, despite effective local treatment. In the absence of robust evidence, there are no standardized guidelines for post-treatment surveillance, resulting in wide variation in imaging modalities, frequency, and duration across physicians and institutions. This study aimed to develop expert consensus recommendations for surveillance strategies in patients with uveal melanoma. METHODS:A modified Delphi method was conducted across three iterative survey rounds between September 2024 and February 2025 using an online platform. Panelists included medical oncologists, ocular oncologists, radiologists, and surgical oncologists from North America. A multidisciplinary steering committee developed statements addressing risk-based surveillance using both molecular and clinical prognostic factors, including gene expression profiling (GEP) and PRAME status. Consensus was defined a priori as ≥70% of panelists rating a statement 7-9 on a 9-point Likert scale. RESULTS:Forty-nine experts were invited, and 41 completed at least one survey round. The panel represented 17 U.S. states, Washington, D.C., and two Canadian provinces. Twelve statements reached stable consensus, including recommendations for imaging modality, frequency, and duration in intermediate- and high-risk patients. Although there was agreement that low-risk patients warrant surveillance, no consensus was reached on the optimal approach for this group. CONCLUSIONS:This is the first study to provide consensus-based guidance incorporating GEP and PRAME status into surveillance recommendations for uveal melanoma, offering a standardized framework to guide clinical practice and future research.

Uveal melanoma frequently metastasizes to the liver, with over 90% of metastatic cases involving hepatic spread. Despite systemic therapy advances, prognosis remains poor in hepatic-dominant disease. Percutaneous hepatic perfusion (PHP) with melphalan, now U.S. Food and Drug Administration (FDA)-approved via the Hepzato Kit, delivers high-dose chemotherapy directly to the liver while reducing systemic toxicity through extracorporeal filtration. This review outlines PHP's rationale, technique, patient selection, and institutional requirements. Ideal candidates have multifocal, bilobar liver metastases and limited extrahepatic disease. PHP requires coordinated care across interventional radiology, anesthesia, perfusion, and pharmacy. Clinical data show encouraging survival and disease control with manageable hematologic toxicity and rapid recovery. Research into improved filtration, optimized dosing, and immunotherapy integration may further improve outcomes.

9550 Background: Nearly 50% of patients with uveal melanoma (UM) develop metastases with the liver being the primary site of disease in > 90% of cases. Control of hepatic tumors is crucial to prolonging overall survival (OS) for metastatic uveal melanoma (MUM) patients. We report results of aPhase II prospective trial [NCT04728633] using high-dose BCNU chemoembolization (TACE) as first-line treatment for limited UM hepatic metastases. Methods: MUM patients with < 50% hepatic tumor burden and no significant extrahepatic disease were treated with hepatic artery infusion of 300mg of BCNU diluted in ethiodized oil followed by gelatin sponge embolization until maximum clinical benefit, hepatic and/or extrahepatic disease progression (PD), or development of significant adverse events (AE). Tumor response (RECIST 1.1) was assessed using CT and MRI. Treatment breaks were allowed for patients with disease control (partial response [PR] + stable disease [SD]) to reduce toxicities and optimize quality of life. Retreatment with TACE was permitted if PD occurred during treatment breaks. OS, progression-free survival from liver (PFS-L) and systemic metastases were analyzed. Toxicities were assessed using CTCAE v5.0. Results: Twenty-eight patients (17 men; median age, 62; range, 39 - 84) were enrolled from October 2021 to January 2025. Bilobar (n=25) or unilobar (n=3) BCNU TACE was performed every 4 or 7 weeks (+/- 7 days), respectively. Median follow-up was 11.6 months (range, 1.8 – 37.6). Median OS was 14.1 months (range, 1.8 – 37.6) with 13 surviving patients. Best treatment response included PR in 8, SD in 18, and PD in 2 patients for an overall response rate of 28.6% and a disease control rate of 92.9%. Twenty-two (78.6%) patients with disease control had treatment breaks. One patient withdrew from the trial to pursue percutaneous hepatic perfusion despite SD for 25 months. Median PFS-L was 9.9 months (range, 1.8 – 36.8). Sixteen (57.1%) patients developed new/nontarget hepatic tumor progression (n=13) or progression of target and nontarget lesions (n=3). Treatment-related grade 3 AEs included pain (n=5), hypertension (n=4), incidental pulmonary emboli (n=3), thrombocytopenia (n=1) and an infected biloma. Self-limiting grade 3 or 4 liver enzyme elevation occurred in 6 patients. Fifteen (53.6%) patients developed extrahepatic disease (median, 7.3 months); 11 patients (7 with stable liver tumors) started systemic therapy off-trial. Three patients developed life-limiting AEs due to checkpoint inhibitor therapy. Conclusions: High-dose BCNU TACE provided disease control in the majority of treatment-naïve patients with limited UM hepatic metastases. PD typically occurred during treatment breaks, as expected. Future trials exploring the combination of BCNU TACE with systemic therapies to address both hepatic and extrahepatic metastases are warranted. Clinical trial information: NCT04728633 .

9586 Background: Metastatic disease occurs in up to 50% of patients with uveal melanoma (UM) despite successful treatment of the primary eye tumor. The liver is the predominant organ of involvement in more than 90% of patients, and control of liver metastases is essential to prolonging overall survival (OS). Immunoembolization (IE) with granulocyte-macrophage colony-stimulating factor +/- interleukin-2 is considered a 1 st line liver-directed therapy for those with <50% hepatic tumor burden at our institution. It is well tolerated, has limited side effects, no cumulative toxicities, and affords good quality of life between scheduled treatments. Methods: A retrospective single-institution chart review was performed on consecutive series of metastatic UM (MUM) patients with hepatic metastasis who were treated at Thomas Jefferson University with IE treatment. The following data were collected from medical records: age, gender, IE treatment history, treatment history before and after IE, last follow-up date, and date of death. Results: 604 MUM patients (median age 62, range 19-91) received IE treatment for UM hepatic metastasis from 11/2000 to 01/2025 for a total of 3,715 IE treatments. 22 patients continue to receive IE. Patients received a median of 4 IE treatments (range 1-45) over 4 months (range 1-118 months). With a median follow-up of 18.3 months (range 0.1-176.4), median OS after IE treatment initiation was 20.0 months (95%CI 18.2-22.3). OS was 73.2% at 1 year, 41.8% at 2 years, 25.3% at 3 years, and 11.2% at 5 years. 30% of patients had treatment of metastatic disease prior to IE and 83% had treatment after IE. 134 patients (22%) had concurrent therapy with IE, most commonly checkpoint inhibitor therapy (48%). Median OS was 21.5 months (95%CI 18.9-23.4) for patients who received IE as first-line metastatic therapy. Except for one patient who died of takotsubo cardiomyopathy after the first IE treatment, IE treatments were well tolerated without serious or long-term complications. Of the subset of patients that experienced a prolonged OS of ≥3 years with IE (n=117), they received a median of 10 treatments over 16 months. Of the patients with prolonged OS of ≥5 years with IE (n=33), they received a median of 12 treatments over 19 months. Patients that experienced prolonged OS with IE ≥3 years were more likely to be female (69%). The longest patient treated with IE was a female who received 45 IE treatments over 10 years. Conclusions: We conducted the largest retrospective study of MUM patients who have received IE treatment. Our real-world data indicates that IE is a safe and effective liver-directed therapy for UM hepatic metastases, and IE should be considered a mainstay of treatment for patients with limited hepatic tumor burden.

Introduction:Percutaneous hepatic perfusion using the HEPZATO KIT™ (Delcath Systems, Inc., Queensbury, NY) is a US Food and Drug Administration approved treatment for liver metastases from uveal melanoma. We discuss the development of sinusoidal obstruction syndrome/veno-occlusive disease after treatment using percutaneous hepatic perfusion. Case Presentation:The patient is a 49-year-old male with a history of hepatic metastatic uveal melanoma. Despite several rounds of trans-arterial chemoembolization, the patient had progression of liver disease and was then treated with percutaneous hepatic perfusion. Several weeks later, the patient was found to have liver injury and was diagnosed with biopsy-proven sinusoidal obstruction syndrome. He was treated with defibrotide and symptoms resolved, but passed away several months later due to progression in metastatic disease. Conclusion:To our knowledge, this represents the first case of sinusoidal obstruction syndrome after melphalan administration for percutaneous hepatic perfusion. Rapid progression of disease versus sinusoidal obstruction disease must be considered in patients who present with signs of liver injury/failure after this procedure as prompt diagnosis and treatment are crucial.

TPS9597 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy, accounting for nearly 90% of ocular melanomas and up to 5% of melanomas overall. Approximately 50% of patients (pts) with UM will develop metastatic disease, with the liver being the most common site of metastases (~90%). The prognosis for pts with metastatic UM (mUM) is poor, with a median overall survival (OS) of approximately 1 year. Effective treatment options for mUM are limited as it responds poorly to single-agent immune checkpoint inhibitors (ICIs; <10% response rate). Response rates are slightly higher with combination therapies (12%–18%), but often at the expense of increased toxicity. Tebentafusp is FDA approved for mUM based on survival benefit; however, its use is restricted to pts who are HLA-A*02:01 positive, and only ~10% of pts achieve an objective response. RP2 is a selectively replication-competent herpes simplex virus type 1–based oncolytic immunotherapy expressing GM-CSF, a fusogenic glycoprotein (GALV-GP-R–), and an anti–CTLA-4 antibody-like molecule. Prior phase 1 preliminary clinical data of RP2 as monotherapy or in combination with nivolumab (nivo) demonstrated a promising safety profile and anti-tumor activity with an ORR of 29.4% in 17 patients with mUM, most of whom had received prior ICIs. This study will assess the efficacy and safety of RP2 + nivo vs ipilimumab (ipi) + nivo in pts with ICI-naïve mUM (NCT06581406; RP2-202). Methods: This is a randomized, controlled, phase 2/3 study. Key eligibility criteria include age ≥18 years and confirmed unresectable mUM with lesions amenable to injection. Pts with metastatic disease who have had prior exposure to ICIs since the time of UM diagnosis, involvement of >33.3% of the liver, or a history of prior liver- or lesion-directed therapy are not eligible for enrollment. Enrolled pts (N = ~280) will be randomized 1:1 to receive either RP2 + nivo or ipi + nivo. In the RP2 + nivo arm, RP2 will be given intratumorally initially at 1 x 10 6 PFU/mL, then every 2 weeks (Q2W) at 1 x 10 7 PFU/mL for 7 doses in combination with intravenous (IV) nivo (240 mg). In the ipi + nivo arm, pts will receive IV ipi (3 mg/kg) and IV nivo (1 mg/kg) Q3W for 4 doses. Pts in both arms may then receive IV nivo at 240 mg Q2W or 480 mg Q4W for up to 2 years from the first dose. The co-primary endpoints are OS and progression-free survival by independent central review using RECIST 1.1. Secondary endpoints are overall response rate, duration of response, disease control rate, clinical benefit rate, duration of clinical benefit, and safety, including incidence of treatment-emergent adverse events (AEs), serious AEs, and immune-mediated AEs. Clinical trial information: NCT06581406 .

To assess efficacy and safety in subgroups of patients treated with Melphalan/Hepatic Delivery System (melphalan/HDS), a drug/device combination for liver-directed treatment of metastatic UM (mUM) patients. Previously reported FOCUS study results indicated melphalan/HDS treatment provides a clinically meaningful response rate and favorable benefit-risk ratio in patients with unresectable mUM. Patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) every 6–8 weeks for up to 6 cycles. Post hoc analyses of efficacy and safety were conducted for patient subgroups based on demographic and baseline disease characteristics. 102 patients with mUM were enrolled; treatment was attempted in 95 patients; 91 patients received treatment. Subgroup analyses showed consistent tumor response regardless of age, sex, geographic region, presence/absence of extrahepatic lesions, and prior therapy. Patients with lower tumor burden had better objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) than those with higher tumor burden (ORR: 51.1 vs. 22.2

e23324 Background: Due to the hepatotropic pattern of metastasis in uveal melanoma (UM), liver directed therapies (LDT) are commonly used for the treatment of advanced disease. The PUMMA meta-analysis (Khoja et al, 2019) assessed patients (pts) with metastatic UM (mUM) treated on trials conducted from 2000-2016 and suggested improved outcomes for those treated with LDT. Methods: Using data from 7 centers in the US, Canada, the UK and Australia collected between as part of the Ocular Melanoma Natural History (OMNi) study, we assessed this finding in a more contemporary dataset and investigated potential global variations in practice patterns. Analysis was performed on data entered as of May 2024. Results: Of 985 pts enrolled, 283 developed mUM and received at least 1 line of treatment (tx; 77-US; 160-Canada; 30-UK; 16-Australia). 164 received regional (R) tx (LDT, surgery, radiation; 41% US pts, 35% Canadian pts, 46% UK pts, 55% Australian pts), with 130 treated in the first-line (1L) setting. 212 received systemic (S) tx (51% US pts, 55% Canadian pts, 51% UK pts, 55% Australian pts), with 137 treated in the 1L setting. Concurrent (C; any R tx delivered while a S tx was ongoing) was administered in 50 patients (18% US pts, 10% of Canada pts, 3% UK, pts 5% Australian pts), with 16 treated in the 1L setting. At the time of 1L tx, median age was 63 (range, 25-92), 62 (range, 24-88), and 64 (range, 42-83) years for those treated with S, R, and C tx, respectively. 47%, 50% and 25% were female of those treated with S, R, and C tx, respectively. Mean diameter of the largest tumor lesion and percentage of cases with stage M1b/c disease at time of 1L tx were 1.5cm and 20%, 1.1cm and 19%, and 0.6 cm and 0% for those treated with S, R or C tx, respectively. There was no significant difference in proportion of patients with liver-only disease who received 1L S or R/C tx (61 vs 62%, respectively). Median overall survival (OS) was 32, 24 and 32 months for those treated with S, R or C tx, respectively, with no significant difference observed across groups (p = 0.09). Conclusions: The use of C tx was more common in the US and Canadian centers when compared with those in the UK and Australia. Patient and tumor characteristics were similar between those treated with 1L S and R therapies, with no difference in OS observed in this dataset based upon initial tx strategy. Clinical trial information: NCT04588662 . Therapy Pts Receiving 1L Systemic Therapy (n = 137) Pts Receiving 1L Regional Therapy (n = 130) Pts Receiving 1L Concurrent Therapy (n = 16) Systemic Regional Checkpoint Blockade 104 (76%) n/a 10 (62%) n/a Targeted Therapy 22 (16%) n/a 6 (38%) n/a Other Systemic Therapy 11 (8%) n/a 0 (0%) n/a Surgery or Radiofrequency Ablation n/a 62 (48%) n/a 3 (18%) Radiotherapy n/a 22 (17%) n/a 4 (25%) Other Liver Directed Therapy n/a 34 (26%) n/a 6 (38%) Radioembolization or Chemoembolization n/a 9 (7%) n/a 2 (12%) Percutaneous Hepatic Perfusion n/a 3 (2%) n/a 1 (6%)

BACKGROUND:Metastatic uveal melanoma (mUM) is rare. Immune checkpoint inhibitors (ICIs) have shown modest efficacy in mUM. Tebentafusp prolonged overall survival (OS) in a phase 3 study. We aimed to investigate the efficacy and safety of the sequence of tebentafusp and ICIs. METHODS:Patients with HLA-A * 02:01 positive mUM, or metastatic GNA11/GNAQ mutant melanocytic tumors treated with tebentafusp followed by ICIs (group 1) or the inverse sequence (group 2) at any treatment line were retrospectively identified. The primary objective was OS rate at 2 years. RESULTS:131 patients were included; 51 in group 1 and 80 in group 2. 30 % in group 1 % and 40 % in group 2 had normal baseline lactate dehydrogenase (LDH, p = 0.05). 94 % in group 1 % and 77 % in group 2 had multilobular liver disease (p = 0.02). Median OS was 22.4 months (95 % CI 19-24.8) in group 1 and 33.6 months (95 % CI 28.9-43) in group 2 (p = 0.004). Total median PFS was 12 months (95 % CI 10.7-18.8) in group 1 and 20.3 months (95 % CI 17.2-27.3) in group 2 (p = 0.04). The frequency of cytokine release syndrome was higher in group 2 (15 % vs 27 %). Other clinical factors were associated with short total PFS in the multivariable analysis. CONCLUSIONS:Both treatment sequences are clinically feasible. A clinical benefit was noted in the sequential combination of ICIs followed by tebentafusp. This observation is limited by the retrospective nature of the study and merits further investigation in prospective clinical trials.