A. BREAKING NEWS – UM CLINICAL TRIAL RESULTS:
Late-Breaking Abstract #59 – Combined Percutaneous Hepatic Perfusion (PHP) with Ipilimumab plus Nivolumab in Metastatic Uveal Melanoma: a single center, open-label, randomized, Phase 2 study (CHOPIN) Ellen Kapiteijn (Leiden Univ. Medical Centre, The Netherlands)
This study evaluated 71 Uveal Melanoma patients who had not been previously-treated for liver-dominant metastatic disease (ablation and surgical resection allowed). Patients were randomized to receive: Two courses of Chemosat/Hepzato® (in weeks 1 and 7) 'with or without' alternating treatment of 4 cycles of ipilimumab + nivolumab (all of these products have been previously approved in the US, EU and internationally).
The Chopin study results:
a. Progression-Free Survival (PFS) at One Year: Combination group: 54.7% vs PHP group: 15.8%
b. PFS Median months: Combination group 12.8 vs. PHP group: 8.3 …Hazard Ratio 0.34, P<0.001
c. Overall Survival (OS)- at One Year: Combination group: 82.8% vs. PHP group: 82.2%
OS at Two Years: Combination group: 49.6% vs. PHP group: 22.1%
OS Median months: Combination group: 23.1 vs. PHP group: 19.6 …Hazard Ratio: 0.39, P = 0.006
d. Best Overall Response Rate: Combination group: 76.3 vs. PHP group: 39.5 …P < 0.001
e. Safety: The combination treatment was well tolerated, with types, rates and frequencies of adverse events consistent with individual use of PHP and checkpoint inhibitors. No new safety signals were identified. This new and interesting clinical trial data might be something you may wish to discuss with your medical oncologist. (Study number NCT04283890, not currently enrolling).
Presidential Symposium Abstract #1600O – Efficacy and safety of IMA203, a PRAME-directed T-cell receptor (TCR) T-cell therapy in patients with previously treated advanced or metastatic uveal melanoma. Sapna P. Patel (Univ. Colorado, UC Health-Aurora) Anzutresgene autoleucel (anzu-cel, formerly IMA-203) is a PRAME-directed TCR T-cell therapy engineered to recognize intracellular PRAME-derived peptides presented by HLA, and initiate a potent and specific anti-tumor response. Dr. Patel presented the initial results from the ongoing Ph1a/b trial (NCT03686124; EudraCT 2019-002370-31). The study includes patients with recurrent and/or refractory solid tumors which ere HLA-A*02:01+, PRAME+, and includes UM patients with prior tebentafusp therapy. Following leukapheresis and IMA203 manufacture, patients underwent lymphodepletion (LD) with Cyclophosphamide and Fludarabine. A single IMA203 infusion was then followed by low-dose IL-2.
Results: As of April 2025, 74 heavily-pretreated patients (median 3 prior lines of therapy) across tumor types were enrolled so far in the Phase 1 study. The most common Treatment-Related Adverse Events were LD-related cytopenias in 99% (G3/4). Cytokine release syndrome occurred in 95%, and was mostly low grade (G1: 37%; G2: 47%; G3: 11%; no ≥G4) and mostly resolved by day 14. ICANS was infrequent (G1/2: 9%; G3: 4%; no ≥G4). Sixteen (16) UM patients were included in the Phase 1b portion: with 13 UM patients (81%) having liver and/or extrahepatic metastases, with a median of 2 prior lines of therapy (62.5% had prior tebentafusp), with 75% of UM patients having their largest metastatic lesion measuring 3.1-8.0 cm in diameter (AJCC M1b), and 56% of the UM patients had an elevated LDH level.
A confirmed Objective Response was achieved by 67% of the UM efficacy-evaluable patients (10/15) (with 1 patient having an ongoing unconfirmed Partial Response); all patients (16/16) experienced tumor shrinkage. Median Duration of Response was 11.0 months (range 1.8+ to 31.6), with 5 of 10 confirmed responses ongoing at a median follow-up of 13.4 mo. Median Progression-Free Survival was 8.5 months (range 1.4 to 32.9), and median Overall Survival was 16.2 months (range 3.2+ to 34.2+). Rapid engraftment (median Tmax: 3 days) and sustained persistence of IMA203 T cells (up to 903 days) were observed in the UM patients, indicating durable in vivo exposure.
The Phase 2 portion of the study is now beginning to enroll patients (Study numbers: NCT03686124, EudraCT 2019-002370-31 in 8 German cancer centres), and the Sponsor Immatics is currently activating additional US cancer centers with uveal melanoma clinical trials experience. ACIS will provide updates on these new sites as the information is made available. These emerging clinical trial data, although initially reporting a limited number of patients with metastatic UM, might be something you may wish to discuss with your medical oncologist.
Late-Breaking Abstract #58 – PLUME: A single-arm phase II trial of pembrolizumab (pembro) plus Lenvatinib (lenva) in patients (pts) with metastatic uveal melanoma (mUM). Manuel J. Rodrigues (Institut Curie, Paris France)
Fifty-one ICI-naïve metastatic UM patients were enrolled in PLUME, a single-arm phase II trial. Two cohorts were assessed: HLA A*02-01 negative patients and tebentafusp-naive patients (Cohort 1, n=22), and HLA A*02-01 positive patients, pretreated with Tebe (Cohort 2, n=29). Patients received pembrolizumab (200 mg q3w, 35 cycles maximum) plus lenvatinib (20mg QD until progression) and had liver MRI and chest-abdomen-pelvis CT every 9 weeks until progression. Primary endpoint was Progression-Free Survival (PFS) at 27+/-2 weeks of treatment. Secondary objectives included PFS according to iRECIST, overall survival, response rate, safety, and quality of life.
Results: All patients were followed for more than 27 weeks. At 27 weeks, 15 progressions were observed in Cohort 1, corresponding to a 27-week PFS of 31.8% (95% confidence interval [CI] 13.9 – 54.9). Cohort 2 had 11 progressions with a 27-week PFS of 60.7% [40.6 – 78.5]. Safety was consistent with prior pembro/lenva trials and manageable. Lenva was held in 39 patients (76%), dose reduced in 13 (26%) and permanently discontinued in 2 (4%) for toxicity. Pembro was held in 11 patients (22%), and permanently discontinued in 2 (4%) for toxicity. No treatment-related deaths occurred. Pembro+lenva met the predefined 27-week PFS success criteria in both Tebe-naïve and Tebe-pretreated cohorts, with particularly encouraging activity in Tebe-pretreated patients. Biomarker and real-world comparisons are ongoing. Lenvatinib and pembrolizumab have previously-approved for other cancers in the US, EU and Internationally. These new clinical trial data, while from a single-arm non-comparative study, might be something you may want to discuss with your medical oncologist. Clinical Trials Identifier NCT05282901 (not currently enrolling).
B. Additional UM Clinical Trial Results:
Abstract # 1602O – Enucleation prevention and vision preservation in primary uveal melanoma (UM): preliminary results from a phase 2 study of neoadjuvant darovasertib. Marcus Butler (Princess Margaret Cancer Centre, Toronto CAN)
IDE196-009 is a Phase 2 study (NCT05907954) testing the safety & efficacy of Darovasertib as neoadjuvant therapy in primary UM patients requiring either enucleation (Cohort 1: Co1), or plaque brachytherapy (PB, Cohort 2: Co2). Primary endpoints: Enucleation Prevention (EP) for Co1 & radiation Dose Reduction (DR) for Co2. Tumor shrinkage by Product of Diameters (PoD: height (ht) * longest basal diameter ) (Co1 & 2) & best corrected visual acuity (BCVA) loss of ≥ 15 letters post PB (Co2) are secondary endpoints, while risk of 20/200 vision assessed by a prognostic tool is exploratory (Co2).
Results: In the safety population, 90 primary UM patients (n=51 Co1, n=39 Co2) received Darovasterib at 300 mg BID in 28-day cycles. All grade treatment related adverse events (TRAEs) in ≥20%; diarrhea (48%), nausea (43%) & fatigue (30%). The only Grade ≥3 TRAE in ≥ 5% pts was hypotension (6.7%). Drug interruption, modification, or discontinuation due to TRAEs was seen in 16 (18%), 7 (8%) & 4 (4%) patients, respectively. The Efficacy population N= 62 (n= 32 Co1, n = 30 Co2) was defined as patients with tumor assessment after ≥ 3 cycles of Darovasterib (or progression/AE requiring early discontinuation). In this efficacy population, 59% (19/32) of patients in Co1 became eligible for Enucleation Prevention; for patients with available paired simulations in Co2 Dose Reduction was seen in 14/17 (82%) patients, with 59% (10/17) showing both ≥ 20% DR and a lower 3-year predicted risk of 20/200 vision. Tumor shrinkage ≥ approx.. 20% in the PoD was noted in 62% (Co1) & 63% (Co2) of pts. Among pts who had EP or DR, the majority had this magnitude of tumor shrinkage. Clinical trial identifier NCT05907954; this Phase 2 study remains open for enrollment in the US, EU, CAN and AU.
Abstract # 1656P – Clinical and molecular outcomes of Tebentafusp in metastatic uveal melanoma (MUM): A retrospective cohort of 168 patients. Raphaël Sanchez (Institut Curie, Paris France)
This was a retrospective collection of clinical and genomic data from MUM patients treated between 2018 and 2024 with tebentafusp. Outcomes included objective response rate (ORR) per RECIST 1.1, Progression-Free Survival (PFS), and Overall Survival.
Results: Among 168 patients (18 from Study IMCgp100-202, 150 from Immunocore's early access program), Tebentafusp was first-line treatment in 82% of patients (n=138). Median follow-up was 20 months, median PFS was 3 months, and the 20-month OS rate was 67%. ORR was 8.9% (n=15) and 46% pts (n=78) had stable disease. Patients with extra-hepatic metastases only (n=4) had the best outcomes (median PFS and OS not reached), while those with hepatic disease only (n=130) or hepatic/extra-hepatic (mixed) disease (n=34) had shorter PFS (3 months in both cases) and OS (28 months for hepatic, 18 for mixed). EIF1AX mutations were associated with sustained disease control and no deaths. BAP1 and SF3B1 mutations were associated with short PFS (median 5 and 8 months, respectively) and OS (median not reached and 27 months, respectively). Disomy 3 tended to be correlated with longer PFS (8 months) and OS (30 months) than monosomy 3 (PFS: 3 months; OS: 28 months). These findings support the efficacy of tebentafusp in MUM patients with outcomes in line with the IMC-gp100-202 trial, and suggest that genomic and metastatic features may help refine prognostic stratification. Further prospective studies are warranted to disentangle prognostic from predictive biomarkers in this setting.
Abstract # 1702e Trial in Progress – A Phase II Trial of Quisinostat for High-risk Uveal Melanoma (UM) Jose Lutzky (Univ. Miami, Florida)
UM tumors can be classified into low (class 1) and high (class 2) metastatic risk categories based on their gene expression profiling (GEP). UM with Castle DecisionDx-UM GEP Class 2 harbor inactivating mutations in the tumor suppressor BAP1, which epigenetically regulates a wide range of genes involved in development and other functions. A novel epigenetic high-throughput drug screen for therapeutic targets that restore epigenetic regulation downstream of BAP1 identified quisinostat as the lead compound capable of reversing phenotypic effects of BAP1 loss in vitro and in vivo with minimal toxicity. Quisinostat is a histone deacetylase (HDAC) inhibitor with distinctive activity against HDAC4, which we showed to be deregulated with BAP1 loss. Based on these data, we initiated a clinical trial to evaluate the efficacy of adjuvant quisinostat treatment in patients with high-risk UM.
Trial design: Open-label, multicenter, investigator-initiated Adjuvant Phase 2 study, with a synthetic control arm, to evaluate the effect of adjuvant quisinostat treatment in high-risk UM patients on distant Metastases-Free Survival (DMFS) at 36 months. A one-sided, one-sample log-rank test from a sample of 60 patients achieves an 85.1% statistical power at a 5% significance level to detect a significant change in 36-month DMFS of 75% in the treatment group when the 36-month DMFS in the historical control group is 60%.
Patients are treated with 12 mg quisinostat orally (P.O.) 3 times a week, taken on a Monday, Wednesday, and Friday regimen for a total period of 51 weeks. Patients are evaluated by routine blood work and physical examination every 3 weeks while they are receiving quisinostat. Imaging studies are performed once at baseline and once every 12 weeks (± 7 days) for the first 24 months and then once every 24 weeks (± 7 days) thereafter. Main inclusion criteria are Castle Decision-UM GEP Class 2, largest basal diameter > 12mm, previously-untreated (for UM) for up to 183 days from their definitive primary (eye) site therapy. Exploratory endpoints include PBMC histone protein and histone acetylation levels and circulating tumor prior to treatment, every 3 months and at relapse. Clinical trial identification: NCT06932757. Additional U.S. clinical trial sites are now being initiated.
Abstract # 2193P – Early Together: Randomized phase 3 trial of Early Palliative Care (EPC) integration in Metastatic Uveal Melanoma (MUM) Sophie Piperno-Neumann (Institut Curie, Paris France)
From July 2020 to January 2024, 162 metastatic UM patients were randomized 1:2 at the two main French UM centres. In the control group (A), palliative care was introduced per guidelines. In the experimental group (B), EPC visits started at announcement of metastases by the oncologist and continued alongside systemic treatment for one year. Needs for information, care and support were assessed using validated questionnaires as detailed in the protocol. The main objective (Primary Endpoint) is to compare the psychological needs at 6 months after randomization (SCNS-SF34 Care and Support Needs domain). Secondary objectives include other needs, quality of life, anxiety, depression, self-efficacy, partners needs, medical interventions, progression-free and overall survival. Investigators received training throughout the study period to improve communication skills about uncertainty and poor prognosis.
Results: 159 evaluable pts (A: 51; B: 108), median age 65 years; Treatment of the primary UM (eye tumor) was radiation therapy in 66%, enucleation in 34%. Median time to metastasis was 23 mo and 41% of pts had prior loco-regional treatment. At baseline, 69% had no sign of disease, while 31% presented with at least one (pain, GI symptoms, weight loss, anxiety); Performance Status was 0 in 46%, and LDH elevated in 27%.
136 and 113 patients completed questionnaires at baseline and 6 months respectively. The score was calculated for all randomised patients. In the 46 non-respondent patients at 6 months, including 11 disease-specific early deaths, a score was assigned using the maximum value (75) observed in respondents (Mean scores were
52.5 (A) versus 53.1 (B) ; p=0.85). Sensitivity analyses were performed, by assigning the minimum value (25) observed in respondents, or by analysing the 113 respondents only.
Conclusions: Overall, there was no difference in the primary endpoint at 6 months. Others domains of SF34, and the QLQ-C30, HADS and GSE questionnaires were analyzed, without highlighting any significant difference.
With a median follow-up of 12 months, there is a trend for better OS in arm B. Further analyses are ongoing.
Clinical trial identification NCT04728113.