ACIS Research Coordinator Kevin attended the 40th Anniversary Meeting of the Society for Immunotherapy of Cancer (SITC)

The 14^th CureOM Global Science Meeting was convened in Amsterdam, just prior to the Opening Ceremonies of SMR 2025. The program had 18 invited presentations from academic investigators and medical oncologists, and the leading Biopharmas and diagnostic/prognostic laboratory partners involved in uveal melanoma research. All attendees had signed confidentiality agreements regarding the presentation materials, so no report of the proceedings are provided here. The academic program chair offered the meeting will be summarized and published later in a patient-oriented format.

1. Clinical Presentationsi. On Sunday October 26, Dr. Justin Moser (Medical Oncologist at HonorHealth, Scottsdale AZ USA) presented initial Overall Survival results from the OptimUM-01 study. The ongoing Phase 2 portion of this clinical trial is evaluating the investigational drug darovasertib in combination with crizotinib
   (both oral tablets), in patients with first-line (newly diagnosed) metastatic uveal melanoma. Dr. Moser reported the following very interesting observations from the initial 41 efficacy-evaluable patients:

• Darovasertib in combination with Crizotinib demonstrated median overall survival (OS) of
  21.1 months, compared to reported historical mOS of approximately 12 months in published meta-analysis of metastatic uveal melanoma in the first-line setting.
• Median progression free survival (PFS) of 7.0 months
• Confirmed overall response rate (ORR) by RECIST 1.1 criteria of 34%, median duration of response (mDOR) of 9 months and disease control rate (DCR) of 90%.

The study Sponsor, Ideaya Biosciences Inc., indicates the Phase 2 portion of the OptimUM-01 study is still open, and  currently recruiting patients that are HLA*A2:01 positive. You may wish to discuss these initial study results with your medical oncologist.

The OptimUM-01 protocol summary, eligibility details and cancer center clinical trial sites can be found at: https://clinicaltrials.gov/study/NCT05987332

Ideaya has also issued a Press Release with further efficacy and safety data from Dr. Moser’s presentation:  https://media.ideayabio.com/2025-10-20-IDEAYA-Biosciences-Reports-Positive-Median-Overall-Survival-Data-from-Phase-2-Trial-of-the-Darovasertib-and-Crizotinib-Combination-in-First-line-Metastatic-Uveal-Melanoma-at-the-2025-Society-for-Melanoma-Research-Congress

2. Also on Sunday, Dr. Sapna Patel, from the Univ. Colorado UC Health-Aurora, provided the SMR attendees her ESMO Presidential Symposium presentation: 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. This ongoing Ph1a/b trial (NCT03686124; EudraCT 2019-002370-31) includes patients with recurrent and/or refractory solid tumors who are 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.

iii. Finally, Dr. Suthee Rapisuwon, from Georgetown University – Wash. DC, presented updated results from the HCRN MEL17-309 study “Adjuvant nivolumab plus ipilimumab in high-risk uveal melanoma: Long-term survival outcomes.” A total of 50 patients with high-risk uveal melanoma were evaluated per-protocol following up to 12 months of nivolumab + ipilimumab immunotherapy. This “adjuvant therapy” was intended to potentially further delay the anticipated onset of later metastases after standard primary treatment (radiotherapy or enucleation – removal of the affected eye).

These patients had Castle Decision Dx UM GEP results of Class 2, and larger primary tumor size (or other ‘high-risk’ size or chromosomal features). These updated study results were compared with published the COOG 1 study results from 119 very similar high-risk UM patients. Dr. Rapisuwon explained the updated data now comes after 52 months of following the patients’ outcomes.

The key measure of Distant Metastasis-Free Survival (alive, without mets) at the 3-year mark was 75% of the 50 patients receiving ipi+nivo, versus 30% of the COOG 1 study’s 119 matched patients.

Overall Survival at the 3-year mark among the 50 patients receiving ipi+nivo was almost 83%, versus 54% of the COOG 1 matched patients. Major side effects from ipi+nivo were as anticipated: most frequently colitis, diarrhea, myocarditis, pneumonitis and hepatitis; each occurring in 10% or less of the patients. Discontinuation due to side effects of ipi+nivo occurred in 22 (44%) of study patients.

You may wish to discuss with your medical oncologist these updated outcomes results of the Phase II single-arm “signal-seeking” clinical trial, for considering participation in further studies of the potential value of adjuvant treatment of high-risk UM patients, including a proposed larger trial of ipi+nivo for these patients. Dr. Rapisuwon acknowledged co-investigators of this study from the Univ. Colorado, Washington Univ., Northwell Cancer Center, Northwesten Univ. and UCSF Diller Cancer Center.

1. Clinical Abstracts and Posters

• Investigators from Rome (Agostino Gemelli Univ. and Univ. Cattolica) provided a poster for their Trial-in-Progress: TEBE-RT, Hepatic Radiotherapy added to tebentafusp for HLA-A*02:01 positive metastatic UM patients. Following one of three tebe dose escalations, after patents reach a total of 68 mg, radiation to target liver lesions will be administered by 8Gy doses for 3 treatments, and then tebe will be continued. Twenty patients are expected to be enrolled and evaluated.
• Replimune presented a Trial-in-Progress poster for the ongoing Phase 2/3 study investigating the combination of RP2 and nivolumab vs. ipilimumab+nivolumab in metastatic uveal melanoma patients who are “immune checkpoint inhibitor-naiive” (and have no more than 1 prior line of metastatic therapy). The study is expected to enroll and randomize 280 patients. (NCT06581406)
• Justin Moser and Advanced Practice Oncology Nurses at HonorHealth-Scottsdale presented a poster on feasibility and advantages of out-patient administration for lymphodepletion chemotherapy in preparation of infusion of tumor-infiltrating lymphocytes (TIL therapy).

• Investigators from the Univ. Zurich, Univ. Hamburg-Eppendorf, and Mass. Gen. Hospital-Boston presented a poster on the OncoBitä prognostic circulating tumor DNA (ctNDA) test, involving

1. Basic Science/Lab Studies Abstracts and Posters

• Investigators from the Univ. Iowa presented a poster on mechanisms of resistance to the clinical combination of darovasertib and crizotinib, from a panel of diverse uveal melanoma cell lines.
  Both PKC-delta and MET-receptor ligand HGF were identified as drivees in the resistant cells, and that recombinant HGH confers drug resistance.They presented another poster demonstrating GPCR over-expression can drive resistance to GNAQ/GNA11and PKC/MET inhibition, by either reactivating MAPK or other signaling. So far,
  the cross-resistance phenotype to a GNAQ/11 inhibitor and darovasertib+crizotinib treated
  UM cells is only observed in BAP-1 deficient cell line MP46. Finally, maintenance of pCREB S133 may play a role in promoting GPCR-mediated survival in UM cells following GNAQ/11 inhibitors.

• Investigators from Thomas Jefferson Univ. – Philadelphia presented a poster on their humanized mouse model. They utilized human bone-marrow derived CD34+ hematopoietic stem cells.
  The model can be used to study the interaction between UM tumors and human immune cells, and serve as a platform to evaluate novel immune therapies.
• Investigators from the All India Institute of Medical Sciences in New Delhi, presented their poster on ferroptosis resistance and mitochondrial dysregulation in promoting aggressive phenotype in uveal melanoma. While ferratin and lipid peroxidation were elevated in UM cells, there was no correlation with genotype or cell survival. They indicate that ferroptosis-associated genes SLC7A11, GPX4 and TRF1 may be clincially0relevant biomarkers and possible therapeutic targets.

• Investigators from Queensland Univ.- Australia presented a poster on epigenetic enzymes as potential molecular targets in uveal melanoma. EHMT2 was overexpressed in 54% of UM cells, offering a possible prognostic and therapeutic target.

Investigators at Macquerie Medical School and the Univ. of Sydney- Australia presented a poster on how crizotinib exerts MET-independent activity in uveal melanoma cell lines. Crizotinib appears to IC50profile strongly correlates with inhibitors of cell cycle progression and tubulin dynamics.