On Nov. 6^th, Chantal and Kevin attended the 2023 CureOM Global Scientific Meeting in Philadelphia.
The following is a summary of the scientific and pharma presentations for ocular melanoma.

Aura Biosciences presented an update on the launch of the new Phase III study for patients with
early-stage choroidal melanoma (small tumors in the back of the eye). This randomized study
called COMPASS will enroll 100 patients and be conducted in 40+ ocular oncology practices, and will evaluate two different doses of “bel-sar” (belzupacap sarotalocan) a ‘virus-like’ particle targeted delivery of a potent cytotoxic drug by intravitreal injection using laser activation. The study is based upon data from a Phase II dose-escalation trial, after 3 cycles of out-patient treatment, the tumor control rate was 80% (8/10) and the visual acuity preservation rate was 90% (9/10).  For the 80% of patients who responded, data showed a statistically significant reduction in tumor growth rate compared to each patient’s documented growth rate at study entry. The overall tolerability profile of bel-sar was favorable, with no dose-limiting toxicities, treatment-related SAEs or significant AEs reported. There was no posterior inflammation and only mild anterior inflammation (Grade 1) in ~18% of the patients which
was self-limited or resolved with a short course of topical steroids. For more information on the Compass Phase III trial and participating ocular oncology centers, please visit:
https://clinicaltrials.gov/study/NCT06007690?term=belzupacap%20sarotalocan&rank=2

TriSalus Life Sciences highlighted late-breaking data presented over the weekend at Society for Immunotherapy of Cancer Meeting, for SD-101 (pressure-enabled drug delivery (PEDD) of TLR9 agonist). The PERIO-01 Phase 1 data demonstrated that delivery of SD-101 by TriNav plus systemic immune checkpoint inhibitor (ICI, ) in uveal melanoma with liver metastases (UMLM) patients results in clinical activity with median progression free survival (PFS) of 11.7 months, myeloid derived suppressor cell (MDSC) re-programming, and evidence of peripheral and intra-tumoral immune activation.
The Phase Ib portion of the trial is ongoing in 10 medical oncology centers, and further information
can be found at:  https://clinicaltrials.gov/study/NCT04935229?term=sd-101&page=2&rank=15

DelCath presented an ad hoc (post-protocol) survival analysis of the Hepzato® FOCUS Phase III trial. Hepzato is therapy for metastatic uveal melanoma comprised of melphalan in the Hepatic Delivery System. With a median of 4 cycles of treatment, among 24 patients who had progressive disease, median Overall Survival (OS) was 12 months. In 34 patients with Stable Disease, median OS was 13 months. In 26 patients who obtained Partial Response, median OS was 28 months. In the 7 patients who obtained Complete Response to Hepzato,  median OS is not yet calculated with these responses and survival still ongoing. The Expanded Access Program remains open at Moffit, Stanford, Duke and the Univ. of Tennessee, while DelCath engages medical oncology centers to provide the now FDA-approved therapy. https://classic.clinicaltrials.gov/ct2/show/NCT05022901?term=NCT05022901&draw=2&rank=1

Ideaya is advancing darovasertib, its protein kinase C inhibitor, with a clinical strategy to broadly address uveal melanoma (UM), in both primary and metastatic disease settings. Recent data has demonstrated eye preservation in 3 of 6 (50%) evaluable patients treated with darovasertib as neoadjuvant therapy for primary uveal melanoma. Ideaya has initiated a potential registration-enabling Phase II/III clinical trial
in 47 centers to evaluate a combination of darovasertib and crizotinib in first-line Human Leukocyte Antigen- (HLA-) A2*02:01 negative serotype (HLA-A2(-)) metastatic uveal melanoma:
https://classic.clinicaltrials.gov/ct2/show/NCT05987332?term=ideaya&draw=2&rank=2
Ideaya also initiated a company-sponsored Phase 2 clinical trial in 11 centers for evaluating
single-agent darovasertib as neoadjuvant and adjuvant therapy in primary UM:
https://classic.clinicaltrials.gov/ct2/show/NCT05907954?term=ideaya&draw=2&rank=3

Replimune highlighted a presentation at the Society for Melanoma Research for an update of the
Phase I study of RP2 (an HSV Type I encoding GM-CSF conjugated to anti-CTLA-4 HuMab). Treatment with RP2 led to an overall response rate (ORR) of 29% (5 of 17 patients; one of the responding patients was treated with RP2 monotherapy and four of the responding patients were treated with RP2 combined with nivolumab), including responses in patients with liver, lung, and bone metastases. The median duration of response (DOR) at the data cutoff was 11.47 months (range of 2.78 to 21.22 with responses ongoing). Nearly all patients (15 of 17, 88%) in the study had progressed on or after immunotherapy with 12 of 17 patients (70.6%) having received both prior anti-PD1 and anti-CTLA-4 therapy, including four of the responding patients. The most common grade 1 or 2 treatment related adverse events (TRAEs) overall in both cohorts were pyrexia (fever), chills, fatigue, hypotension (low BP) and pruritis (itching). Six patients had grade 3 TRAEs, including two cases of hypotension. There were no
grade 4 or 5 TRAEs. The Phase I study is currently being conducted in the UK and Spain.

Finally, Dr. Justin Moser, Medical Oncologist from HonorHealth in Scottsdale, presented an overview of several novel therapies in early clinical trials for metastatic uveal melanoma:

• Phase I dose escalation study of the first oral allosteric modulator of phosphoinositide
  3-kinase inhibitor delta (PI3Kδ): roginolisib (IOA-244). The Eurpoean Sponsor IOnctura, has stated
  their Phase I study is fully enrolled with final data expected Q1 2024. Across all patients treated to date, roginolisib monotherapy has shown 7% Grade 3/4 toxicities, with no dose limiting toxicities, drug-related serious adverse event (SAE) or drug related adverse event (AE) leading to dose interruption or discontinuation. While median Overall Survival has not yet been reached, 62% of patients were alive at 12 months, which compares favorably to historical controls of 34% in the same setting. A new US-based clinical trial is expected to be announced shortly.
• Phase I Study of a Targeted Alpha Particle Radiotherapy (225Ac-MTI-201) for Metastatic Uveal Melanoma. Modulation Therapeutics is developing 225Ac-MTI-201, which is is a combination of a radiotherapy particle (Actinium 225) and a “carrier” molecule peptide mimetic, which specifically targets Melanocortin-1 receptor (MC1R) variants found on melanoma cells. The field (area) of radiation on the targeted tissues is very small, and the product is eliminated from the body quickly.

Eligible patients: histologically confirmed metastatic uveal melanoma, with progression after at least one prior line of metastatic therapy.  Through up to 12 escalating dose levels, the study will determine the maximum-tolerated dose (MTD) of 225Actinium-MTI-201 in participants with metastatic uveal melanoma. The secondary aims are to describe the pharmacokinetics and the toxic effects of 225Ac-MTI-201. The only study site is Moffitt Cancer Center, Tampa FL. The study is summarized at this link:
https://classic.clinicaltrials.gov/ct2/show/NCT05496686?term=225Ac-MTI-201&draw=2&rank=1

• A novel T-Cell therapy: TScan Therapeutics is evaluating “TScan 002” as a multi-plex TCR (T-Cell Receptor) which targets 6-8 HLA types. A Phase I screening trial is now open at 5 US cancer centers, to first profile patients’ metastatic tumor cells, before entry into the multi-level treatment section of the study. The clinical trials may be viewed at this link: https://classic.clinicaltrials.gov/ct2/show/NCT05812027?term=tscan002&draw=2&rank=2
• Tumor-Infiltrating Lymphocytes (TILs) are now being evaluated for combination with T-Cell bispecifics.
• Dr. Jose Lutzky at Univ. Miami is investigating relatlimab (LAG-3 antibody) in combination with nivolumab in a Phase II study in patients with metastatic uveal melanoma (now closed for accrual).
  Among 20 patients enrolled, the preliminary Objective Response Rate is 11%.