Abstract 4546: Pegargiminase and melphalan as a novel drug combination strategy for uveal melanoma

Abstract

Abstract Uveal melanoma (UM) is a hard-to-treat arginine auxotrophic cancer with approximately 50% of patients succumbing to metastases predominantly to the liver with a median overall survival of 19-22 months and a 5 year survival of around 10%. Novel drug strategies are urgently needed beyond the currently available immunotherapies that provide durable disease control in a small subset of patients. Arginine deprivation with pegylated arginine deiminase (ADI-PEG20; pegargiminase) is a novel anti-metabolite therapy which demonstrated activity in early phase trials in patients with UM, and more recently, increased survival in patients with the aggressive arginine-dependent cancer, non-epithelioid mesothelioma in the global phase 3 trial, ATOMIC-Meso. Here, we investigated the preclinical rationale for combining pegargiminase with melphalan, a drug which is delivered directly to the liver using an FDA-approved device from Delcath for patients with hepatic-centric UM disease. Two of four uveal melanoma cell lines were negative for expression of the rate-limiting enzyme for arginine production, argininosuccinate synthetase 1 (ASS1) and were submitted for drug evaluation accordingly. ADI-PEG20 treatment of ASS1-deficient cell lines 91.2 and MP41 demonstrated sensitivity to ADI-PEG20 (500ng/ml) compared to MP38 and MP46 ASS1-proficient cell lines. Moreover, the combination of ADI-PEG20 and melphalan (0.77µM) had at least an additive effect on ASS1 negative cell lines in 2D assay (92.1 p-value 0.0061; MP41 p-value is 0.0053). UM cell line proliferation was decreased by 50% in the combination group compared to ADI-PEG20 alone by 6 days of culture. Experiments to assess cytotoxicity and cell death analysis are ongoing. This drug combination therapy has the potential to improve outcomes in patients with uveal melanoma. Based on the good tolerability and safety of both drugs in patients, a clinical trial of pegargiminase with melphalan is planned for 2024 (ATOMIC-UM). Citation Format: Iuliia Pavlyk, Josephine Carpentier, Emilia Appolonia Szlosarek, Pui Ying Chan, John S. Bomalaski, Peter Wojciech Szlosarek. Pegargiminase and melphalan as a novel drug combination strategy for uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4546.