Tumors with low argininosuccinate synthetase 1 (ASS1) expression have impaired arginine synthesis and are dependent on extracellular arginine for survival. Pegzilarginase (AEB1102) is a pegylated, recombinant, cobalt-substituted human arginase I that depletes plasma arginine. MTD was previously reported as 0.33 mg/kg weekly (AACR 2018). Here we update the preliminary safety and activity of monotherapy pegzilarginase in uveal (UM) and cutaneous (CM) melanoma cohorts of an ongoing Phase 1 study (NCT02561234).
Adult patients (pts) with metastatic UM or CM were eligible after prior standard treatments. IV pegzilarginase was administered at the MTD. Primary objective was safety (CTCAE v4.03); additional endpoints included PK, PD, tumor ASS1 expression, and preliminary anti-tumor activity (RECIST 1.1).
At analysis, 16 pts with melanoma (11 UM, 5 CM) received pegzilarginase in cohort expansions. 5 dose-escalation pts with UM (3) or CM (2) were also treated at MTD. For the 21 pts with UM or CM treated at MTD, treatment-related AEs (TRAE) in > 10% pts included fatigue, nausea, diarrhea, vomiting, decreased appetite, dizziness, gait disturbance, muscular weakness, and tremor. No Grade ≥4 TRAEs were observed, and Grade 3 TRAEs were reported by one pt each: asthenia, failure to thrive, and hypophosphatemia. Median weeks on pegzilarginase was 5.9 (range 0 [1 dose] to 17.1 weeks). Pegzilarginase depleted plasma arginine from a median of 58 µM at baseline to a median of 4 µM at 72 hours post-dose (n = 12). In 13 pts with week 8 response assessment, 6 had stable disease. 13 pts with UM or CM had prior IO therapy; 7 had PD as best response to last prior therapy. 10/16 tumors showed no or low ASS1 expression.
The safety, PD, and activity profile of pegzilarginase at the MTD continues to support weekly administration with a margin for dose adjustment. Given very poor outcomes in pts with advanced UM and CM, pre-clinical data showing enhanced effects of pegzilarginase when combined with PD-L1 inhibition, and the observation of stable disease this trial, further development of pegzilarginase in combination with anti-PD-L(1) therapy is warranted for these tumors.
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Abstract was prepared by Aeglea Biotherapeutics.
R.J. Sullivan: Consultant: Novartis, Merck, Amgen, Syndax, Replimmune, Array Biopharma. D. Davar: Corporate-sponsored research (clinical trial support): Merck and Bristol-Myers Squibb. H. Lara-Guerra, S.E. Alters, S. Eckert, S.W. Rowlinson, J.E. Wooldridge: Full-time employee: Stock options: Aeglea Biotherapeutics. S. Ferrati: Full-time employee: Aeglea Biotherapeutics. R.D. Carvajal: Consulting: BMS, Castle Biosciences, Foundation Medicine, Immunocore, Incyte, Merck, Roche/Genentech advisory board: Aura Biosciences, Chimeron, Rgenix. All other authors have declared no conflicts of interest.