A Phase 1 study of ADI-PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1-negative metastatic uveal melanoma

Pui Ying Chan, Melissa M Phillips, Stephen Ellis, Amanda Johnston, Xiaoxing Feng, Amit Arora, Gordon Hay, Victoria M L Cohen, Mandeep S Sagoo, John S Bomalaski, Michael T Sheaff, Peter W Szlosarek, Pui Ying Chan, Melissa M Phillips, Stephen Ellis, Amanda Johnston, Xiaoxing Feng, Amit Arora, Gordon Hay, Victoria M L Cohen, Mandeep S Sagoo, John S Bomalaski, Michael T Sheaff, Peter W Szlosarek

Abstract

Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI-PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose-expansion study of patients with argininosuccinate synthetase (ASS1)-deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m2 ) and Cis (75 mg/m2 ) every 3 weeks plus weekly intramuscular ADI (36 mg/m2 ), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1-deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression-free survival of 3.0 months (range, 1.3-8.1) and a median overall survival of 11.5 months (range, 3.2-36.9). Despite anti-ADI-PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re-expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional anti-metabolite strategies.

Keywords: ADI-PEG20; ASS1; arginine auxotrophy; cisplatin; pemetrexed; uveal melanoma.

Conflict of interest statement

XF, AJ and JSB are employees of Polaris Pharmaceuticals Inc. MTS has an advisory role with Roche Molecular Diagnostics. PWS has received honoraria from Merck & Co Inc., Merck KGaA, Roche, Bristol‐Myers Squibb and Boehringer Ingelheim. PWS is a recipient of research funding from Polaris Pharmaceuticals Inc. All remaining authors have declared no conflicts of interest.

© 2022 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
(a) Spider plot showing the percentage change in the sum of the target lesion diameters over time. (b) Swimmer plot showing time on treatment with ADIPemCis and ADI‐PEG20, time to raised plasma arginine levels and time to progression. (c) Waterfall plot showing the best percentage change in the sum of the target lesion diameters. (d) Kaplan–Meier analysis of overall survival (OS) in all patients. (e) Kaplan–Meier analysis of progression‐free survival (PFS) in all patients
FIGURE 2
FIGURE 2
(a) Mean plasma concentration of arginine and citrulline at each week of treatment for the study population. (b) Mean plasma anti‐ADI‐PEG20 antibody titres at each week of treatment for the study population. Error bars indicate the standard error of the mean (SEM). Ab, antibody; ADI‐PEG20, pegylated arginine deiminase
FIGURE 3
FIGURE 3
Representative ASS1 tumoural expression at baseline (a, grey arrow, liver deposit with weak staining intensity) and at progression (b, black arrow, skin deposit with moderate‐strong staining intensity) in a patient with metastatic UM (×400). The larger strongly ASS1 expressing cells in the baseline and progression biopsies are consistent with macrophages (i.e. melanophages, white arrows)

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