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A Phase 1 Study of ADI-PEG20 (Pegargiminase) Combined with Cisplatin and Pemetrexed in ASS1-Negative Metastatic Uveal Melanoma

Chan, Pui Ying; Phillips, Melissa M; Ellis, Stephen; Johnston, Amanda; Feng, Xiaoxing; Arora, Amit; Hay, Gordon; ... Szlosarek, Peter W; + view all (2022) A Phase 1 Study of ADI-PEG20 (Pegargiminase) Combined with Cisplatin and Pemetrexed in ASS1-Negative Metastatic Uveal Melanoma. Pigment Cell & Melanoma Research , 35 (4) pp. 461-470. 10.1111/pcmr.13042. Green open access

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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 three 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 antimetabolite strategies.

Type: Article
Title: A Phase 1 Study of ADI-PEG20 (Pegargiminase) Combined with Cisplatin and Pemetrexed in ASS1-Negative Metastatic Uveal Melanoma
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/pcmr.13042
Publisher version: https://doi.org/10.1111/pcmr.13042
Language: English
Additional information: Copyright © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: ADI-PEG20, ASS1, Uveal melanoma, arginine auxotrophy, cisplatin, pemetrexed
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10147824
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