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

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.

Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants

“…ASS1-deficient lung cancers are being exploited for therapies using ADI, an arginine deaminase that catabolizes arginine to citrulline and urea. 42 , 43 , 44 , 45 , 46 , 47 , 48 We, therefore, examined whether ADI treatment, similar to arginine depletion, provokes R>C substitutants. To test this, we incubated A549-KRT8s-V5 cells with increasing concentrations of arginine in the presence or absence of 1 μg/mL recombinant ADI protein.…”

Arginase-induced cell death pathways and metabolic changes in cancer cells are not altered by insulin

“…Metabolic therapy with enzymes that deplete the amino acid arginine, are in early phase I and II clinical trials for the treatment of malignant melanoma, metastatic uveal melanoma, and hepatocellular carcinoma 5 , 7 , 8 . These tumour types are frequently reported to lack ASS1 expression, the rate-limiting enzyme for the de novo biosynthesis of arginine 14 .…”

“…However, some cancer cells are dependent on extracellular sources of arginine due to rapid growth requirements or an inability to synthesise arginine due to a lack of argininosuccinate synthetase (ASS1) expression 2 , 4 . These cells are auxotrophic for arginine, and depletion of arginine using arginine-depleting enzymes such as arginase (ARG) and arginine deaminase (ADI) has been proposed as a form of cancer therapy 5 – 8 .…”

Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment

“…Finally, a phase I dose-expansion study assessed the safety and preliminary activity of ADI-PEG 20 combined with pemetrexed and cisplatin chemotherapy in patients with metastatic uveal melanoma and ASS1 deficiency. Although seven patients had stable disease with a median progression-free survival of 3.0 months and a median overall survival of 11.5 months, tumor re-biopsies at progression revealed ASS1 re-expression as an escape mechanism, indicating the need for further investigation of arginine deprivation in uveal melanoma [ 110 ].…”