Assessment of pegylated arginine deiminase and modified FOLFOX6 in patients with advanced hepatocellular carcinoma: Results of an international, single‐arm, phase 2 study

Abstract

BACKGROUND: Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. METHODS: This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m 2 . RESULTS: In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progressionfree survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). CONCLUSIONS: Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued.

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

“…However, a phase III study did not show a significant difference in overall survival or progression-free survival between ADI-PEG 20 and placebo [ 103 ]. Another phase II study found ADI-PEG 20 to be safe and effective in stabilizing the progression of heavily pretreated advanced HCC in an Asian population, while a study evaluating the combination of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients with advanced HCC who had progressed on at least two prior lines of treatment exhibited limited antitumor activity [ 104 ].…”

Arginine regulates HSPA5/BiP translation through ribosome pausing in triple-negative breast cancer cells

“…This strategy is a desirable option because cancer cells frequently alter their metabolic and nutrient acquisition pathways to overcome numerous tumour microenvironmental stresses that threaten their survival and ability to proliferate [ 4 ]. Arginine, a semi-essential amino acid, is involved in numerous metabolic pathways [ 5 , 6 ] and arginine deprivation has been used to treat cancer in clinical trials [ 7 , 8 ] like normal cells which can de novo synthesise arginine, frequent deregulation of argininosuccinate synthase 1 (ASS1) in TNBC makes these cancer cells highly dependent on the uptake of extracellular arginine [ 9 ]. This arginine-auxotrophic phenotype is commonly seen in the metabolic reprogramming of cancer cells [ 10 , 11 ].…”

Combined FOLFOX4 with all-trans retinoic acid versus FOLFOX4 with placebo in treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a randomized, double-blind comparative study

“…The encouraging results of two phase III studies conducted by Qin et al 13 and Lyn et al 14 revealed that FOLFOX4 (oxaliplatin +5-fluorouracil/leucovorin) may confer some benefits to advanced HCC patients in Asia, with an acceptable safety profile. Although the FOLFOX4 regimen has gained approval for the treatment of advanced HCC in China and has served as an empiric treatment option by some physicians in the United States, [15][16][17] it must be acknowledged that the benefits that advanced HCC patients receive from current chemotherapy regimens are still very limited, and the incidence of AEs is also relatively high. Additionally, we consider that the prognosis of advanced HCC patients is highly heterogeneous and needs to be reclassified for treatment.…”