Pegylated recombinant human arginase monotherapy well tolerated in post-sorafenib HCC

Pegylated recombinant human arginase (PEG-BCT-100) monotherapy is well tolerated and offers a modest disease control rate (DCR) as second-line treatment in chemotherapy-naïve hepatocellular carcinoma (HCC) patients who failed sorafenib, according to results of a phase II clinical study.

“The survival advantage of argininosuccinate synthase [ASS]-negative HCC over ASS-positive HCC is shown for the first time in humans, which supports the potential role of ASS negativity as a predictive biomarker for patient selection for PEG-BCT-100 monotherapy,” said the authors. [Invest New Drugs 2021;doi:10.1007/s10637-021-01111-8]

Results from preclinical studies showed that arginine deprivation due to loss of ASS, frequently observed in arginine auxotrophic cancers such as HCC, could induce tumour regression. Identification of patients with ASS-negative tumours was thus proposed as a strategy for selecting those who are most likely to respond to arginine deprivation therapy. [Cancer Res 2007;67:309-317; Br J Cancer 2000;83:800-810]

In the current single-arm, open-label phase II study, 27 chemotherapy-naïve patients (median age, 61.1 years; male, 88.9 percent) with HCC previously treated with sorafenib received weekly intravenous injection of PEG-BCT-100 monotherapy at 2.7 mg/kg on days 1, 8 and 15 every 3 weeks, without dose interruption between each cycle. Enrolled patients from Prince of Wales Hospital were required to undergo pretreatment liver biopsy for ASS and omithine transcarbamylase (OTC) expression assessment by immunohistochemistry.

Of note, all patients had Child-Pugh class A liver function, with 96.3 percent having Barcelona-Clinic Liver Cancer (BCLC) stage C disease. The median serum alpha-fetoprotein (AFP) level was 325 ng/mL.

PEG-BCT-100 monotherapy was well tolerated, with fatigue (59.3 percent), constipation (37.0 percent) and limb oedema (25.9 percent) being the most frequently reported adverse events. Grade ≥3 adverse events of anaemia and hyponatraemia were reported in 7.4 percent and 11.1 percent of patients, respectively. Treatment interruption was required in 22.2 percent (n=6) of patients, with two cases due to treatment-related adverse events.

Results of European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ C-30) and QLQ-HCC18 questionnaire showed no improvement in symptom control with PEG-BCT-100 treatment.

Overall, 85.2 percent of patients received ≥1 dose of the study treatment and had undergone ≥1 postdose response assessment. Both median time to progression (TTP) and progression-free survival (PFS) were 6.0 weeks. Median overall survival (OS) was 23.7 weeks, while DCR was 21.7 percent (stable disease, n=5).

Post hoc analysis showed an increase in median OS with continued deprivation of arginine, with a median OS of 25.29 weeks vs 16.57 weeks for patients who received ≥1 vs <1 cycle of PEG-BCT-100 monotherapy.

Among 20 patients who had tumour tissue sampled, 65 percent (n=13) of patients had received >1 cycle of treatment and had undergone postdose response assessment. No/low expression of OTC and ASS (ASS-negative) was reported in 23.1 percent and 76.9 percent of patients, respectively.

Patients with ASS-negative HCC had favourable OS and TPP outcomes compared with those with ASS-positive HCC (median OS, 35.0 weeks vs 15.1 weeks) (median TPP, 6.07 weeks vs 6.00 weeks). No correlation between expression of OTC and treatment outcomes was observed.  

“Further studies are currently underway to confirm the role of ASS-negativity as a predictive OS biomarker for treatment of arginine auxotrophic cancers with PEG-BCT-100,” concluded the authors.