Arginine-Depleting Agent Added to Standard Therapy Shows Promise in Pancreatic Cancer

Maeve A. Lowery, MD

The addition of ADI-PEG 20, a pegylated form of an arginine-depleting enzyme, to nab-paclitaxel (Abraxane) and gemcitabine has encouraging activity in patients with advanced pancreatic adenocarcinoma while demonstrating minimal additional toxicity over that with cytotoxic therapy alone.

In an open-label, single-arm phase Ib dose-escalation trial, 7 of 18 patients (39%) treated with various doses of ADI-PEG 20 combined with nab-paclitaxel and gemcitabine experienced partial response (PR) per RECIST v1.1 criteria, and 10 patients (56%) had stable disease (SD), according to data presented at the 2017 Gastrointestinal Cancers Symposium in San Francisco.¹Seven patients experienced ≥3 toxicity that was considered to be potentially caused by ADI-PEG 20, including neutropenia in 4 patients.

Data from the phase Ib clinical trial were presented in poster format by Maeve A. Lowery, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

Pancreatic cancers are often deficient in argininosuccinate synthetase (ASS), the rate-limiting enzyme involved in arginine synthesis. Arginine has multiple intracellular roles, including nitric oxide formation and protein biosynthesis. In a preclinical study, arginine depletion with ADI-PEG 20 has been shown to be synthetically lethal with ASS deficiency.²Synergy between ADA-PEG 20 and docetaxel has also been demonstrated in both preclinical studies and in a phase I study of patients with various solid tumors.

For the phase Ib study presented by Lowery, 9 patients with metastatic pancreatic cancer who received up to 1 line of prior treatment were enrolled. The dose of ADI-PEG 20 was escalated using a 3+3 design in which cohorts of 3 to 6 patients were enrolled to 1 of 3 dose levels of ADI-PEG 20 (9, 18, or 36 mg/m²) with gemcitabine and nab-paclitaxel. After the recommended phase II dose was established, an additional 9 patients with untreated disease were treated at this dose level. Four patients (44%) in the dose escalation phase received prior 5-fluorouracil-based chemotherapy for metastatic disease.

Of the 6 patients who received 36 mg/m²of ADI-PEG 20 in the dose-escalation phase, 1 had a dose-limiting grade 3 liver toxicity, which was considered potentially to be related to the study drug. The recommended phase II dose of ADI-PEG 20 was set at 36 mg/m².

Fifteen patients were treated at the recommended phase II dose. Best response among these 15, per RECIST v1.1 criteria, was PR in 6 patients (40%) and SD in 8 (53%). One patient came off the study due to disease progression. Four patients (26.7%) had SD ≥8 weeks, and the disease control rate at 24 weeks was 47%. The median progression-free survival was 6.5 months and 3 of the 15 patients (20%) were progression-free at 12 months. Two patients remained on study. The median overall survival was 11.3 months (95% CI, 4.9 months to not reached).

The authors measured ASS expression and found that median levels were 20% to 95% among the 4 patients with a confirmed PR, and ranged from 5% to 95% in those with SD. Arginine depletion was also confirmed in responders; the median duration of depletion to ≤10µm was 16 weeks for patients with PR and 13 weeks for patients with SD.

Overall, 7 patients (39%) had ≥3 toxicity that was considered potentially related to ADI-PEG 20, including 4 (22%) with neutropenia, 3 (17%) with lymphopenia, and 1 (5%) with thrombocytopenia. Six patients (33%) reported a rash, predominantly at the injection site, all of which were grade 1 or 2. There were no systemic allergic reactions or seizures attributed to ADI-PEG 20.

“Preliminary assessment of efficacy among patients treated at the maximally tolerated dose [36 mg/m²] is encouraging, with responses observed in ASS1-deficient and -proficient tumors,” the authors indicated. A phase II trial comparing this regimen to chemotherapy alone in patients with advanced pancreas adenocarcinoma is planned.

References:

1. Lowery MA, Harding JJ, Yu KH, et al. Phase IB trial of ADI-PEG 20 (A) plus nab-paclitaxel (nab-P) and gemcitabine (gem) in patients with advanced pancreatic cancer (PC). Presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA. Abstract 295.
2. Kim RH, Coates JM, Bowles TL, et al. Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis.Cancer Res. 2009;69(2):700-708. doi:10.1158/0008-5472.CAN-08-3157.