ADI-PEG 20 Added to Standard Therapy Shows Potential Promise in Pancreatic Cancer

The addition of ADI-PEG 20, a pegylated form of an arginine-depleting enzyme, to nab-paclitaxel and gemcitabine showed encouraging activity and minimal additional toxicity in the treatment of patients with advanced pancreatic adenocarcinoma.

Maeve A. Lowery, MD

The addition of ADI-PEG 20, a pegylated form of an arginine-depleting enzyme, to nab-paclitaxel (Abraxane) and gemcitabine showed encouraging activity and minimal additional toxicity in the treatment of patients with advanced pancreatic adenocarcinoma. These data were presented at the 2017 Gastrointestinal Cancers Symposium in San Francisco.1

Seven of 18 patients (39%) in the trial treated with various doses of ADI-PEG 20 plus nab-paclitaxel and gemcitabine experienced partial response (PR) per RECIST v1.1 criteria. Ten patients (56%) demonstrated stable disease (SD), and 7 patients experienced >3 toxicity—including neutropenia in 4 patients—which was considered to potentially be caused by ADI-PEG 20.

Maeve A. Lowery, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, and her colleagues presented the data from the open-label, single-arm phase Ib dose-escalation study.

In the trial, 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/m2 of ADI-PEG 20 in the dose-escalation phase, 1 experienced a dose-limiting grade 3 liver toxicity, which was considered to be potentially 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).

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.2 Synergy 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.

The authors of the current study 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.