The Lynx Group

First CD73 Inhibitor Induces Responses in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

April 2021, Vol 12, No 2

A small-molecule CD73 inhibitor (AB680) induced a 41% overall response rate (ORR) when combined with chemotherapy (with nab-paclitaxel and gemcitabine), plus the novel PD-1 inhibitor zimberelimab, as a first-line treatment for patients with metastatic pancreatic ductal adenocarcinoma, according to results of the dose-escalation portion of a phase 1/1b study known as ARC-8.

A total of 19 patients with metastatic pancreatic cancer received from 25 mg to 100 mg of AB680 plus nab-paclitaxel, gemcitabine, and zimberelimab. Only 1 dose-limiting adverse event occurred in the ongoing study, at 50 mg of AB680, which resolved completely with steroid treatment. The data were presented as a poster at the 2021 ASCO Gastrointestinal Cancers Symposium.

“I am encouraged by the emerging safety and efficacy data from this AB680-based novel therapeutic regimen in my patients,” said co-investigator Johanna C. Bendell, MD, Director, GI Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN.

“The initial response rate is promising, and thus far there has not been significant additive toxicity from AB680 to chemotherapy. There is a need for advances in the treatment of metastatic pancreatic cancer, and this unique molecule has the potential to improve outcomes for patients with this difficult-to-treat disease,” Dr Bendell said.

First Small-Molecule CD73 Inhibitor

AB680 is the first small-molecule CD73 inhibitor developed with the aim of eliminating adenosine-mediated immunosuppression in the tumor microenvironment. KRAS mutations, which are linked to more than 90% of pancreatic cancers, are associated with high CD73 expression, the researchers noted. Increased CD73 expression correlates with worse survival in patients with pancreatic cancer, regardless of KRAS status.

The ARC-8 study is enrolling patients with confirmed metastatic pancreatic cancer who have not received treatment for metastatic disease. Previous neoadjuvant treatment (chemotherapy or radiotherapy) was allowed if completed ≥6 months before study enrollment.

The study’s dose-escalation phase had a standard 3 + 3 design in which AB680 is administered at dosages of 25 mg, 50 mg, 75 mg, or 100 mg, once every 2 weeks, plus standard doses of nab-paclitaxel, gemcitabine, and zimberelimab 240 mg.

The patients’ mean age was 64 years; 11 of the 19 patients were men. Overall, 17 were evaluable for efficacy, with a data cutoff of December 9, 2020. A total of 16 of the evaluable patients continued active treatment at the time of the efficacy data cutoff, all receiving 100 mg of AB680; 15 of the 17 (88%) patients had at least some tumor shrinkage.

The ORR was 41% with the addition of AB680 compared with 23% to 29% with chemotherapy with nab-paclitaxel plus gemcitabine. All 7 responses were partial responses, including 3 confirmed responses. Of the 4 unconfirmed responses, 3 responded at the first tumor assessment and all 4 remain on study treatment.

Based on the results to date, 100 mg of AB680 every 2 weeks has been selected as the dose for the phase 1b expansion portion of the trial.

Safety Profile

All 19 patients were evaluable for safety. Across all 4 dose-escalation cohorts, no significant new adverse events from AB680 were observed beyond that expected with the combination of nab-paclitaxel, gemcitabine, and a PD-1 inhibitor (ie, zimberelimab). The 1 dose-limiting adverse event was a grade 2 autoimmune hepatitis that resolved completely with steroid treatment, and the patient resumed treatment without subsequent autoimmune adverse events.

The most common treatment-emergent adverse events with the regimen were fatigue (68%), anemia (53%), alopecia (42%), diarrhea (42%) and neutrophil count decrease (42%).

Grade 3 adverse events related to the study drug (ie, AB680) were anemia in 2 patients, a decrease in the neutrophil count in 2 patients, a decrease in the lymphocyte count in 1 patient, a decrease in the platelet count in 1 patient, and Clostridium difficile colitis in 1 patient.

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