[Abstract:] A recently reported clinical trial yielded positive results for a CD73 inhibitor that reduces production of immunosuppressive adenosine in patients with pancreatic cancer. The patients, who also received chemotherapy and a PD-1 checkpoint inhibitor, had an overall response rate of 41%. Tumors shrank or stabilized in 85% of patients who received the drug for 16 weeks.

A recently reported phase I trial suggests that a small-molecule CD73 inhibitor that curbs adenosine production can shrink pancreatic cancer when combined with chemotherapy and a checkpoint inhibitor. The findings provide some of the first evidence that blocking adenosine pathways can overcome immunosuppression and potentially extend survival in patients with pancreatic cancer.

Immunotherapy has performed poorly against pancreatic cancer in clinical trials. The PD-1 inhibitor pembrolizumab (Keytruda; Merck) is the sole immunotherapeutic approved to treat the disease—but only in the roughly 1% of patients who have metastatic microsatellite instability–high or mismatch repair–deficient tumors.

One reason that pancreatic tumors are so hard to treat with immunotherapy is that they often overexpress CD73, an enzyme in the metabolic pathway that generates adenosine. That molecule, in turn, impairs the activation and proliferation of T cells, makes dendritic cells more tolerant of cancer antigens, and induces other immunosuppressive effects. Although more than 20 clinical trials have evaluated drugs that disrupt adenosine metabolism, few have included patients with pancreatic cancer.

Yet, the rationale for targeting adenosine in pancreatic cancer “makes so much sense,” noted Detlev Boison, PhD, of Rutgers Robert Wood Johnson Medical School in Piscataway, NJ, who wasn't connected to the study.

In the ARC-8 trial, Gulam Manji, MD, PhD, of Columbia University Medical Center in New York, NY, and colleagues tested the investigational drug AB680 (Arcus Biosciences) in previously untreated patients with metastatic pancreatic adenocarcinoma. The treatment regimen included the standard chemotherapeutics gemcitabine and nab-paclitaxel (Abraxane; Bristol Myers Squibb), the PD-1 inhibitor zimberelimab (Arcus Biosciences), and one of four doses of AB680, which inhibits CD73.

At the American Society of Clinical Oncology 2021 Gastrointestinal Cancers Symposium, held virtually in January, researchers reported on 19 patients (J Clin Oncol 2021; 39 [suppl 3; abstr 404]). The most common side effects were fatigue, which affected 68% of patients, and anemia, which affected 42%. One patient developed grade 2 autoimmune hepatitis but resumed treatment after receiving steroids. Because the safety profile is similar to that of chemotherapy alone, “we should be able to continue treatment for a long time, which has been the issue for other combination studies” that included chemotherapy, immunotherapy, and other immunomodulatory agents, Manji said.

The quartet of drugs also demonstrated effectiveness. Among 17 evaluable patients, the overall response rate was 41%. Eleven of the 13 patients who received the treatment for at least 16 weeks saw their tumors shrink or stabilize. “It's early, but the number of patients who experienced responses and disease control is very encouraging,” said Manji. Arcus Biosciences has launched a phase I dose-expansion study and is planning a placebo-controlled phase II study.

“The disease control rate after 16 weeks is promising,” said Osama Rahma, MD, of Dana-Farber Cancer Institute in Boston, MA, who wasn't involved in the study. However, he cautioned that “we should not get too excited about efficacy” based on limited data from a phase I trial until “future larger controlled studies are conducted.”

Boison added that because AB680 is a small molecule, it stands out from other adenosine-blocking treatments being tested, which are monoclonal antibodies. “That's a major advantage,” he said. Unlike monoclonal antibodies, AB680 “can penetrate deep into cancers.” –Mitch Leslie