'Encouraging' Antitumor Activity in Pancreatic Ca With CD40 Agonist

ATLANTA -- Use of the novel CD40 agonist APX005M with or without nivolumab (Opdivo) led to responses in more than half of patients with metastatic pancreatic cancer on first-line chemotherapy, results of a phase Ib found.

Among 24 patients with untreated metastatic disease, 13 achieved a partial response to the chemotherapy-immunotherapy combination and an additional nine had stable disease, Mark O'Hara, MD, of the University of Pennsylvania in Philadelphia, reported here at the American Association for Cancer Research annual meeting.

"Those numbers, while it's a very small population, are very encouraging," O'Hara told MedPage Today. "The response rate was 54%, which is much higher than what we'd anticipate with pancreatic cancer, and the disease control rate was 92%."

Past chemotherapy trials in metastatic pancreatic cancer have had modest rates of response and disease control. In 171 patients treated with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), 32% responded and the disease control rate was 70%.

In a 2013 study of 431 patients treated with gemcitabine (Gemzar) and nab-paclitaxel (Abraxane), the standard chemotherapy used in the current study, 23% responded while the rate of disease control was 48%. And in a recent phase I study, adding nivolumab did not appear to lead to further gains, with rates of 18% and 64%, respectively.

APX005M is an agonist of CD40, which is present in both cancer and immune cells, and engaging with CD40 primes and activates antigen presenting cells and leads to stimulation of the immune system, O'Hara explained. Pancreas cancer models in the lab showed that adding APX005M to gemcitabine/nab-paclitaxel increased T-cell dependant tumor destruction in mice, which led the researchers to add nivolumab, and the four-drug combination improved survival in mice with pancreatic cancer.

For the current phase Ib study, O'Hara's group enrolled patients into four cohorts from 2017 to 2018, each of which included six patients who received first-line gemcitabine/nab-paclitaxel. Safety of APX005M at doses of 0.1 mg/kg and 0.3 mg/kg was established in the first two cohorts, and researchers then enrolled two more cohorts of chemotherapy plus standard dose nivolumab, and APX005M at either 0.1 mg/kg or 0.3 mg/kg.

There were no complete responses in the study, but partial responses were observed in all four cohorts, and eight of the 12 patients on nivolumab plus APX005M responded to treatment (67%).

Two dose-limiting toxicities emerged during the trial -- grade 3 neutropenic fever in the 0.3 mg/kg APX005M arm and grade 4 neutropenic fever in the 0.1 mg/kg APX005M plus nivolumab arm, though both were believed to be secondary to chemotherapy, said O'Hara.

Common treatment-related adverse events in the full safety cohort of 30 patients -- which included patients who had at least one dose of any treatment -- included decreased lymphocyte count (67%), neutropenia (40%), anemia (33%), fatigue (27%), increased aspartate aminotransferase (23%), and leukopenia (20%). There was one treatment-related death, though this was thought to be unrelated to APX005M. O'Hara said the side effects were significant but relatively manageable, and patients were able to stay in the study.

"To have a potentially effective and safe combination is exciting," he said. "The thing we don't know, because it's so early, is how durable are these responses? Are they going on for much longer than we anticipate, are people living longer? That's just data we don't have yet."

He highlighted one patient from the first cohort to enroll in the study -- chemotherapy plus 0.1 mg/kg APX005M -- who has been on trial for about 18 months. "We do have these anecdotes with chemotherapy alone too, but I do think that people have been on this a little bit longer than we would anticipate," said O'Hara.

Most patients received typical doses of chemotherapy, he said, even with the combination of APX005M. "We know that chemotherapy works in pancreatic cancer -- and works is sort of in quotes because it's not overly effective," he added. "You don't want to give them ineffective treatment by dose-reducing their chemotherapy."

Louis Weiner, MD, of Georgetown University and the Lombardi Comprehensive Cancer Center in Washington, told MedPage Today that the vast majority of pancreatic cancer patients present with metastatic disease, and modern chemotherapy approaches have pushed out average survival to roughly a year, but that the prognosis remains dismal. "It has been essentially a death sentence," he said.

Weiner added that the study from the University of Pennsylvania demonstrates that it's "possible to stimulate the host immune response" in patients with pancreatic adenocarcinoma, a poorly immunogenic cancer, increasing the likelihood of longer response duration.

The phase Ib trial included adult patients with untreated metastatic pancreatic adenocarcinoma. All had ECOG performance status ≤1 and adequate hematologic, hepatic, and kidney function. Most patients had liver, lung, or peritoneal metastases. Those with symptomatic central nervous system involvement were excluded, as were those with a history of autoimmune disorders. Among the 30 patients (median age 66) in the safety cohort, 53.3% were men and most were white (86.7%). Median time on treatment was 30.3 weeks.

A planned phase II study will evaluate responses and survival in further detail with the APX005M 0.3 mg/kg dose. The three-arm trial will test chemotherapy (gemcitabine/nab-paclitaxel) plus nivolumab versus chemotherapy with APX005M versus chemotherapy with APX005M and nivolumab, with the primary outcome being 1-year overall survival compared with historical controls with gemcitabine/nab-paclitaxel.