IMMUNOTHERAPY FOR PANCREATIC CANCER

Overall survival was improved in patients with metastatic pancreatic cancer through an innovative immunotherapy strategy in a multicenter study to be reported at the 2014 Gastrointestinal Cancers Symposium(Abstract 177). The results were announced at a press briefing prior to the meeting.

“This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer,” said Dung T. Le, MD, Assistant Professor of Medicine at theSidney Kimmel Comprehensive Cancer Center, Baltimore. “This is just a first step, and we believe we’ll be able to take this approach further.”

How the Treatment Works

The novel treatment, which may be better tolerated than standard chemotherapy, involves two different anticancer vaccines: GVAX Pancreas followed by CRS-207. GVAX is composed of pancreatic cancer cells that have been genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine), which stimulates the immune system. GVAX is given with low-dose cyclophosphamide to inhibit regulatory T cells, which are immunosuppressive, and boost the vaccine’s efficacy. The second vaccine, CRS-207, is live-attenuated Listeria monocytogenes (Lm) that has been genetically modified to be safe for human use while retaining its ability to stimulate an immune response against the protein mesothelin on pancreatic tumor cells.

The combination essentially trains the body to recognize and attack pancreatic tumors. In mouse tumor models, Lm/GVAX vaccines are synergistic, and in a phase I study of CRS-207, patients with pancreatic ductal adenocarcinoma who had received prior GVAX lived more than 15 months, Dr. Le explained.

Study Details

The study randomly enrolled 90 patients with pancreatic adenocarcinoma patients in whom prior chemotherapy had failed (half had prior treatment) or who refused chemotherapy. Patients were randomly assigned 2:1 to two doses of GVAX followed by four doses of CRS-207, or to six doses of GVAX alone, every 3 weeks. Courses could be repeated. The primary endpoint was overall survival.

At a planned interim analysis, and at a median follow-up of 7.8 months, median overall survival was 6.1 months with the combination vs 3.9 months with GVAX alone, a 41% reduction in risk with the combination immunotherapy (P = .03).

“One-year probability was doubled, to 24% in the GVAX/CRS-207 arm from 12% in the GVAX arm,” Dr. Le said.

The greatest differences were observed in patients who received at least two doses of GVAX and at least one dose of CRS-207, and in those who had received at least two prior treatment regimens, she said.

In the per-protocol analysis of patients who received at least three doses (one of which was CRS-207), median overall survival was 9.7 months with the combination vs 4.6 months with GVAX alone, a 47% reduction in risk (P = .03). .

“The interim analysis met the early stopping rule for efficacy,” Dr. Le said, “and patients on the GVAX arm were rolled over to the combination treatment arm.”

The vaccines appeared to be safe and well tolerated.

A three-arm study is underway to evaluate the combination compared to CRS-207 alone and to chemotherapy.

Smitha Krishnamurthi, MD, Associate Professor of Medicine at University Hospitals of Case Medical Center and Case Western Reserve University, who moderated the press briefing, commented, “This is exciting research in a poor-prognosis cancer. And this is the first randomized study of immune therapy in metastatic pancreatic cancer, showing an improvement in survival. With one dose of CRS-207, we saw a doubling in overall survival, and this was accomplished without the side effects of chemotherapy.”