SAN FRANCISCO—The combination of two anticancer vaccines doubled median overall survival (OS) compared with a single vaccine in patients with metastatic pancreatic ductal adenocarcinoma who had failed or refused chemotherapy, updated results of a phase 2 open-label randomized trial presented at the 2014 Gastrointestinal Cancers Symposium have found.
“This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer. This study is just a first step, and we believe we’ll be able to take this approach further,” said Dung T. Le, MD, an assistant professor of medicine at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD.
The GVAX vaccine, comprising irradiated, granulocyte macrophage colony-stimulating factor–secreting allogeneic pancreatic cell lines, “is given intradermally to elicit a broad antigenic response.” To inhibit regulatory T-cells, low-dose cyclophosphamide (CY) is given prior to GVAX. CRS-207 is a live-attenuated Listeria monocytogenes vaccine that expresses mesothelin and stimulates innate and adaptive immunity.
The 20-week treatment course randomly assigned patients 2:1 to receive two doses of CY/GVAX followed by four doses of CRS-207 (n=61) or six doses of CY/GVAX alone (n=29) every 3 weeks. Additional courses could be administered if patients were clinically stable. Of the patients, 51% had received two or more chemotherapy regimens for metastatic pancreatic ductal adenocarcinoma.
The primary endpoint was OS. At interim analysis, the study was stopped for efficacy, Dr. Le reported, and patients were allowed to cross over from the single vaccine to the combination vaccine arm.
At a median follow-up of 7.8 months, CY/GVAX with CRS-207 resulted in median OS of 6.1 months (95% CI: 4.4-9.2 months) versus 3.9 months (95% CI: 2.8-4.9 months) for CY/GVAX alone (hazard ratio [HR], 0.593; one-sided log rank P = 0.0172 and two-sided log rank P = 0.0343). In addition, the 1-year survival probability was doubled: 24% in the CY/GVAX with CRS-207 arm versus 12% in the CY/GVAX-alone arm.
In addition, among patients who received at least three doses of vaccine (about 70% of all patients), those in the CY/GVAX with CRS-207 arm who received two doses of GVAX and at least one dose of CRS-207 had a median OS of 9.7 months (95% CI: 6.1-10.5 months) compared with 4.6 months (95% CI: 3.8-8.5 months) with GVAX alone (HR, 0.529; one-sided log rank P = 0.0167 and two-sided long rank P = 0.0335).
The treatment effect was particularly evident in patients who received two or more prior regimens for metastatic pancreatic ductal adenocarcinoma, she noted, with median OS of 5.1 versus 3.7 months (HR, 0.34; P = 0.001). CA19-9 stabilization was observed in 32% versus 13% of patients (P = 0.06).
Toxicities included local reactions after CY/GVAX and transient fevers, rigors, and lymphopenia after CRS-207, which is infused over 2 hours. None of these responses worsened with subsequent treatment doses.
A three-arm phase 2 study to evaluate the combination of CY/GVAX with CRS-207 to CRS-207 and to chemotherapy as second-line or greater therapy for metastatic pancreatic cancer is ongoing, Dr. Le said. Also being explored is combining GVAX/CRS-207 with immune checkpoint inhibitors, such as ipilimumab and anti-PD-1/PD-L1. A trial testing GVAX/ipilimumab as a maintenance treatment for patients whose disease became stable on FOLFIRINOX recently opened.
The 2014 Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association (AGA) Institute, the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Surgical Oncology (SSO).