Dung T. Le, MD
Combining two specific anti-cancer vaccines, rather than administering one as monotherapy, doubles the 1-year survival probability in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), according to the results of a phase II study presented January 14, two days in advance of the American Society of Clinical Oncology’s (ASCO) 2014 Gastrointestinal Cancers Symposium.
Adding the immunotherapy CRS-207 to GVAX Pancreas, rather than giving GVAX alone, sparked the improvement, most markedly in patients who received at least two doses of GVAX and at least one dose of CRS-207, and in those who had received two or more prior treatment regimens, the study’s researchers found in the randomized study.
“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 lead study author Dung T. Le, MD, an assistant professor of Medicine at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. “Various chemotherapy drugs are used, but there are no standard treatment options for second- or third-line therapy in this setting. We’re excited these patients may soon have an alternative to chemotherapy that could come with fewer side effects.”
Advanced pancreatic cancer has a very poor prognosis, ASCO said in a written statement. The best reported median survival of 11 months comes from first-line treatment with the chemotherapy regimen FOLFIRINOX. However, due to its side effects, only the fittest patients qualify for this treatment, and reported survival with other chemotherapy regimens is lower, according to the statement. For patients whose disease progresses despite first-line treatment, the median survival ranges from 4 to 6 months with second-line therapy, and 2 to 4 months with third-line therapy.
The new study tested an innovative strategy designed to stimulate an immune response against pancreas tumor cells, potentially improving outcomes for such patients with a regimen that appears to be better tolerated than chemotherapy.
GVAX is made from two pancreatic cancer cell lines that are irradiated so that they secrete the protein GM-CSF, which stimulates the immune system. The drug is given intradermally after low-dose cyclophosphamide (CY), which inhibits regulatory T cells, Le explained. CRS-207 is composed of live-attenuated Listeria monocytogenes
engineered to stimulate an immune response against the protein mesothelin, which is present at high levels on pancreatic cancer cells, the authors and ASCO wrote.
In mouse tumor models, the two types of vaccines have proved synergistic, and in a phase I study of CRS-207, three patients with PDAC who had received prior GVAX lived ≥15 months, the authors noted.
The study by Le et al included 90 patients with metastatic PDAC, the most common form of pancreatic cancer, who were randomly assigned 2:1 to treatment with two doses of CY/GVAX followed by four doses of CRS-207 (arm A), all three weeks apart for a 20-week course of treatment; or six doses of CY/GVAX every three weeks (arm B). Courses could be repeated. The primary endpoint was overall survival (OS), and secondary endpoints were safety and clinical and immune responses. Nearly all patients had received at least one prior course of chemotherapy, and 51% of them had received two or more prior regimens.
At a planned interim analysis, with a median follow-up of 7.8 months, the median OS was 6.1 months for the two-vaccine therapy compared with 3.9 months for therapy with GVAX (hazard ratio [HR] = 0.59, two-sided log rank P
= .03). About 24% of patients in arm A were still alive after 1 year, compared with 12% in arm B, Le said.
Among patients who received at least three doses of vaccine (about 70% of all patients), those in arm A who received two doses of GVAX and at least one dose of CRS-207 had a median OS of 9.7 months compared to 4.6 months for those who took three or more doses of CY/GVAX alone (HR = 0.53, two-sided log rank P
= .03). Investigators observed stabilization of CA19-9, a tumor marker in PDAC, in 32% of patients in arm A versus 13% of patients in arm B.
Based on the benefit observed at this interim analysis, the study was stopped and patients were allowed to cross over from arm B to arm A.
The side effects of the vaccine were relatively mild, resolved quickly, and did not get worse with each dose of treatment (as is often the case with chemotherapy), ASCO wrote. The side effects included local reactions after GVAX, and transient fevers, rigors, and lymphopenia after CRS-207, according to the authors.
“CY/GVAX followed by CRS-207 shows extended survival with manageable toxicity in previously treated metastatic PDA and warrants further study,” the authors concluded.
The GVAX/CRS-207 combination is also being looked at in other clinical studies. The researchers are about to launch a large phase II study that will compare the vaccine combination versus CRS-207 alone versus chemotherapy as second-line or greater therapy for metastatic pancreatic cancer, according to ASCO. They are also looking at combining GVAX/CRS-207 with immune checkpoint inhibitors such as ipilimumab and anti-PD-1/PD-L1. A study testing GVAX/ipilimumab as a maintenance treatment for patients whose disease became stable on FOLFIRINOX has recently opened.
Le DT, Wang-Gillam A, Picozzi V Jr, et al. A phase 2, randomized trial of GVAX Pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: Updated results. Presented at: the ASCO Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, California. Abstract 177.
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