Combined Vaccines Study Misses Primary Endpoint in Pancreatic Cancer

Andrew Ko, MD

A regimen combining the vaccines CRS-207 and GVAX Pancreas failed to improve overall survival (OS) versus either CRS-207 alone or chemotherapy in patients with metastatic pancreatic cancer who had failed at least 2 prior therapies, according to Aduro Biotech, the company that manufactures the vaccines.

In the phase IIb ECLIPSE trial, the median OS was 3.8 months for patients receiving CRS-207/GVAX compared with 5.4 and 4.6 months for patients receiving CRS-207 alone and chemotherapy, respectively.

“As the scientific community continues to discover the optimal approach toward enlisting the power of the immune system in the fight against elusive diseases such as pancreatic cancer, I applaud Aduro for their pioneering contributions to the field. Immunotherapy is ushering in a new era in our fundamental understanding of human biology, and although the results are not what we had hoped for from this well-executed trial, they will provide important information for changing the treatment paradigm in the future,” Andrew Ko, MD, professor, Department of Medicine (hematology/oncology) at the University of California San Francisco, said in a statement.

GVAX is made from 2 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. 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 open-label ECLIPSE trial was conducted at over 20 locations in the United States and Canada at which a total of 303 previously treated patients with metastatic pancreatic cancer were enrolled. Patients were randomized to the dual vaccine regimen along with low-dose cyclophosphamide, CRS-207 alone, or chemotherapy. Individuals on the chemotherapy arm received gemcitabine, capecitabine, 5-FU, irinotecan, or erlotinib in accordance with the defined treatment regimen. The primary endpoint was OS, with secondary outcome measures including safety and evaluation of clinical and immune response.

“In the overall survival analysis, we were intrigued by activity seen with CRS-207 as a single-agent. While the median duration of 5.4 months appears greater for CRS-207, the overall survival curve of CRS-207 alone was comparable to overall survival seen with chemotherapy. Of note, due to a disproportionately high dropout rate in the single-agent chemotherapy arm, most of these patients instead received a variety of combination treatments, including chemotherapies, immunotherapies and targeted therapies,” Dirk Brockstedt, PhD, executive vice president, research and development for Aduro, said in a statement.

The vaccines were well tolerated overall, and there were no unexpected toxicities with the immunotherapy combination, according to Aduro.

Data reported at the 2014 Gastrointestinal Cancers Symposium had previously shown that combining GVAX with CRS-207 improved OS versus GVAX alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

The phase IIa study1 included 90 patients with metastatic PDAC who were randomly assigned 2:1 to treatment with 2 doses of CY/GVAX followed by 4 doses of CRS-207 (arm A), all 3 weeks apart for a 20-week course of treatment; or 6 doses of CY/GVAX every 3 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 2 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 2-vaccine therapy compared with 3.9 months for therapy with GVAX (HR, 0.59, 2-sided log rank P = .03). About 24% of patients in arm A were still alive after 1 year, compared with 12% in arm B.

Among patients who received at least 3 doses of vaccine (about 70% of all patients), those in arm A who received 2 doses of GVAX and at least 1 dose of CRS-207 had a median OS of 9.7 months compared to 4.6 months for those who took 3 or more doses of CY/GVAX alone (HR, 0.53, 2-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. The side effects included local reactions after GVAX, and transient fevers, rigors, and lymphopenia after CRS-207.

“This is an unexpected outcome, and we are disappointed particularly for the pancreatic cancer patients who are in need of additional treatment options,” Stephen T. Isaacs, chairman, president and CEO of Aduro, said in a statement. “We would like to thank the patients and their families, investigators and staff involved in this phase IIb trial for their support and participation in this study. While we are well aware of the very difficult-to-treat nature of late-stage metastatic pancreatic cancer, we are surprised by the divergence of these data from the results of our phase IIa study. At the same time, we continue to look forward to the interim results later this year from our ongoing STELLAR trial, which is evaluating CRS-207 and GVAX Pancreas with and without the anti-PD1 checkpoint inhibitor nivolumab as a second-line therapy for patients with metastatic pancreatic cancer.”

ECLIPSE is the second pancreatic cancer trial to recently report disappointing results. Earlier this month, NewLink Genetics announced that its investigational investigational pancreatic cancer vaccine algenpantucel-L failed to improve OS versus standard of care in the phase III IMPRESS trial.

Reference

1. 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.