CHICAGO – Giving the telomerase peptide vaccine GV1001, either sequentially or concurrently, with standard chemotherapy added no overall survival benefit in one of the largest trials ever performed in locally advanced or metastatic pancreatic cancer.
Median overall survival was 7.9 months for gemcitabine (Gemzar) and capecitabine (Xeloda) chemotherapy alone, 6.9 months for 8 weeks of gemcitabine and capecitabine followed by GV1001 vaccinations until progressive disease then gemcitabine and capecitabine, and 8.4 months for GV1001 given concurrently with gemcitabine and capecitabine chemotherapy.
One-year survival rates were 33.7%, 25.3%, and 32.3%. The difference in overall survival did not meet the criterion for statistical significance (P value less than .0175) for sequential (hazard ratio, 1.19; P = .046) or concurrent (HR, 1.05; P = .63) chemoimmunotherapy.
Further, sequential chemoimmunotherapy was associated with a statistically poorer response rate, compared with standard chemotherapy (8.6% vs. 17.6%; unadjusted P = .000), and shorter time to progression (4.54 months vs. 6.35 months; P less than .001), Dr. Gary W. Middleton reported at the annual meeting of the American Society of Clinical Oncology.
The results of the 1,062-patient TeloVac study are disappointing in light of phase I/II results in which an intermediate dose of GV1001, without any chemotherapy at all, produced an immune response in 75% of patients and a median overall survival of 8.3 months, explained Dr. Middleton of the University of Birmingham, England.
Invited discussant Dr. Hedy Lee Kindler, medical director of gastrointestinal oncology at the University of Chicago Medical Center, questioned whether this signal was sufficiently robust to proceed directly to a 1,000-plus–patient phase III trial, given that the phase I/II trial was not randomized, did not include chemotherapy, and had significant imbalances in performance status and disease extent between arms that made it difficult to draw conclusions about the outcomes.
"Perhaps a randomized phase II trial of chemotherapy plus/minus vaccine would have been informative," she said.
Although TeloVac is one of a long line of negative phase III trials in pancreatic cancer, recent data challenge the assumption that pancreas cancer is poorly immunogenic, Dr. Kindler said. Going forward, the optimal immunotherapy trial will need to use the best antigen, increase vaccine potency by optimizing the adjuvant, uncouple tolerance mechanisms either by blocking immunologic checkpoints or manipulating the tumor microenvironment using agonistic anti-CD40 antibodies, and identify predictive biomarkers, she said.
Chemoradiotherapy in LAP 07
During the same session at ASCO, final results were reported from the phase III international LAP 07 study evaluating chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine chemotherapy with or without erlotinib (Tarceva).
Median overall survival in patients allocated to 2 additional months of chemotherapy was 16.4 months vs. 15.2 months in those allocated to receive 54 Gy and capecitabine (HR, 1.03; P = .83). Progression-free survival was also similar at 11.8 months and 12.5 months (HR, 0.9; P = .21).
The internal data monitoring committee confirmed that the futility boundary was crossed for the hypothesis of chemoradiotherapy superiority, and that the second interim analysis could be considered the study’s final analysis. "It was clear that to continue the study would not change the final results," said Dr. Pascal Hammel, Beaujon Hospital, Clichy, France.
When survival was analyzed based on first-round chemotherapy, there was a trend for inferior survival with gemcitabine plus erlotinib compared with gemcitabine alone, although the data are not mature (median 11.9 months vs. 13.6 months; HR 1.19; P = .09). The addition of erlotinib was not beneficial in locally advanced pancreatic cancer and increased toxicity, he said.
"In locally advanced pancreatic cancer, standard of care should remain chemotherapy; chemoradiotherapy being an option after tumor control by chemotherapy," Dr. Hammel concluded.
An audience member objected to CRT as an option, in light of the negative results, but Dr. Kindler agreed with the authors’ conclusion.
There are many potential explanations for "these somewhat surprising results," including inadequate radiation or inadequate chemotherapy during the first round or during radiotherapy. It’s also possible that only a subset of patients benefit from CRT, something that is being examined in ongoing correlative studies from LAP 07. Two ongoing trials – Radiation Therapy Oncology Group 1201 of high vs. standard intensity local or systemic therapy and the proposed Alliance/Eastern Cooperative Oncology Group phase II trial – could also help answer some of these questions, she said.
TeloVac was funded by Cancer Research UK; Roche supplied capecitabine for the trial; and KAEL-GemVax provided the vaccine and additional support to the Cancer Research UK Liverpool Cancer Trials Unit. Dr. Middleton and his coauthors reported no relevant disclosures.