July 7, 2008 — A heat-shock-protein–peptide complex that was showing promise in early study has failed a phase 3 trial. The work, the largest study to date, which was published online July 4 in the Lancet, shows that the vaccine vitespen (Oncophage, Antigenics) did not improve recurrence-free survival in patients who had undergone a nephrectomy for renal cell carcinoma. It is a disappointing turn of events and one that lead investigator Christopher Wood, MD, from the MD Anderson Cancer Center in Houston, Texas, chalks up to the difficulties of adjuvant trials in an evolving field.
"Vaccine therapies continue to hold promise," Dr. Wood told Medscape Oncology. "The problem is these studies are difficult to conduct and are a lot of work. You need huge numbers, and the time to recurrence is long."
During an interview, Sunny Uberoi, vice president of corporate communications for Antigenics in New York, pointed out that repeating this trial would take about 10 years and US$500 million. "When this study was started, no one really knew which cancer patients might benefit," he said. Investigators are now exploring whether the vaccine will improve recurrence-free survival in patients with early-stage disease.
But in an accompanying editorial, James Yang, MD, from the National Cancer Institute in Bethesda, Maryland, accuses the company of being over zealous. He cites post hoc analyses and misleading company press releases as examples.
"The credibility of the field of cancer immunotherapy is weakened when some investigators, and particularly vaccine companies, cannot accept the results of randomized trials," he writes. "There has been extensive use of post hoc subset analyses to salvage underpowered studies or those that fail to reject the null hypothesis. Such practices are akin to shooting the arrow first and being permitted to draw the target afterwards."
Data Must Drive the Field, Says Editorialist
Dr. Yang criticizes recent company press releases highlighting the approval of vitespen in Russia for patients with intermediate-risk renal cell cancer. He points out that the release uses relative rather than absolute risk and fails to mention that the analysis was not prespecified in the protocol and was conducted on a subset — the 25th percentile — of the data.
The company is working to launch vitespen in Russia in the second half of 2008. It is also working with the European Medicines Agency on conditional approval of the vaccine.
"Most cancer vaccines lack robust evidence of potent immunostimulation, as judged by immunological monitoring," Dr. Yang points out. He suggests the vaccines are intrinsically not very immunogenic in human beings.
Although augmentation of immune responses to renal cancer in vitespen-immunized patients has not been studied, he notes, results in patients with colorectal cancer show at best 1 new T cell per hundreds to thousands of circulating T cells.
"The rare vaccines that do generate brisk B cell or T cell responses apparently do not induce the correct effector functions to reject tumors, or perhaps cannot overcome inhibitory factors that block the necessary effector functions." However, he adds, "adoptive T cell transfers do suggest that highly activated immune cells can indeed reject advanced cancer in some patients so the goal can be realized."
Immunotherapy Research Challenging, But Feasible
In the current multicenter, open-label, randomized phase 3 trial, Dr. Wood and his team compared vitespen with observation in patients at high risk for recurrence after resection of a primary renal cell carcinoma. The peptide-bound heat-shock protein was purified from patient tumors. More than 400 people entered each group and just over 360 per group were used in the analysis to determine the primary end point of recurrences.
After a median follow-up of 1.9 years, investigators observed 136 recurrences in the vitespen group and 146 in the observation group (37.7% vs 39.8%; hazard ratio, 0.92; 95% confidence interval, 0.73–1.17). The difference in overall survival between the 2 groups was not statistically significant.
The study has several methodologic problems, Dr. Wood pointed out to Medscape Oncology. In all, 90 patients were randomized but did not meet postsurgery inclusion or exclusion criteria; these patients were never treated and were excluded from all analyses. After the protocol was amended to prevent this situation, 124 of 728 subsequent patients were found to have metastatic disease at the time of randomization. These patients were therefore ineligible, but did enter the intention-to-treat analysis.
The analysis was planned for after 214 or more recurrences had occurred, but a subsequent audit confirmed only 149 of these recurrences, so 17 months of unaudited data were added. Exploratory subset analyses showed fewer recurrences with vitespen in patients with stage 1 and 2 cancers. This finding did not reach statistical significance (19 vitespen patients vs 31 observation patients; hazard ratio, 0.58; 95% confidence interval, 0.32–1.02).
The results are disappointing after phase 2 data showed that patients who received vitespen seemed to be doing better than historic controls. "As with virtually every cancer vaccine, there was also no important toxicity, which made it easier to accept any implication of efficacy," Dr. Yang added.
"A challenge of future trials of adjuvant agents — especially immunotherapies," Dr. Wood and his team note, "will be how to efficiently incorporate an objective, more reliable determination of disease response earlier in the data-collection process." Lack of established surrogate markers, such as immune response, they note, makes the difficulty of establishing the efficacy of an adjuvant immunotherapy even more formidable and merits continued research.
The study was funded by Antigenics Inc.
Lancet. Published online before print July 4, 2008.
Medscape Medical News © 2008 Medscape
Cite this: Vaccine Shows No Benefit in Renal Cell Carcinoma - Medscape - Jul 07, 2008.
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