Vaccine Therapy Disappoints for Kidney Cancer

By Crystal Phend
HOUSTON, 5 july 2008-- The tumor-derived vaccine vitespen (Oncophage) does not prevent renal-cell carcinoma recurrence or improve survival despite promising early results, researchers said.
The combined rate of recurrence and death was similar through almost two years of follow-up in nephrectomy patients given the autologous vaccine as adjuvant therapy compared with observation (37.7% versus 39.8%, P=0.506), reported Christopher Wood, M.D., of the University of Texas M.D. Anderson Cancer Center here, and colleagues online in The Lancet.
After an additional 17 months of follow-up in the randomized phase III trial, survival still showed no improvement with the vaccine against peptide-bound heat-shock protein purified from patients' tumors (P=0.896).
An exploratory analysis of early-stage kidney cancer patients (stage I or II disease) had signaled a possible reduction in recurrence with the vaccine (15.2% versus 27%, hazard ratio 0.576, P=0.056), which the researchers said would require further validation.
However, in an accompanying editorial, James C. Yang, M.D., of the National Cancer Institute in Bethesda, Md., criticized such "use of post-hoc subset analyses to salvage underpowered studies." He criticized the study and the sponsoring company for conduct that included differences between the published results and those reported in a company press release.
A press release from Antigenics, the manufacturer of vitespen, on April 8, 2008 highlighted "a clinically significant improvement in recurrence-free survival of approximately 45% over patients in the observation arm" among the intermediate-risk patients.
But, Dr. Yang wrote, the company did not point out that this was not a prespecified analysis nor was a further subset analysis of 25th percentile data mentioned in the release.
"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 said.
A spokesperson for the company called these comments inaccurate and inapppropriate. "We've been fully transparent with the data," he said.
He noted that the press release discussed more up-to-date data than those appearing in The Lancet. Longer follow-up yielded stronger, significant P-values in findings filed in a regulatory submission that led to approval for intermediate-stage kidney cancer in Russia, he said.
While acknowledging caution with non-prespecified endpoints, such as survival at the 25th percentile, "it gives you the sense the patients are trending in the right direction," the spokesperson said.
On the basis of signals of clinical activity and tumor-specific immune responses in phase I and II trials in renal-cell carcinoma and other cancer as well as a phase III study in melanoma, vitespen looked promising for the phase III trial in renal cell cancer.
The intent-to-treat analysis of the open-label trial included 728 patients in North America, Europe, Russia, and Israel.
Patients were randomized to observation after surgery or treatment with vitespen intended to start within eight weeks of surgery. The vaccine was given at a dose of 25 μg intradermally once a week for four weeks, then every two weeks until vaccine supply depletion or disease progression for a total of 12 injections on average.
However, the trial stumbled early on, with more than 40% of the reported events that triggered the final analysis on Nov. 4, 2005 rejected by the adjudication committee as not being true events of recurrence.
A total of 124 patients had remaining disease at baseline after surgery rendering them ineligible for the trial. And of these, 92 were reported to have disease recurrence whereas they actually had disease progression.
The researchers cautioned that their finding of a nonstatistically significant reduction in recurrence events among patients with stage I or II kidney cancer with vitespen, while in a prespecified analysis, could have been a result of statistical noise resulting from the small sample size of patients with more advanced cancer.
"Nonetheless, the observation that treatment with vitespen confers an apparent clinical benefit to patients with earlier stage disease with better prognosis is biologically plausible," they said.
Later-stage tumors have more mechanisms to resist immunotherapy, they noted. "Additional research is thus warranted to further explore the use of vitespen in patients with early stage renal cell carcinoma."
Although the lack of treatment-related grade 3 or 4 adverse events makes it easier to accept any implication of efficacy, Dr. Yang warned that "commercially driven efforts that spin or obfuscate the conclusions of such a trial should be vigorously resisted because such efforts severely erode its value."
The study was funded by Antigenics of New York.
Dr. Woods and several co-authors reported consulting for and receiving honoraria from Antigenics. Co-authors reported other conflicts of interest for Antigenics, including employment, founding the company, and owning stock in the company.
Dr. Yang reported no conflicts of interest.
Primary source: The LancetSource reference:Wood C, et al "An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial" Lancet 2008. Additional source: The LancetSource reference: Yang JC "Vitespen: a vaccine for renal cancer?" Lancet 2008.