ORLANDO, FL—The oral angiogenesis inhibitor pazopanib significantly reduced the risk of progression in patients with advanced and/or metastatic renal cell carcinoma, interim results of a Phase III trial show.
The early results also suggest that pazopanib may help to extend survival times compared with placebo, Cora N. Sternberg, MD, Chairman of Medical Oncology at San Camillo Forlanini Hospitals in Rome, reported here at the ASCO Annual Meeting.
During an oral presentation, Dr. Sternberg said that the investigational agent inhibits vascular endothelial growth-factor receptor, platelet-derived growth-factor receptor, and the cytokine receptor c-kit, and that clinical efficacy had been demonstrated in advanced renal cell carcinoma in a Phase II trial reported at the 2007 ASCO Annual Meeting by Thomas E. Hutson, DO, PharmD, et al.
The Phase III trial, funded by GlaxoSmithKline and conducted at 80 sites in 22 countries, enrolled 435 patients between April 2006 and April 2007, randomized in a two-to-one fashion to either 800 milligrams of pazopanib, once daily, or a matching placebo.
As of May 23, 2008, there was a significant, 54% reduction in the risk of progression—the trial's primary endpoint—in the pazopanib arm, compared with the placebo arm, Dr. Sternberg reported.
The median progression-free survival time was 9.2 months in the pazopanib arm, compared with 4.2 months in the placebo arm.
“The results were even more impressive when the analysis was restricted to [the 233] treatment-naïve patients,” she said. In these patients, the median time to progression was 11.1 months in the patients receiving pazopanib arm vs 2.8 months in the placebo arm, corresponding to a significant, 60% reduction in the risk of progression in the treatment arm.
In the 202 patients who had received a prior cytokine, the median time to progression was 7.4 months in the pazopanib arm vs 5.4 months in the placebo arm, for a 54% reduction in the risk of progression in the treatment arm.
Prespecified subgroup analyses showed that progression-free survival times were significantly longer in pazopanib-treated patients, regardless of age, gender, performance status, or Memorial Sloan-Kettering Cancer Center risk category, Dr. Sternberg said.
The overall response rate was 30% in the pazopanib-treated patients vs 3% in those receiving placebo. As of the May 23, 2008 cutoff date, the median duration of response was 59 weeks.
As of that time, the median overall survival time was 21.1 months in the pazopanib arm vs 18.7 months in the placebo arm, corresponding to a 27% reduction in the risk of death in the treated arm.
“It should be noted that as of the cutoff date, 48% of placebo patients had crossed over to pazopanib because of progression,” Dr. Sternberg said.
The most common adverse effects associated with the new drug were diarrhea, hypertension, and hair color changes.
“The median exposure of pazopanib-treated patients was twice that of placebo, 7.4 vs 3.8 months. I personally have patients who are still on pazopanib after 120 weeks,” she added.
Overall, 33% of pazopanib-treated patients suffered Grade 3 events, compared with 14% of those getting placebo.
“What's extremely impressive is the low rate of myelosuppression,” which was less than 1% in terms of Grade 3 and 4 events in both arms, Dr. Sternberg said, adding that there were no difference in health-related quality-of-life between the two groups on three different scales.
Calling the talk an “elegant presentation,” study discussant Nicholas J. Vogelzang, MD (now with US Oncology in Las Vegas but until recently Head of the Genitourinary Cancer Program at the Nevada Cancer Institute) said that the improvement in progression-free survival times associated with pazopanib is “striking” and that the subgroup analyses are “impressive.”
“The tumor response rates are also very striking and similar to those associated with sunitinib,” he said. He noted that the two drugs are being compared in a Phase III trial. There is “no question that these are highly active agents,” Dr. Vogelzang said, adding that he expected pazopanib to be approved by the FDA.
IF + Bevacizumab
At the same session, two other teams of researchers reported results of Phase III trials showing that interferon plus bevacizumab did not significantly improve overall survival rates compared with treatment with interferon alone, in patients with advanced kidney cancer.
Noting that earlier results from the trials showed that the combination treatment was associated with an improvement in progression-free survival rates, Dr. Vogelzang, also the Discussant for those studies, said the overall survival analyses “left us a little bit disappointed.”
On the other hand, “we should not be unhappy,” as the findings speak to the “embarrassment of riches” when it comes to targeted agents for treating renal cell carcinoma, he said. “Overall survival may no longer be a valid endpoint,” since patients now have choices when their disease progresses and these subsequent therapies may increase overall survival.
“Since survival is a moving target, progression-free survival and toxicity may need to be the new endpoints,” he explained.
CALGB 90206 Trial
In the Cancer and Leukemia Group B 90206 study, 363 patients received interferon-alpha monotherapy and 369 received interferon-alpha plus bevacizumab.
As reported by Brian I. Rini, MD, of the Department of Solid Tumor Oncology and Associate Director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute, the median overall survival time was 18.3 months for patients receiving the combination, compared with 17.4 months for interferon alone, a difference that did not reach statistical significance.
In contrast, the median progression-free survival time was 8.4 months in the combination arm vs 4.9 months in the monotherapy arm, corresponding to a significant, 29% reduced risk of progression in the combination arm.
The response rate was 25.5% in the combination arm, compared with 13.1% in the monotherapy arm, also a significant difference.
Over half, 54%, of patients in the combination arm and 62% of those in the interferon arm received second-line treatments, largely consisting of VEGF-targeted therapy, Dr. Rini reported.
In patients well enough to receive second-line therapy, “survival times are impressive in both arms”—31.4 months and 26.8 months in the combination and monotherapy arms, respectively, he said.
In contrast, the median overall survival times of patients who did not receive second-line therapy were only about 13 and nine months, respectively. “Clearly the most robust overall survival is achieved in patients with favorable underlying disease biology who are able to receive subsequent therapy,” Dr. Rini said.
In the second study, known as AVOREN (Avastin for Renal Cell Cancer), funded by Hoffman LaRoche, 649 patients were randomized to bevacizumab plus interferon or placebo plus interferon.
As reported by Bernard J. Escudier, MD, Head of the Immunotherapy Unit at Institut Gustave Roussy in Villejuif, France, the median overall survival time was 23.3 months in the combination arm and 21.3 months in the interferon arm, a nonsignficant difference.
Again, the time to progression was significantly longer in the combination arm: 10.4 months vs 5.5 months in the interferon arm. The response rate was 31% in the bevacizumab arm vs 12% in interferon arm, also a significant difference.
A total of 55% of patients in the bevacizumab arm and 63% of patients in the interferon arm received subsequent therapy.
As in CALBG 90206, patients treated with subsequent therapy fared better, with overall survival times ranging from about 39 and 44 months in the bevacizumab arm and 31 to 40 months in the interferon arm, Dr. Escudier said.
“The observed overall results may have been influenced by subsequent anti-neoplastic therapy, which was not prespecified in the protocol and represents an uncontrolled element of the overall survival analysis.”