The FDA’s Oncologic Drugs Advisory Committee (ODAC) has recommended the approval of pazopanib (Votrient, GlaxoSmithKline) but ruled against the agent ridaforolimus (Taltorvic, Merck) to treat sarcoma, a rare cancer that occurs in the bones and soft tissue.
The advisory panel voted 11 to 2 in favor of recommending the approval of pazopanib and 13 to1 against ridaforolimus. The vote for pazopanib arrived despite concerns that clinical trials did not demonstrate prolonged overall survival (OS), while the vote against ridaforolimus was based on concerns that the benefits did not outweigh the risks.
“Treatment options for patients with advanced soft tissue sarcoma are limited; we are therefore pleased that the committee took a favorable view of the clinical data for Votrient,” said Rafael Amado, senior vice president, GlaxoSmithKline Oncology, in a statement. “We look forward to continuing the regulatory process.”
The positive vote for pazopanib was based largely on the results of a phase III clinical trial, VEG110727. In that trial, patients in the pazopanib arm had significantly higher progression-free survival (PFS) compared with patients in the placebo arm. PFS in the pazopanib arm was 4.6 months, compared with 1.6 months in the placebo arm, with a hazard ratio (HR) of 0.35 (95% CI, .26-.48; P
However, there was no statistically significant difference in OS between the 2 arms. In the final analysis, median OS in the pazopanib arm was 12.6 months (95% CI, 10.9-14.9) compared with 10.7 months in the placebo arm (95% CI, 9.0, 13.1) with a HR of 0.87 (95% CI, 0.67-1.12; P
Additionally, a number of serious adverse events were linked to pazopanib. A total of 34 patients (14%) in the pazopanib arm discontinued the drug due to toxicity, compared to 1 patient (1%) in the placebo arm. Among the pazopanib-treated patients who discontinued due to drug-related toxicity, the most common reasons were liver toxicity, hemorrhagic events, hypertension, proteinuria, and myocardial dysfunction.
Ridaforolimus was investigated as a maintenance therapy in the phase III P011 trial, which served as the main basis for the ODAC decision. Patients that had achieved a complete response, partial response, or stable disease after 4-12 cycles of chemotherapy were enrolled in the study.
The median time of PFS in the ridaforolimus arm was 16.1 weeks compared to 14 weeks in the placebo arm (P
= .0006). The median OS for patients who received ridaforolimus was 20.8 months compared to 19.6 months in patients who had received the placebo, which the authors did not consider to be statistically significant.
Stomatitis occurred in 82% of patients in the ridaforolimus arm, and approximately half of the patients discontinued therapy due to side effects. The side effect profile and high levels of discontinuation prompted the panel to vote against approving the agent.
"Merck remains confident in the potential of the investigational agent ridaforolimus for an indication where patients have limited options," said Eric Rubin, MD, vice president, Clinical Research Oncology at Merck, in a press release. "We remain committed to bringing forward this promising therapy for patients with metastatic sarcoma, and look forward to further discussions with the FDA regarding this application."
The FDA is scheduled to make a decision on pazopanib no later than May 6, 2012. The action date for ridaforolimus is slated for June 5, 2012. While the regulatory agency is not required to follow ODAC recommendations the panel’s decision plays a role in determining a drug’s eligibility for approval.
According to the National Cancer Institute, an estimated 11,280 new cases of adult soft tissue sarcoma are expected in 2012. Approximately 3900 patients will die from the disease this year. Lower grade tumors can usually be cured through surgery, but higher-grade tumors often result in local treatment failure and an increased risk of the tumor becoming metastatic.
The FDA previously approved Pazopanib in 2009 to treat patients with renal cell carcinoma.