SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13-1 that the investigational agent ridaforolimus did not have a favorable risk-benefit profile when used as maintenance therapy in patients with metastatic soft-tissue or bone sarcomas that had stabilized with chemotherapy.
Members of the FDA’s Oncologic Drugs Advisory Committee cited the marginal effect on progression-free survival and the toxicity profile associated with the drug in a phase III clinical trial reviewed at a meeting on March 20.
While several panelists noted the need for such a treatment, ODAC’s chair, Dr. Wyndham H. Wilson, pointed out that patients are exposed for a longer period of time when a drug is approved as maintenance therapy. Therefore, the data showing benefit have to be more robust than do the data supporting use in a treatment setting, and the drug should be "reasonably well tolerated," said Dr. Wilson, chief of the lymphoma therapeutics section at the National Cancer Institute, Bethesda, Md.
Manufacturer Merck Sharp & Dohme Corp. has proposed that ridaforolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), be approved as a maintenance treatment at a dose of 40 mg daily for 5 days of the week.
The study involved 711 patients with metastatic soft-tissue sarcoma (STS) or bone sarcoma that had not progressed after at least four cycles of chemotherapy. Their median age was 53 years; 12 patients were aged 12-17 years. Most (90%) had soft-tissue sarcomas; the rest had bone sarcomas. About two-thirds of the tumors were high grade. About half the patients were in the United States.
Median progression-free survival, the primary end point, reached 17.7 weeks among those on ridaforolimus, compared with 14.6 weeks among those on placebo – a statistically significant difference that represented a reduced risk of 28% of disease progression or death, according to Merck’s analysis.
Overall survival was 91 weeks with ridaforolimus vs. 85 weeks with placebo. This was not significantly different, but the study was not powered to evaluate overall survival.
The safety profile was similar to the safety profile with other mTOR inhibitors, and there were more grade 3/4 adverse events among patients on ridaforolimus (64% vs. 25% on placebo). In all, 14% of those on ridaforolimus discontinued treatment, compared with 2% of those on placebo.
Grade 3/4 stomatitis (12% vs. 1%) and hyperglycemia (13% vs. 2%) were more common with ridaforolimus. There were also more cases of interstitial pneumonitis and renal failure.
Among the main issues raised by the FDA reviewers were that the clinical importance of the statistically significant improvement in progression-free survival was unclear, maintenance treatment did not lead to longer overall survival, and adverse events were a concern for a maintenance treatment in patients with stable disease. The panel agreed with the FDA reviewers.
To date, the FDA has approved three agents as maintenance therapy in patients with cancer: pemetrexed (Alimta) in nonsquamous non–small cell lung cancer (NSCLC), erlotinib (Tarceva) for NSCLC, and rituximab (Rituxan), for non-Hodgkin’s lymphoma. No drug has been approved for maintenance therapy in patients with sarcoma.
If approved, Merck plans to market ridaforolimus as Taltorvic; it is also being studied for various types of solid-tissue cancers, including lung, breast, endometrial, and ovarian cancer, according to the company.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.
Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in this meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.