ODAC Rejects Temodal for Use in Advanced Melanoma

BETHESDA, Md—The Oncology Drugs Advisory Committee (ODAC) has voted not to recommend that the FDA approve Temodal (temozolomide, Schering) for the first-line treatment of patients with metastatic malignant melanoma. The 10 to 0 vote, with one member abstaining, followed a spirited discussion in which committee members not only questioned the value of Temodal in advanced melanoma, but also that of DTIC-Dome (dacarbazine, Bayer), which the FDA approved in 1975 for treating the disease.

In early January, the same committee recommended that the FDA grant accelerated approval to Temodal for the treatment of recurrent anaplastic astrocytoma.

In its quest to expand Temodal’s approval to advanced melanoma, Schering presented data from one randomized clinical trial that compared the drug to DTIC-Dome in 305 patients treated at 34 sites in 14 countries. None of the treatment centers were in the United States. Temo-dal is essentially an analog of dacarbazine. However, it can be given orally, while DTIC requires IV administration.

“We recognize that Temodal is not a breakthrough in the treatment of metastatic melanoma,” said Colin Turnbull, PhD, Schering’s vice president for Oncology Clinical Research. However, the company argued that Temodal’s equivalent effectiveness to DTIC, its safety profile, and its ease of administration made the drug approvable.

Six-month median survival was 7.7 months among the 156 Temodal-treated patients vs 6.4 months for the 149 DTIC-treated patients (P = .2). The Temodal group had 4 complete and 17 partial responders vs 4 complete and 14 partial responders in the DTIC group (P = .7), according to the company’s analysis.

The FDA reviewers, however, reported 4 complete and 15 partial responders among Temodal recipients, compared to 4 complete and 10 partial responders among those who got DTIC (P = .43). Among responders, the median response duration was 5.53 months in the Temodal group vs 3.22 months in the DTIC patients.

Overall survival in the 305 patients was the study’s primary endpoint. According to Schering, 13 patients in the Temodal group were alive at 2 years, compared with 5 patients in the DTIC group. The company also reported that among responders, 19 in the Temodal group were alive at 12 months; 15 at 18 months; and 13 at 24 months. In the DTIC group, 13 responders were alive at 12 months; 10 at 18 months; and 5 at 24 months.

“The problem is that equivalence of temozolomide to dacarbazine in survival does not demonstrate temozolomide’s efficacy (effect on survival) because dacarbazine has not been shown to have any effect on survival in advanced, metastatic malignant melanoma,” an FDA staff document noted.

ODAC members agreed. “I don’t think the results of this study demonstrate that temozolomide has been shown to be an effective drug in this disease,” said David H. Johnson, MD, director of medical oncology at Vanderbilt University.

The Schering-sponsored study was designed to demonstrate the superiority of Temodal to DTIC. Its failure to do so weighed heavily in the ODAC discussions. Several committee members suggested that the problem really lay with DTIC, which they viewed as ineffective against metastatic melanoma despite its nearly quarter century on the market.

“We have the opportunity to say that in 1975 an error was made,” said Derek Raghavan, MD, PhD, associate director of the University of Southern California’s Norris Comprehensive Cancer Center. “Patients with melanoma deserve effective treatment. They don’t deserve ineffective treatment, and that’s probably what DTIC is.”