BETHESDA, MdThe 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
In its quest to expand Temodals 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,
Scherings vice president for Oncology Clinical Research.
However, the company argued that Temodals 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 companys 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 studys 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 temozolomides 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 dont 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 Californias Norris Comprehensive Cancer
Center. Patients with melanoma deserve effective treatment.
They dont deserve ineffective treatment, and thats
probably what DTIC is.