Advisory Committee Recommends Against Approval of Two New Cancer Drugs
An advisory committee to the U.S. Food and Drug Administration (FDA) last week recommended against the approval of two drugs for the treatment of advanced melanoma and brain metastases, respectively. In both cases, the drugs' manufacturers had submitted applications for FDA approval of their products based on the results of a single phase III clinical trial in which the drug did not achieve the trial's primary endpoint.
During its May 3 meeting, the FDA Oncologic Drugs Advisory Committee reviewed data on efaproxiral (RSR13), a "radiation sensitizer" intended to be used as an adjunct to radiation therapy to make it more effective, and oblimersen (Genasense), part of a new class of "antisense" drugs thought to inhibit the production of proteins that protect cancer cells from treatments like radiotherapy and chemotherapy.
Efaproxiral was being considered as an adjunct to whole brain radiation therapy (WBRT) for brain metastases in patients with breast cancer. Approximately 20-30 percent of breast cancer patients develop brain metastases. In a 538-patient, randomized, open-label trial, the combination of WBRT and efaproxiral failed to improve overall survival compared to WBRT alone. A subgroup analysis not called for in the original trial design, however, found that the WBRT/efaproxiral combination nearly doubled the median survival rate of breast cancer patients with brain metastases compared to WBRT alone (8.67 vs. 4.57 months).
In its own review, the FDA argued that the subgroup analysis was prone to false-positive results. The committee appeared to agree, voting 16-1 that the data presented "did not constitute substantial evidence of efficacy." In February, Allos Therapeutics launched a similar phase III trial, but with breast cancer patients as the intent-to-treat group. The committee agreed that replication of the first trial's results in this subsequent trial would likely smooth the path to FDA approval.
With oblimersen, the committee was again faced with data from a phase III trial that failed to meet its primary endpoint of improvement in overall survival. In a 771-patient trial, patients with advanced metastatic melanoma were treated with dacarbazine (a standard chemotherapy agent) and oblimersen, or dacarbazine alone. New treatments for advanced melanoma have been sparse, yet they are desperately needed. Advanced melanoma is the most lethal form of skin cancer and melanoma incidence has increased more rapidly than any other cancer, more than doubling in the last 30 years.
Although the oblimersen/dacarbazine combination did not improve overall survival compared with dacarbazine alone, it did appear to improve progression-free survival (74 days vs. 49 days) and the antitumor response (11.7 percent vs. 6.8 percent). Based on that and other data, the committee voted 11-5 that the combination had a real effect on response rates.
However, again agreeing with the FDA assessment, committee members felt that the data may not be providing an accurate picture. Committee members questioned the differences in patients' assessment schedules to measure progression-free survival and the process by which tumor response analysis was conducted, both of which could have significantly biased the results. As a result, by a 13-3 margin, the committee voted that the data presented could not be considered substantial evidence of effectiveness.
According to Dr. James Zwiebel, of the National Cancer Institute's Cancer Therapy Evaluation Program, NCI is currently sponsoring 18 studies of oblimersen to treat a variety of both solid and hematologic malignancies. In addition, results from two pivotal phase III trials of oblimersen that Genta has sponsored, in chronic lymphocytic leukemia and multiple myeloma, are anticipated by the end of year. NCI is also sponsoring a phase I/II study of efaproxiral in patients with progressive or recurrent high-grade gliomas.