BURROUGHS WELLCOME’s ALKERAN I.V. STUDIES DO NOT SUPPORT EFFICACY AS MELANOMA SURGERY ADJUNCT -- ADVISORY COMMITTEE; LIMITED USE IN MYELOMA OKAYED

Burroughs Wellcome's studies for Alkeran (melphalan) are not supportive of the alkylating agent's efficacy in hyperthermic isolated-limb perfusion as an adjunct to surgery for locally- advanced malignant melanoma of the extremities, FDA's Oncologic Drugs Advisory Committee decided Jan. 31. The committee had difficulty with the two studies presented by Burroughs Wellcome due to the small numbers of patients involved and the fact that they were evaluated retrospectively. The company said a retrospective analysis was necessary because not enough melanoma patients are available for prospective trials. The NDA (20-207) was filed in July 1991. Committee member David Ahmann, MD, Mayo Medical School, Rochester, Minn., said: "I really personally don't feel that the evidence suggests that this is compelling." He added: "I don't think it has been shown that [there is] long-term benefit, and there are some unpleasant side effects" from Alkeran. Discussing one of the two studies, committee reviewer Charles Schiffer, MD, University of Maryland Cancer Center, Baltimore, said: "I think the retrospective study unfortunately really doesn't give us any compelling advice as to how to move on this." The retrospective, U.S. cohort-controlled study compared 152 stage III patients regionally perfused with melphalan or a combination of drugs including melphalan to 142 nonperfused control patients after surgical incision. In its questions to the committee, FDA noted that overall survival in both groups was similar and that "overall there was no significant difference in time to progression" of the disease. The second study was a prospective, randomized trial conducted by Prof. Ghussen at the University of Cologne that compared melphalan injection to no treatment following surgery in patients with stage I, II and III/IV melanoma. The trial, conducted from 1980-83, involved 107 evaluable patients. In the question handout, FDA noted that the trial "when properly randomized, shows no significant difference in survival or time to systemic metastases between the group randomized to initial perfusion versus the group randomized to no initial perfusion." "Time to recurrence was significantly different (two-sided p values: all stages [of melanoma], p < 0.001; stage I, p = 0.02, stage II, p < 0.01, and stage III/IV, p = 0.07)," FDA stated in the question handout. However, the committee could not decide whether time to recurrence was a sufficient endpoint for approval. FDA reviewer Grant Williams, MD, Division of Oncology and Pulmonary Drugs, said "I think the quality of the data we have is not very good and I don't consider it reliable by our usual standards." However, Williams pointed out that he considers it "likely that [melphalan] works, that you do get responses here." Committee reviewer Nancy Kemeny, MD, Memorial Sloan-Kettering Cancer Center, stated that she "would like to see a larger study and I don't know why a larger randomized study can't be done. I think using retrospective studies in this day and age is really bad." She suggested that Australia could provide a sufficient pool of patients for such a study due to the high rates of melanoma in that country. FDA's Williams noted that the World Health Organization is sponsoring an ongoing stage I adjuvant trial in 700 patients. Burroughs Wellcome was also seeking approval of Alkeran injection as a palliative treatment of multiple myeloma. Alkeran already is approved in tablet form for the palliative treatment of multiple myeloma and palliation of nonresectable epithelial ovarian cancer. The injectable formulation can offer more dependable bioavailability than the tablets, the company indicated. In a five-to-four vote, the committee determined that there was sufficient evidence of safety and efficacy of the injectable formulation to justify approval for its use in myeloma when oral medications are not indicated. The committee voted unanimously against approving I.V. Alkeran for first-line therapy of myeloma, because the data did not show that the injectable and oral form of the drug have equivalent efficacy and because the injectable caused hypersensitivity.