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ICI’s NOLVADEX (TAMOXIFEN) SHOULD BE INDICATED FOR ADVANCED MALE BREAST CANCER BUT NOT AS ADJUVANT THERAPY IN MEN, ONCOLOGICS ADVISORY CMTE. CONCLUDES

Executive Summary

ICI Pharmaceuticals' Nolvadex (tamoxifen) should be approved as a treatment for advanced metastatic breast cancer in men but should not be indicated as adjuvant therapy based on available data, FDA's Oncologic Drugs Advisory Committee recommended Nov. 16. The male breast cancer indication covers a small patient population. The American Cancer Society estimates that there will be 1,000 new cases of breast cancer diagnosed in men in the U.S. this year, compared to 180,000 new cases in women. Tamoxifen is already indicated as adjuvant therapy for breast cancer in women and as a single therapy against advanced metastatic breast cancer in women. The committee voted 10-to-zero, with one abstention, for approval of Nolvadex for use in advanced disease. The recommendation was based largely on the database available for tamoxifen use in women breast cancer patients and a belief that the disease is the same for men and women. Committee member Harold Harvey, MD, University Hospital, Hershey, Pa., said that "endocrinologically and biologically, the diseases are the same." He pointed to data in men on "the pattern of failure, the patterns of recurrence, the natural history, the sequential responses to [additive and ablative] hormonal therapies, the [tamoxifen] flare in a few cases: in every instance the one disease behaves exactly as the other." In addition to believing the disease is the same in the two patient populations, in the case of tamoxifen "what we have is some data to suggest that we have an approximately appropriate dose [that] will provide some efficacy...and some reasonable assurance [there is] no large change in the toxicity profile," Burke said. "Although the database is less than ideal, it does appear that tamoxifen can produce objective responses in men with metastatic breast cancer," committee member James Ingle, MD, Mayo Clinic, noted. Data on tamoxifen use in men submitted by ICI consisted of 16 case reports submitted to the company; 24 case reports from Christy Hospital, Manchester, England, published by Ribeiro et al. in 1988; and 98 additional published cases. "If this were an NDA for a new molecular entity in this small population of males treated with breast cancer I don't think we'd even be here discussing this. We are basically relying on what we do know about the database on tamoxifen in general," FDA Oncology & Pulmonary Drug Products Division Director Gregory Burke, MD/PhD, told the group. ICI submitted the supplemental application (SNDA 17-970) for male breast cancer in April. For the advanced disease indication, Ingle noted, "if you look at the ICI case report forms, at least...there are three well- documented responses where the case report forms have been reviewed and the supporting material has been corroborated. The Ribeiro series is large and certainly does report responses on the order of what we'd expect from what I think many would consider to be the standard, which is orchiectomy [removal of one or both testes]." The tamoxifen response rate reported by ICI in 35 Ribeiro patients was 40%, compared to a response rate of about 50% for orchiectomy reported by ICI consultant Aman Buzdar, MD, M.D. Anderson Cancer Center. Ingle pointed out that tamoxifen acceptability among male patients is "substantially better" than orchiectomy. The committee voted unanimously not to recommend approval of tamoxifen for adjuvant therapy in male patients. "There is clearly insufficient scientific basis...to include tamoxifen in the adjuvant area," Ingle stated. Data submitted for the adjuvant indication -- the delaying of breast cancer recurrence after mastectomy and radiotherapy in men with axillary node-positive breast cancer -- included six ICI case reports and 39 cases reported in a historically-controlled study by Ribeiro et al. published earlier this year. The study compared five-year, disease-free survival of 39 patients treated with tamoxifen as adjuvant therapy beginning between 1976 and 1988 to 130 patients treated only with mastectomy and breast irradiation between 1942 and 1975. "The concerns of such comparisons with historical controls are well recognized and in this instance could include factors such as variation in disease stage in the presentation, changes in surgical technique and nature of radiotherapy over time apart from the use of adjuvant therapy," Ian Jackson, MD, ICI medical affairs department, conceded. The committee felt these factors confounded the data. Committee member Steven Piantadosi, MD/PhD, Johns Hopkins Oncology Center, noted that even if a multivariant analysis of the data were undertaken, the number of patients was not great enough to reach significance with survival as an endpoint. Ingle pointed out that "many of the similarities -- high level of estrogen receptor, benefit in the adjuvant setting in women -- have led many clinicians to offer [tamoxifen] to [male] patients. On the other hand, I don't think that I'm ready to vote to have it included as an indication."
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