SILVER SPRING, Md—The Oncologic Drugs Advisory Committee (ODAC) unanimously recommended that the FDA approve Taxol (paclitaxel for injection, Bristol-Myers Squibb) for use in the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin(Drug information on doxorubicin)-based combination therapy.
The major issue in the panel’s debate centered on whether to exclude estrogen- and progesterone(Drug information on progesterone)-receptor-positive patients from the indication. Such women gained no benefit from Taxol in the large, single study presented by Bristol-Myers Squibb to support its application.
Taxol was first approved in the United States in late 1992 for the second-line treatment of ovarian cancer. It has since won approval for use in breast cancer after failure of combination chemotherapy for metastatic disease; for the first-line treatment of ovarian cancer in combination with cisplatin(Drug information on cisplatin) (Platinol); for the second-line treatment of AIDS-related Kaposi’s sarcoma; and in combination with cisplatin for the first-line treatment of non-small-cell lung cancer.
To support its new application, Bristol-Myers Squibb presented data from a randomized phase III study involving 3,170 women enrolled between May 1, 1994, and April 15, 1997. The study was coordinated by the Cancer and Leukemia Group B, with participation by the Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group.
The company called the study “the largest adjuvant breast cancer study ever conducted” and said the results constitute “a major advance similar to that seen nearly 30 years ago when it was discovered that combination chemotherapy after surgery improved breast cancer survival compared to surgery alone.”
The study’s aim was to assess the effects of three doxorubicin doses (60, 75, and 90 mg/m²) in combination with a fixed dose of cyclophosphamide(Drug information on cyclophosphamide) (600 mg/m²) and to assess the effects of the sequential addition of Taxol (4 courses at 175 mg/m² over 3 hours).
Women were randomized to one of the three doxorubicin doses and then either to Taxol therapy (1,570) or no Taxol (1,551). All women with hormone-receptor-positive tumors were to receive 5 years of tamoxifen(Drug information on tamoxifen) (Nolvadex) therapy after completing chemotherapy.
The study’s primary endpoint was disease-free survival. The separate analyses presented by the company and by an FDA review team were in close agreement regarding the results. The FDA review found that 624 relapses occurred within 3 years among the 3,121 women included in the trial results.
At 3 years, 76.6% of the Taxol-treated women were disease-free, compared with 73.0% of the control group, a statistically significant difference of 3.6%. Among receptor-negative women, 67.3% of the Taxol group were disease free, compared with 56.8% in control group, a statistically significant difference of 10.5%.
However, among receptor-positive women, 81.2% of the Taxol group and 81.6% of controls were disease free at 3 years, and among receptor-positive women who received tamoxifen, 81.9% of Taxol patients and 82.7% of controls were disease free at 3 years. Neither of these two findings regarding receptor-positive women was statistically significant.
These data “provide little justification for believing that Taxol sequential [to doxorubicin and cyclophosphamide] confers added benefit to patients with ER-positive and/or PR-positive tumors,” said FDA reviewer James O’Leary, MD.
In its analysis of receptor-positive women, the company presented disease-free survival at 3 yearly intervals. At 1 year, 97.7% of the Taxol group and 94.5% of the control group were disease free. At 2 years, the Taxol group still had an advantage, 89.6% vs 87.7%, but at 3 years, 81.5% of both groups were disease free.
“Six percent of the women in the study were age 65 or older, and there was no difference in results between patients over age 65 and those under age 65,” said Renzo Canetta, MD, vice president for clinical oncology at Bristol-Myers Squibb.
Although the company said the study revealed no toxicity problems that had not been observed in previous Taxol trials, the FDA emphasized that Taxol therapy poses a risk of serious toxicity. “At least two deaths [in the study] were attributed to Taxol,” the FDA noted. During Taxol treatment, 15% of patients experienced grade 4 neutropenia, 15% grade 2-3 neurosensory toxicity, 23% grade 2-3 myalgias, and 46% alopecia.
Much of the ODAC discussion focused on whether, given the efficacy findings and the safety risks associated with Taxol use, women with hormone-receptor-positive tumors should be excluded from the indication. Members debated the details of the data on the receptor-positive women and the reliability of using subset analyses in making their decision.
At one point, Larry Norton, MD, of Memorial Sloan-Kettering, serving as a sponsor consultant, said: “I think there is a danger that people who could potentially benefit from Taxol may end up not getting it, depending on what the committee does. It would be a very bad thing if that happens.” The company said that about 40% of the 180,000 women diagnosed annually with breast cancer would be candidates for the adjuvant therapy.
In the end, the committee decided against excluding women with receptor-positive tumors. Derek Raghavan, MD, PhD, of the University of Southern California, said the discussion had persuaded him that “the damage we would do by withholding the drug with the knowledge base we have is more than the damage we would do by letting it through.”
The panel did, however, advise the FDA that, if it approved the new indication, it should highlight the findings regarding receptor-negative and receptor-positive tumors in the clinical studies section of the package labeling and specifically refer physicians to that data in the indications section.
