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Ixabepilone, a member of a new class of cytotoxic drugs called epothilones, significantly improved progression-free survival and overall response rates when combined with capecitabine in a randomized, phase III trial in patients with chemotherapy-resistant metastatic breast cancer.
Compared with capecitabine (Xeloda) alone, the combination increased progression-free survival from 4.2 months to 5.8 months—a highly significant difference with a P value of .0003, said Dr. Linda T. Vahdat of Weill Cornell Medical College in New York. She reported having no significant financial relationships to disclose.
Overall response, a combination of complete and partial response rates, was nearly 2.5 times as great in the combination arm: 35% vs. 11% with capecitabine alone. This difference, too, was highly significant (P = .0001).
The international open-label trial enrolled 752 women with metastatic or locally advanced breast cancer resistant to anthracyclines and taxanes. Virtually all subgroups benefited, including patients with visceral disease and those who were "triple negative" with estrogen receptor-negative, progesterone receptor-negative, and HER2-negative tumors, Dr. Vahdat said.
Shortly afterward, trial sponsor Bristol-Myers Squibb announced that the U.S. Food and Drug Administration had accepted its new drug application for filing and review of ixabepilone (BMS247550). The company described the proposed indications as "a monotherapy to treat patients with metastatic or locally advanced breast cancer after failure of an anthracycline, a taxane, and capecitabine and in combination with capecitabine to treat patients with metastatic or locally advanced breast cancer after failure of an anthracycline and a taxane." The company said that the FDA had granted a priority review with an action date in late October.
Ixabepilone, an analogue of epothilone B, is designed to interfere with cell division by inhibiting microtubule function. It is also under study in other cancers. "It is attractive because it has low susceptibility to tumor-resistance mechanisms," Dr. Vahdat said.
The phase III trial randomized 375 women to ixabepilone plus capecitabine and 377 to capecitabine alone. All patients met a strict definition of tumor progression in the adjuvant or metastatic setting after they received both anthracyclines and taxanes. Exclusion criteria included more than three prior chemotherapy regimens, grade 2 or greater motor/sensory neuropathy, reduced hematologic function, and brain metastases. The protocol was amended to exclude patients with poor liver function because of hepatic toxicity that emerged during the trial.
Dr. Vahdat emphasized that the population was "very heavily pretreated" and had a high disease burden. Most patients had received one or two prior metastatic chemotherapy regimens. About 90% had two or more disease sites, and 84% had visceral metastases in the liver and/or lung.
Patients in the combination arm received 40 mg/m² of ixabepilone intravenously over 3 hours on day 1 of a 3-week cycle and 2,000 mg/m² of capecitabine orally in two divided doses on days 1-14 of the same cycle. Women randomized to capecitabine alone received 2,500 mg/m² orally in two divided doses on the same schedule.
Dr. Vahdat reported 35 deaths in the combination arm and 39 with capecitabine alone. Of these, 12 and 2, respectively, were attributed to neutropenia. Grade 3 and 4 toxicities were much more common in the combination arm, most notably for neutropenia and leukopenia. "As expected, 20% of patients ended up on growth factors," she said.
Peripheral neuropathy stood out among nonhematologic toxicities, with 23% in the combination arm vs. none with capecitabine alone. Most grade 3 and 4 cases were cumulative and reversed in 6 weeks. After excluding patients with hepatic dysfunction, the safety profile was manageable, Dr. Vahdat said.
In a discussion of the trial, Dr. Luca Gianni suggested that some of the toxicity may have resulted from the capecitabine dose. "The dose of capecitabine matches the label but not clinical practice. It may be responsible for the deaths in the combination arm," said Dr. Gianni of the Istituto Nazionale dei Tumori in Milan. He predicted that ixabepilone's future will be linked to studies of comparative efficacy with taxanes in metastatic breast cancer and early breast cancer.
Vahdat L.T. et al. Phase III trial of ixabepilone plus capecitabine compared to capecitabine alone in patients with metastatic breast cancer (MBC) previously treated or resistant to an anthracycline and resistant to taxanes. Abstract 1006.
Commentary |
This is the first phase III trial demonstrating the benefit of combining an epothilone with another chemotherapy agent in patients with metastatic breast cancer. Ixabepilone, as a single agent, has been evaluated extensively in phase II trials in metastatic breast cancer patients, who had received varying numbers of prior chemotherapy regimens. These trials have been consistent in showing the antitumor activity of ixabepilone. Vahdat and coworkers demonstrated that adding ixabepilone to capecitabine modestly (in a clinical sense) improves the time until disease progression over what can be achieved with capecitabine alone. In contrast, the response rate was much greater with the combination, compared with single-agent capecitabine. The response rate in those patients receiving single-agent capecitabine is notable, however, regarding how low it is in comparison to other trials in which a similar patient population was treated with other agents. In addition, the side effects associated with ixabepilone stand out with respect to peripheral neuropathy (23% with the combination vs. 0% with capecitabine alone). These comments are not meant to diminish the results of this trial, but rather place the positioning of ixabepilone in perspective. The trial by Vahdat and coworkers will have its strongest impact as evidence for the FDA approval process. The real question will be how ixabepilone compares with any of the taxanes as treatment for metastatic breast cancer, both in terms of efficacy and tolerability. Evaluation of this drug in other combinations and earlier in the course of metastatic breast cancer will also be of interest. — William J. Gradishar, M.D.
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