Adding the investigational agent ixabepilone to capecitabine (Xeloda) resulted in a significant improvement in progression-free survival (PFS), compared with capecitabine alone
ASCOAdding the investigational agent ixabepilone to capecitabine (Xeloda) resulted in a significant improvement in progression-free survival (PFS), compared with capecitabine alone, Linda Vahdat, MD, of Weill Cornell Medical College, New York, reported at the American Society of Clinical Oncology 2007 meeting (abstract 1006). The study included 752 patients with metastatic or locally advanced breast cancer resistant to anthracyclines and taxanes.
Larry Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs, Memorial Sloan-Kettering Cancer Center, told ONI, "I think this is one of the more interesting studies presented at ASCO this year. It appears that ixabepilone is helping a population of patients who are not responding to capecitabine."
Ixabepilone is a semisynthetic analog of epothilone B. Epothilones and their analogs are a potential new class of antineoplastic agents. They have low susceptibility to tumor resistance mechanisms and have shown preclinical synergy with capecitabine, Dr. Vahdat said.
Last month, FDA accepted Bristol-Myers Squibb's New Drug Application for ixabepilone and granted the NDA priority review, with a target action date of late October. The proposed indications are as monotherapy in advanced breast cancer after failure of an anthracycline, a taxane, and capecitabine, or with capecitabine after anthracycline and taxane failure.
In the open-label, multicenter, randomized phase III trial, patients received capecitabine 1,250 mg/m2 twice daily for 14 days every 3 weeks, or capecitabine 1,000 mg/m2 twice daily for 14 days plus ixabepilone 40 mg/m2 IV on day 1 every 3 weeks.
Dr. Vahdat pointed out that the patients represented a very heavily pretreated population. "Close to 40% of patients were receiving study treatment as their third-line therapy for metastatic breast cancer," she said. They also had a high disease burden, with most patients having at least two sites of disease and 84% having visceral metastases. "In addition, a quarter of the patients were ER, PR, and HER2 negative, the so-called triple negative phenotype," she said.
The combination more than doubled the response rate and reduced the risk of disease progression by 25%. By independent review, the response rates were 35% for the combination vs 14% for single-agent capecitabine (P < .0001). At a median follow-up of 2.5 years, by independent radiologic review, PFS was 5.8 months for the combination vs 4.2 months for capecitabine alone (P = .0003), Dr. Vahdat reported. The combination regimen improved PFS in all prespecified subsets, including the triple-negative patients. Overall survival data are not mature, she said.
As expected, grade 3-4 hematologic toxicities were more common in the combination arm, Dr. Vahdat said. Treatment-related deaths were observed in 12 patients on the combination arm, compared with 2 on the single-agent arm. Deaths on the combination arm were attributed to neutropenia, and most occurred in patients with underlying liver disease. The protocol was therefore amended during the study to exclude patients with grade 2 or higher liver dysfunction.
The main grade 3-4 nonhematologic adverse event was peripheral neuropathy, which occurred in 23% of patients receiving the combination therapy regimen and in no patients on the single agent. Grade 3-4 neuropathy was cumulative and reversible, typically resolving within 6 weeks, Dr. Vahdat reported. She pointed out that the addition of ixabepilone did not exacerbate typical capecitabine-associated toxicities, including hand-foot syndrome, diarrhea, and mucositis.
Discussant for the abstract, Luca Gianni, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, said that ixabepilone shows "good activity across trials" and "has the potential to widen the treatment choices for metastatic breast cancer." He noted that the 2,500 mg/m2 daily dose of capecitabine was higher than most clinicians use, and said the dose may have been a factor in the "excessive" toxic deaths seen in the combination arm. "I think the future of ixabepilone will be determined by studies showing comparative efficacy with taxanes in the metastatic and adjuvant settings," he said.