The addition of bevacizumab to ixabepilone could be a promising treatment strategy for a group of patients with cancer currently lacking therapeutic options, according to data presented during the virtual edition of the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer.1 In heavily pretreated patients with platinum-resistant or refractory ovarian cancer, the combination of bevacizumab plus ixabepilone significantly improved objective response rate, progression-free survival, and overall survival compared with single-agent ixabepilone. Results of the randomized phase II trial showed that 33% of patients responded to bevacizumab plus ixabepilone vs 8% of those given ixabepilone alone, and median progression-free survival more than doubled with the combination (5.5 vs 2.2 months; hazard ratio [HR] = 0.33).
Dana M. Roque, MD
“Weekly ixabepilone and biweekly bevacizumab is well tolerated and effective, even in the platinum-refractory setting,” said first author Dana M. Roque, MD, Assistant Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of Maryland School of Medicine.
Ixabepilone, an epothilone that functions as a microtubule-stabilizing agent, was approved in 2007 for the treatment of breast cancer, but it has shown activity in other disease sites, including prostate, pancreatic, lung, and gynecologic malignancies.2 It has also been studied by the Gynecologic Oncology Group in phase II settings for platinum-resistant ovarian cancer and in endometrial cancer as a second-line agent, with objective response rates of 12% to 15%.3,4
“Unfortunately, median overall survival in platinum/taxane-resistant ovarian cancer is only approximately 12 months,” said Dr. Roque. “It’s obvious that additional treatment strategies are warranted.”
Published in 2014, the AURELIA trial found that in patients treated with up to two prior regimens, the addition of bevacizumab to chemotherapy, which included investigators’ choice of pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan, improved progression-free survival from 3.4 to 6.7 months and objective response rates from 12.6% to 30.9%—but not overall survival.5
This phase II study randomly assigned 76 patients with recurrent or persistent platinum-resistant or refractory epithelial (nonmucinous) ovarian, fallopian tube, or primary peritoneal cancers at 2 U.S centers. Key additional eligibility criteria included measurable disease, tumor availability for immunohistochemistry, and prior receipt of at least three cycles of paclitaxel, but there was no limit on prior lines, including bevacizumab.
The study’s primary endpoint was progression-free survival. Secondary endpoints included overall survival, safety, and objective response rate.
Patients were stratified by prior receipt of bevacizumab as well as study site and were subsequently randomly assigned to receive ixabepilone monotherapy at 20 mg/m2 (on days 1, 8, and 15 of a 28-day cycle) or ixabepilone in conjunction with bevacizumab at 10 mg/kg (on days 1 and 15). Patients were evaluated for Response Evaluation Criteria in Solid Tumors response every two cycles. There was no crossover from the monotherapy arm to the combination-therapy arm.
Promising Efficacy in Heavily Pretreated Patients
As Dr. Roque reported, this was a heavily pretreated population, with approximately 50% of patients in both arms receiving more than three lines of prior treatment. Additionally, 56% of patients had received prior bevacizumab.
Findings showed that the objective response rate with the combination of ixabepilone plus bevacizumab improved to 33% vs 8% with ixabepilone alone. In addition, the combination arm demonstrated an improvement in progression-free survival to 5.5 months vs 2.2 months with ixabepilone alone. Although the study was underpowered, overall survival was also improved significantly, from 6 months on ixabepilone monotherapy to 10 months on the combination-therapy arm.
“In the subgroup analysis, we found that prior receipt of bevacizumab did not influence progression-free or overall survival,” said Dr. Roque. “We also found no effect of heavy pretreatment, poor performance status, nonserous histology, or elderly status on these outcomes.”
Safety analysis identified peripheral neuropathy, neutropenia, and fatigue as dose-limiting toxicities. Patients in the combination-therapy group were more likely to experience hypertension (36% vs 8%) and peripheral neuropathy (51% vs 19%). However, no differences in serious adverse events were observed between the two treatment groups.
At the time of clinical data cutoff, 78% of patients on the ixabepilone arm had died vs 72% of those on the combination arm.
“The respectable objective response rate by RECIST of 33% with the combination of ixabepilone and bevacizumab compares favorably with the 27% reported in the AURELIA trial with chemotherapy plus bevacizumab,” said Dr. Roque. “Our toxicity profile was also similar to the AURELIA trial. Future studies should focus on predictive biomarkers as well as cost-effectiveness using biosimilars,” she concluded.
DISCLOSURE: Dr. Roque reported no conflicts of interest.
1. Roque DM, Siegel ER, Buza N, et al: Randomized phase II trial of weekly ixabepilone with or without biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer. SGO 2021 Annual Meeting on Women’s Cancer. Abstract 11570. Presented March 25, 2021.
2. Rosenberg JE, Weinberg VK, Kelly WK, et al: Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients: Randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer 110:556-563, 2007.
3. De Geest K, Blessing JA, Morris RT, et al: Phase II clinical trial of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant ovarian or primary peritoneal cancer: A Gynecologic Oncology Group study. J Clin Oncol 28:149-153, 2010.
4. Dizon DS, Blessing JA, McMeekin DS, et al: Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: Gynecologic Oncology Group trial 129-P. J Clin Oncol 27:3104-3108, 2009.
5. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 32:1302-1308, 2014.
Discussant of this phase II study, Thomas Herzog, MD, Deputy Director of the University of Cincinnati Cancer Center and Professor of Obstetrics and Gynecology at the UC College of Medicine, called the results “very exciting.”
“The 33% response rate with the combination of ixabepilone plus...