Two Trials Explore the Evolving Role of Bevacizumab in Ovarian Cancer
The optimal use of bevacizumab (Avastin) in ovarian cancer appears to be in high-risk subgroups and in patients with platinum-resistant ovarian cancer, according to results of two phase III trials presented at the 2013 European Cancer Congress (ECC) in Amsterdam. AURELIA investigated the safety and efficacy of bevacizumab in a range of chemotherapies in patients with platinum-resistant ovarian cancer,1 and ICON7 looked at the effect of bevacizumab on survival in women with newly diagnosed ovarian cancer.2
AURELIA met its primary endpoint, significantly improving progression-free survival from 3.4 to 6.7 months with the additional of bevacizumab in patients with platinum-resistant ovarian cancer. Also, bevacizumab improved median overall survival from 13.3 to 16.6 months compared with chemotherapy alone (including paclitaxel, topotecan, and liposomal doxorubicin), but the survival benefit did not reach statistical significance.
“No single agent has shown superiority to weekly paclitaxel, topotecan, or liposomal doxorubicin. Median survival in platinum-resistant ovarian cancer is typically around 12 months,” said lead author Petronella O. Witteveen, MD, PhD, of University Medical Centre, Utrecht, The Netherlands. “AURELIA is the first phase III study to evaluate the addition of bevacizumab in platinum-resistant disease [defined as progression within 6 months of last platinum-containing therapy],” she added.
The study randomly assigned 361 patients to bevacizumab plus investigator’s choice of chemotherapy vs chemotherapy alone and patients were treated until progression, unacceptable toxicity, or consent withdrawal. At progression, patients in the chemotherapy arm were allowed to cross over to bevacizumab monotherapy, but bevacizumab was not continued in the bevacizumab-plus-chemotherapy arm after progression.
The two arms were well balanced for demographic and disease characteristics. About 25% had a progression-free interval of less than 3 months.
“At baseline, these were very sick patients,” Dr. Witteveen said.
Bevacizumab almost doubled progression-free survival from a median of 3.4 months to 6.7 months (P < .001). Median overall survival was 13.3 months with chemotherapy only vs 16.6 months with bevacizumab, a difference that was not statistically significant.
The study was limited because it was not powered to detect a statistically significant difference in overall survival, and also due to the planned nonrandomized crossover to bevacizumab in the chemotherapy arm, Dr. Witteveen noted. Seventy-two patients did cross over to bevacizumab and received a median of 4.5 cycles of therapy.
In an exploratory subgroup analysis of overall survival, weekly paclitaxel was the winner when combined with bevacizumab. In the cohort treated with liposomal doxorubicin, median overall survival was 13.7 months in those randomized to bevacizumab plus chemotherapy vs 14.1 months with chemotherapy only. For the topotecan-treated cohort, median progression-free survival was 13.8 vs 13.3 months, respectively. However, in the weekly paclitaxel cohort, median overall survival was 22.4 months for bevacizumab vs 13.2 months in controls, representing a 35% relative improvement favoring bevacizumab.
“The effect of weekly paclitaxel should be considered exploratory and requires prospective validation,” Dr. Witteveen said.
An updated safety analysis did not reveal any new safety concerns from the previous safety analysis in 2012, she said. The main grade 3 or higher toxicities in the bevacizumab arm were hypertension (7.8%) and proteinuria (2.2%).
In the ICON7 trial, the previously reported primary analysis of progression-free survival demonstrated the benefit of bevacizumab added to standard chemotherapy in newly diagnosed ovarian cancer: 19 vs 17.3 months (P = .0041).3
In the final survival analysis presented at the ECC, median overall survival was 58 months in the study for both arms. However, poor-prognosis patients experienced a 4.8-month prolongation of survival (from 34.5 to 39.3 months) if they received bevacizumab.
“The survival benefit in the overall trial of 0.9 months [using a restricted means analysis] is not clinically meaningful. However in the high-risk subgroup, bevacizumab did show a clinically meaningful benefit of 4.8 months,” said Amit M. Oza, MD, of Princess Margaret Cancer Center, University of Toronto, Canada.
The study was conducted at 263 sites around the world and randomly assigned 1,528 women to six cycles of every-3-week carboplatin/paclitaxel vs carboplatin/paclitaxel plus bevacizumab for five or six cycles followed by bevacizumab for 12 additional every-3-week cycles until disease progression. One-third of the women were considered high risk (stage III with > 1 cm residual disease, stage IV, and nondebulked).
Patients were prestratified according to stage, extent of debulking, and time of therapy.
At a median follow-up of 49 months, progression-free survival was not significantly different between the two arms, similar to the first interim analysis presented previously. Because nonproportional hazards were detected, the final overall survival analysis was conducted using restricted mean survival time, and the difference between the two arms was 0.9 months, which was not statistically or clinically meaningful, Dr. Oza said.
In a predefined high-risk subgroup of patients, the overall survival curves for the two arms separated, and the bevacizumab arm did better throughout the study, with a 4.8-month improvement over the control arm. Dr. Oza said this difference was “highly clinically meaningful, with a significant interaction between treatment and survival in high-risk patients.”
Bevacizumab showed a significant effect according to stage and amount of residual disease, with a greater impact on higher stage and greater burden of disease, he added. ■
Disclosure: Drs. Witteveen and Oza reported no potential conflicts of interest.
1. Witteveen P, Lortholary A, Fehm T, et al: Final overall survival (OS) results from AURELIA, an open-label randomized phase III trial of chemotherapy with or without bevacizumab for platinum-resistant recurrent ovarian cancer. European Cancer Congress. Abstract 5. Presented September 29, 2013.
2. Oza AM, Perren TJ, Swart AM, et al: ICON7: Final overall survival results in the GCIG phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. European Cancer Congress. Abstract 6. Presented September 29, 2013.
3. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484-2496, 2011.
Formal discussant of the AURELIA and ICON7 presentations, Rebecca Kristeleit, MD, University College London Hospital, London, said that a consistent message in both trials was the benefit of bevacizumab (Avastin) in high-risk disease.
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