Based on preclinical (in vitro and in vivo) data, there is a strong biologic rationale for the addition of an antiangiogenic drug strategy in the treatment of epithelial ovarian cancer.1 Single-agent trials have confirmed both the biologic and clinical activity of bevacizumab (Avastin) in the management of ovarian cancer.2 This experience naturally led to the development and conduct of a number of phase III randomized studies in several clinical settings, examining the potential clinical utility of this agent in combination with chemotherapy.1
The results of these trials exploring the addition of bevacizumab to standard cytotoxic chemotherapy have now been published in the peer-reviewed literature.1 Of considerable interest, the universal finding, regardless of the study setting (primary therapy, recurrent platinum-sensitive or -resistant disease), has been that the addition of the antiangiogenic agent resulted in a statistically significant improvement in progression-free survival, but these studies have failed to demonstrate this strategy leads to longer overall survival.
Closer Look at ICON7
The publication of the overall survival results from the ICON7 study by Oza and colleagues—reviewed in this issue of The ASCO Post—supports this basic conclusion.3 In this large (1,528 patients) international phase III trial examining the addition of bevacizumab to carboplatin plus paclitaxel as primary treatment of ovarian cancer, patients were randomized to receive either chemotherapy alone delivered on an every-3-week schedule or chemotherapy with bevacizumab (delivered during chemotherapy and as a subsequent maintenance strategy).
Although the trial demonstrated a statistically significant improvement in progression-free survival (median 21.8 months with bevacizumab vs 20.3 months with chemotherapy alone with 759 total events; hazard ratio [HR] = 0.81, P = .004), there was no evident statistically significant impact on overall survival when the entire population entered into the trial was considered (median 58.0 months with bevacizumab vs 58.6 months with chemotherapy only).
However, among a prespecified group of patients (n = 502) defined as being at particularly high risk for progression when they entered the trial (eg, inoperable stage III, unable to be debulked to < 1 cm maximum disease, stage IV disease), an improvement in overall survival was observed with bevacizumab (median 39.7 months vs 30.2 months, P = .003).
In another analysis, the restricted mean survival time in this poor-risk population was 39.3 months vs 34.5 months (HR = 0.78; 95% confidence interval [CI] = 0.63–0.97). In addition, progression-free survival was prolonged in this subgroup (20.0 months vs 15.9 months, P = .001). There was no difference in overall survival among those without a poor prognosis.
In fact, it should be noted that in the updated analysis involving 1,080 events, in contrast with the initial report on progression-free survival from the trial,4 progression-free survival of the entire population entered into the trial was no longer statistically significant (restricted mean progression-free survival, 29.2 months vs 27.7 months, P = .25), with a statistically defined benefit appearing to be relatively limited to the high-risk patient population.
More About Overall Survival
One well-discussed and critical reason other studies have failed to date to confirm an overall survival benefit associated with adding antiangiogenic agents to primary chemotherapy in the management of ovarian cancer is the demonstrated utility of a variety of treatment approaches following the completion of the front-line therapeutic regimen. Such treatment may include the use of this specific class of agents in the second-line (or later) setting or alternative programs.1 The difficulty in demonstrating an improvement in survival in a setting in which it is known there may be extended survival due to both the natural history of a cancer and the availability of clinically active antineoplastic agents has been extensively discussed in the literature.5
Critical Questions Remain
These provocative results suggest that the patient population with the most advanced ovarian cancers (as defined in this protocol) may experience the greatest clinical benefit when bevacizumab (or perhaps other antiangiogenic agents) is added to a standard cytotoxic chemotherapy regimen. Support for this hypothesis comes from the suggestion that the most advanced or aggressive ovarian cancers may be the malignancies that are most “driven” by angiogenic factors. Although other clinical data support this concept, it is premature to draw any definitive conclusions regarding this perspective.
This report by Oza and colleagues adds to the growing body of peer-reviewed literature that has documented the unquestionable clinical utility of antiangiogenic agents in the management of advanced epithelial ovarian cancer. However, critical questions remain, including further defining the population that is most likely to benefit (to which the results reported in this study are particularly relevant), the establishment of a molecular profile of specific cancers that are likely (or unlikely) to benefit from this strategy, and whether the use of this approach may be beneficial in multiple lines of treatment. It is hoped that future studies of the quality reported by Oza and colleagues will help provide answers to these highly relevant questions. ■
Disclosure: Dr. Markman reported no potential conflicts of interest.
References
1. Eskander RN, Tewari KS: Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications. Gynecol Oncol 132:496-505, 2014.
2. Cannistra SA, Matulonis UA, Pernon RT, et al: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25:5180-5186, 2007.
3. Oza AM, Cook AD, Pfisterer J, et al: Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial. Lancet Oncol 16:928-936, 2015.
4. 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.
5. Tate Thigpen J: Contemporary phase III clinical trial endpoints in advanced ovarian cancer: Assessing the pros and cons of objective response rate, progression-free survival, and overall survival. Gynecol Oncol 136:121-129, 2015.
