Comment
Several studies have assessed the activity of bevacizumab when added to chemotherapy in ovarian cancer. In Europe, bevacizumab is approved by the European Medicines Agency in combination with carboplatin and paclitaxel in newly diagnosed ovarian cancer, with carboplatin and gemcitabine in platinumsensitive relapse ovarian cancer, and with chemotherapy in platinum-resistant relapse ovarian cancer. In the USA, bevacizumab is approved by the Food and Drug Administration when combined with chemotherapy for platinum-resistant relapse ovarian cancer. These approvals were based on progression-free survival improvements, but so far no overall survival benefit has been noted with the addition of bevacizumab to chemotherapy in any overall study population.2–5 In The Lancet Oncology, Amit Oza and colleagues1 report the mature overall survival data from ICON7, an open-label randomised phase 3 trial comparing bevacizumab plus six 3-weekly cycles of carboplatin and paclitaxel chemotherapy followed by bevacizumab maintenance versus the carboplatin and paclitaxel chemotherapy regimen alone. The study participants were patients with newly diagnosed ovarian cancer following cytoreductive surgery or patients with advanced-stage disease who had no further surgery planned.1 The primary endpoint of this trial, progressionfree survival, has been reported previously.2 Concordant with the results of GOG-218,3 another phase 3 trial comparing chemotherapy and bevacizumab versus chemotherapy alone in upfront therapy for ovarian cancer, progression-free survival was 21·8 months with the addition of bevacizumab compared with 20·3 months with chemotherapy alone in the overall study, and 18·1 months versus 14·5 months in a predefined high-risk population of patients with suboptimally cytoreduced stage III or stage IV disease.2 ICON7 was also designed and powered to assess overall survival, for which the mature data are now reported. Oza and colleagues found no overall survival difference with the addition of bevacizumab to chemotherapy in the overall study population (restricted mean survival 44·6 months [95% CI 43·2–45·9] with standard chemotherapy vs 45·5 months [44·2–46·7] in the bevacizumab group). However, in a high-risk subset of 502 patients with inoperable or suboptimally
cytoreduced stage III or stage IV disease, they did note an overall survival benefit, with a mean overall survival of 34·5 months (95% CI 32·0–37·0) in the chemotherapy alone group compared with 39·3 months (37·0–41·7) with the addition of bevacizumab (log-rank p=0·03). No overall survival benefit was recorded in any other predefined subgroups, including clear cell, early-stage high-grade, or low-grade serous tumours. When considering the various treatment options available to patients with newly diagnosed ovarian cancer, improved overall survival is an important goal. Thus, the findings reported by Oza and colleagues raise the question of whether or not bevacizumab should be considered as first-line therapy for selected patients at high risk of recurrence. Notably, however, in a post-hoc exploratory analysis in GOG-218 of a similar population to that reported by Oza and colleagues (suboptimally cytoreduced stage III or stage IV disease), improvement in overall survival with bevacizumab was not significant, with median overall survival of 38·6 months on standard chemotherapy compared with 42·1 months with chemotherapy and bevacizumab (hazard ratio [HR] 0·86 95% CI 0·71–1·04; p=0·055).6 When we place these findings into clinical context, the different treatment options for patients with newly diagnosed advanced ovarian cancer should also be considered. Although ICON7 used a chemotherapy backbone of 3-weekly carboplatin and paclitaxel, the JGOG-3016 trial done by Katsumata and colleagues7 reported a significant progression-free and overall survival benefit when they substituted weekly paclitaxel for every-3-week paclitaxel. This benefit was most pronounced in suboptimally cytoreduced disease, with an increase in median overall survival from 33·5 months to 51·2 months (HR 0·75 [95% CI 0·57–0·97]; p=0·0027).7 GOG-262, which also compared carboplatin and weekly paclitaxel versus carboplatin and paclitaxel every 3 weeks but allowed bevacizumab at the discretion of the investigator, showed no progression-free survival benefit when bevacizumab was added to weekly paclitaxel; the small percentage of patients who received weekly paclitaxel without bevacizumab seemed to have similar progression-free survival as those receiving bevacizumab.8 Although based on a small subset of patients (112 [16%] of 692 patients),
www.thelancet.com/oncology Published online June 24, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00064-9
Centre Jean Perrin/ISM/SPL
Bevacizumab in newly diagnosed ovarian cancer
Lancet Oncol 2015 Published Online June 24, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00064-9 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(15)00086-8
1
Comment
this finding raises the possibility that either weekly paclitaxel or bevacizumab might be sufficient to achieve a progression-free survival benefit in patients with advanced-stage disease. Finally, in patients with advanced ovarian cancer, neoadjuvant chemotherapy and delayed interval cytoreductive surgery to reduce surgical morbidity has been established as a potential treatment option;9,10 however, the long half-life and side-effect profile of bevacizumab means that the administration of this agent in the neoadjuvant setting is problematic. Therefore, clinicians now face the challenge of selecting the most appropriate first-line therapy for patients with advanced ovarian cancer. Although the results of ICON7 offer the tantalising possibility that a patient subgroup might derive an overall survival benefit from first-line bevacizumab, caution should be exercised when interpreting subset analyses, and additional questions remain unanswered regarding the use of bevacizumab in newly diagnosed ovarian cancer. Only a small proportion of patients in ICON7 received bevacizumab after disease recurrence, and therefore whether or not bevacizumab use in the recurrent setting could offset the overall survival benefits recorded in this high-risk population remains unknown. Additional studies to understand the effect of subsequent bevacizumab treatment on survival and to further identify and validate molecular markers of antiangiogenic response will be important to better define our understanding of the role of bevacizumab therapy in ovarian cancer.
JFL is the site principal investigator of clinical trials sponsored by Genentech/ Roche, AstraZeneca, Merrimack Pharmaceuticals, and Atara Biotherapeutics. UAM has received personal and non-financial support from AstraZeneca; personal fees from Immunogen, Clovis, and Momenta; grants and personal fees from Merck; and non-financial support from Sanofi, outside the submitted work. Copyright © Liu et al. Open Access article distributed under the terms of CC BY-NC-ND. 1
2 3 4
5
6 7
8
9
10
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 2015; published online June 23. http://dx.doi.org/10.1016/S14702045(15)00086-8. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–96. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473–83. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30: 2039–45. 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 2014; 32: 1302–08. Coleman R, Burger RA, Brady MF, et al. Analysis of survivorship in high-risk patients on treated on GOG-218. Gynecol Oncol 2013; 130: e112–13. Katsumata N, Yasuda M, Isonishi S, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013; 14: 1020–26. Chan J, Brady MF, Penson RT, et al. Phase III trial of every-3-weeks paclitaxel versus dose dense weekly paclitaxel with carboplatin +/- bevacizumab in epithelial ovarian, peritoneal, fallopian tube cancer: GOG 262 (NCT0116712). Int J Gynecol Cancer 2013; 23 (8 suppl 1): 9–10. Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet 2015; published online May 19. http://dx.doi.org/10.1016/S01406736(14)62223-6. Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363: 943–53.
*Joyce F Liu, Ursula A Matulonis Gynecology Oncology Program, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA (JFL, UAM)
[email protected]
2
www.thelancet.com/oncology Published online June 24, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00064-9
