Production of vascular endothelial growth factor (VEGF) is increased during normal ovulation, and can account for much of the reversible toxicity associated with ovarian hyperstimulation.1,2 We also have compelling data from multiple clinical trials to validate the importance of tumor-associated angiogenesis in the growth of ovarian cancer, including the effects of agents that sequester VEGF (with an emphasis on bevacizumab [Avastin]), small-molecule tyrosine kinase inhibitors that inhibit VEGF receptor signaling, antibodies that can prevent VEGF receptor activation, and a synthetic binding protein (trebananib) that sequesters angiopoietin-1 and angiopoietin-2. While there are additional “upstream” drivers and “downstream” signals, this commentary will focus on VEGF and angiopoietin-1/2.
Important Data
After more than 10 years of investigation of bevacizumab, it is instructive to consider a few key points:
Two single-agent nonrandomized phase II trials documented impressive tumor and ascites response in approximately 20% of patients with recurrent disease, regardless of prior chemotherapy history or platinum resistance.3,4 A number of responses were sustained > 1 year and associated with control of disease-related symptoms.
Randomized phase III trials in the front-line setting with concurrent chemotherapy followed by extended monotherapy (as maintenance) have documented modest, statistically significant, improvements in progression-free survival, but without an impact on overall survival, and without convincing evidence of clinical benefit.5,6 Of note, the majority of patients in these trials underwent primary cytoreductive surgery, achieving optimal (small-volume) residual disease at study entry, without disease-related symptoms.
In a retrospective analysis of one study (ICON7),6 a subset of patients with more-advanced or bulky disease showed modest improvement in overall survival, but this has generally been attributed to infrequent postprogression crossover, compared to similar studies with a 30% rate of crossover.
Randomized studies in combination with chemotherapy in the setting of platinum-sensitive and platinum-resistant recurrent disease have documented significant and more sustained improvements in progression-free survival, with strong hazard ratios, but generally without improved overall survival.7,8
Two studies of recurrent disease have documented improved overall survival, including chemotherapy with cediranib (VEGF receptor tyrosine kinase inhibitor) in ICON6 and a subset analysis of bevacizumab with weekly paclitaxel in AURELIA (but without an overall survival benefit in combination with polyethylene-glycosylated liposomal doxorubicin or topotecan). The significance of these findings is unclear, and lack of crossover or access to subsequent therapy could have influenced overall survival.
We do not yet have any reliable biomarkers to predict who is most likely to benefit, or not benefit, from antiangiogenic therapy, although certain clinical parameters, such as bulky disease and tumor-associated ascites or pleural effusions, may identify patients more likely to benefit from bevacizumab.9
Several antiangiogenic agents have successfully met predesigned primary study objectives for progression-free survival in large placebo-controlled randomized trials, but have not yet achieved U.S. Food and Drug Administration (FDA) regulatory approval in ovarian cancer.
In spite of the lack of FDA regulatory approval in the United States, the majority of patients now receive bevacizumab at some point during their treatment, often in the setting of recurrent disease, and it is generally covered by insurance, based on compendia listings and published studies.
Regulatory Approval
We do not yet have a standardized approach for determination of clinical benefit based on progression-free survival. Small, but statistically significant improvements in progression-free survival (eg, < 3 months) are clearly not sufficient and are unlikely to drive regulatory approval. Prolonged progression-free survival benefit, perhaps >12 months, would likely be viewed as clinically significant, but this is an infrequent occurence. Progression-free survival integrated with clinical outcomes, such as delay in subsequent therapy, quality adjustments, or sustained management of disease-related symptoms, might be viewed as clinically significant, but this is currently considered on a case-by-case basis.
In December 2011, bevacizumab received marketing approval through the European Medicines Agency for patients with newly diagnosed ovarian cancer (based on ICON7 and GOG0218). This was followed by European approvals for bevacizumab in combination with chemotherapy for platinum-sensitive recurrent disease (based on OCEANS) in October 2012 and with chemotherapy for platinum-resistant recurrent disease (based on AURELIA) in August 2014. Bevacizumab has not yet received FDA regulatory approval in the United States for any setting in ovarian cancer, but it is undergoing priority review for platinum-resistant disease as of July 2014.
Clinical Impact
Against this background, we have the well-designed, 919-patient, placebo-controlled, randomized phase III trial of the angiopoietin-1/2 inhibitor trebananib reported by Monk et al in The Lancet Oncology and reviewed in this issue of The ASCO Post.10 Trebananib provided a modest (< 2 month) improvement in progression-free survival with a hazard ratio of 0.66 in the setting of platinum-resistant recurrent disease, confirming earlier data from a randomized phase II trial reported by Karlan et al.11
While the primary endpoint for this trial was met on statistical terms, the clinical impact of these findings needs to be considered in the context of treatment-related toxicity (particularly edema), as well as the results previously reported with bevacizumab in a similar patient population (AURELIA). The authors state that, in combination with weekly paclitaxel, “trebananib provided a clinically meaningful prolongation in progression-free survival,” but they do not convincingly state how this conclusion would be substantiated.
As in other trials, the study required prescheduled cross-sectional imaging to monitor tumor response, and the vast majority of patients had disease progression declared based on asymptomatic changes in cross-sectional imaging, as evidenced by the stepwise decrements in actuarial progression-free survival that correlate with the timing of cross-sectional imaging. Of note, the reported benefit in progression-free survival is very close to one cross-sectional imaging time interval (8 weeks).
Our continued emphasis on measuring small changes in cross-sectional imaging makes it more difficult to determine if the investigational regimen might have delayed tumor progression and initiation of subsequent therapy or contributed to improved patient outcomes, even if the estimated progression-free survival based on cross-sectional imaging was similar.
Next Steps
Where do we go from here? Robert Fulghum has suggested that “All I Really Need to Know I Learned in Kindergarten.”12 Without being overly simplistic, it is conceivable that most of what we really needed to know we learned from two small single-arm phase II trials in the setting of recurrent disease.
These studies educated us about the importance of tumor-associated angiogenesis, targeted therapeutics, toxicity, safety, efficacy, and clinical principles of patient selection (favoring large-volume disease, often with ascites or pleural effusion, and without regard to prior platinum exposure or chemotherapy resistance). The fact that nearly 20% of patients had objective evidence of tumor response, often sustained, and associated with improvement in disease-related symptoms, was consistent and astounding. Taken together, publication of these trials has guided the use of antiangiogenic treatment in a large proportion of women with recurrent ovarian cancer, in spite of the lack of FDA regulatory approval.
Our subsequent randomized trials have been informative, and we are grateful for the infrastructure that made these studies possible, as well as the enthusiastic participation of so many women with ovarian cancer. However, after this extraordinary commitment of time, clinical resources, finances, and laboratory expertise, we have made only incremental progress. It is now clear that angiopoietin-1/2 has been validated as an important component of tumor angiogenesis, together with VEGF, and we await smaller innovative trials to bring true clinical benefit to our patients in the best clinical context. ■
Disclosure: Dr. Bookman has received compensation for participation in independent data monitoring committees for phase III trials with antiangiogenic agents from Genentech-Roche and Boehringer Ingelheim, and he has also received travel support and compensation for participation in multiple ad hoc advisory boards related to the development of clinical trials in ovarian cancer with nonmarketed investigational drugs, including from Amgen, Boehringer Ingelheim, and Genentech-Roche. He has no financial holdings in the pharmaceutical industry.
References
1. Ferrara N, Chen H, Davis-Smythe T, et al: Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med 4:336-340, 1998.
2. Giles J, Requena A, García-Velasco JA, et al: GnRH analogue for the prevention of ovarian hyperstimulation syndrome: A pilot study. Fertil Steril 91(4 suppl):1366-1369, 2009.
3. Cannistra SA, Matulonis UA, Penson 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.
4. Burger RA, Sill MW, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group Study. J Clin Oncol 25:5165-5171, 2007.
5. Burger RA, Brady MF, Bookman MA, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473-2483, 2011.
6. 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.
7. 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.
8. 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 30:2039-2045, 2010.
9. Ferriss JS, Java J, Burger RA, et al: Ascites predicts degree of treatment benefit of bevacizumab in front-line therapy of advanced epithelial ovarian, fallopian tube, and peritoneal cancers. Society of Gynecologic Oncology Annual Meeting. Abstract 62. Presented March 23, 2014.
10. Monk BJ, Poveda A, Vergote I, et al: Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): A randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15:799-808, 2014.
11. Karlan BY, Oza AM, Richardson GE, et al: Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol 30:362-371, 2012.
12. Fulghum R: All I Really Need to Know I Learned In Kindergarten, pp 6-7. New York, Villard Books, 1990.
Dr. Bookman is Professor of Medicine, Division of Hematology-Oncology, University of Arizona Cancer Center, Tucson.
