ABSTRACT & COMMENTARY

Role of Anti-VEGF Therapy in Platinum-resistant Recurrent Ovarian Cancer

By Robert L. Coleman, MD

Professor, University of Texas; M.D. Anderson Cancer Center, Houston

Dr. Coleman reports no financial relationships relevant to this field of study.

SYNOPSIS: Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor and has documented single-agent activity in patients with recurrent ovarian cancer. The current study demonstrated that when combined with standard recurrent chemotherapy, bevacizumab can significantly improve progression-free survival and objective response rate without diminishing quality of life.

SOURCE: Pujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized Phase III trial. J Clin Oncol 2014;32:1302-1308.

Patients presenting with platinum-resistant recurrent ovarian cancer are usually treated with single-agent chemotherapy; there are many acceptable options, with previous Phase 3 trials failing to demonstrate a clear "winner." Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has been extensively studied in ovarian cancer, and has clinical activity as a single agent and in combination with platinum-based chemotherapy both in the front-line and in recurrent platinum-sensitive settings. AURELIA is the first randomized, Phase 3 trial combining bevacizumab with chemotherapy in platinum-resistant ovarian cancer.1 Eligible patients had measurable/assessable disease, progressing within 6 months of completing platinum-based therapy. Patients with refractory disease, history of bowel obstruction, or more than two prior anticancer regimens were ineligible. After investigators selected chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks, depending on the regimen) until progression, unacceptable toxicity, or consent withdrawal. Crossover to single-agent bevacizumab was permitted after progression with chemotherapy alone.

The primary endpoint was progression-free survival (PFS) by response evaluation criteria in solid tumors (RECIST). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. The PFS hazard ratio (HR) was 0.48 (95% confidence interval [CI], 0.38-0.60; unstratified log-rank P < 0.001) representing a median PFS of 3.4 months with chemotherapy alone to 6.7 months with bevacizumab-containing therapy. RECIST ORR was 11.8% vs 27.3%, respectively (P < 0.001). The OS HR was 0.85 (95% CI, 0.66-1.08; P = 0.174; median OS, 13.3 vs 16.6 months, respectively). Grade 2 or higher hypertension and proteinuria were more common with bevacizumab. Gastrointestinal perforation occurred in 2.2% of bevacizumab-treated patients vs 0 in the chemotherapy-treated patients. Adding bevacizumab to chemotherapy statistically significantly improved PFS and ORR; the OS trend was not significant. No new safety signals were observed.

Commentary

This trial addressed the one previously untested setting for bevacizumab in ovarian cancer, namely, patients with recurrent ovarian cancer, platinum-resistant disease. This cohort of patients represents one of the most challenging because they are identified by their short-term recurrence (6 months or less) from platinum. While it is well recognized that only rarely are patients with recurrent disease cured of their ailment, patients with platinum-resistant recurrence are unlikely to survive more than 2 years, and often are on continuous therapy.2 This presents two important contexts for the current trial: clinical efficacy and quality of life. Since quantity of life is so difficult to enhance in this setting, quality of life becomes a premium endpoint. In addition, since patients with recurrent resistant disease are more likely to be symptomatic than their platinum-sensitive counterparts, resolution of symptoms can be PFS and ORR, which were significantly enhanced. An accompanying article detailing the impact of therapy on patient-reported outcomes and quality of life demonstrated that a significantly greater proportion of patients on combination therapy had a > 15% improvement in their gastrointestinal/abdominal symptoms compared to the standard-of-care arm.3

The impact of the study is dramatic, but not without its criticisms. For one, the study was not blinded. This is a major issue in clinical trials reporting bias-sensitive endpoints, such as ORR and time to progression. Patients and caretakers in the non-combination arm may be more likely to discontinue therapy in ambiguous settings, biasing toward the combination arm. Second, while the choice of standard-of-care regimens was left to the treating physician, the temporal choice was unbalanced. Investigators early in the study favored weekly paclitaxel, given its track record in this setting, and put better prognosis patients on the trial during that phase. This is visible by looking at the PFS curves in the control arms of each regimen. Third, while billed as a Phase 3 trial, the target sample was adjusted two times during the trial and the three individual chemotherapy arms were ultimately capped at 120 patients each, essentially limiting the power of each analysis to a randomized Phase 2 setting. Fourth, no difference in OS was seen in the initial and (recently presented) final assessment of this long-term endpoint. It is believed this may have been due to the high amount of crossover therapy in the non-bevacizumab arm (40%), but also could represent a different tumor biology induced by bevacizumab exposure. And finally, there is reason to believe that bevacizumab as a single-agent may be efficacious in this setting, but it was not considered.

Fortunately, no new safety signals were identified. There was significant concern that mucositis and palmar-plantar erythrodysesthesia (PPE, a painful blistering eruption of the hands and soles of the feet) could be enhanced with delayed healing in the combination of liposomal doxorubicin and bevacizumab. In the study, the rate was about two-fold higher but overall, high-grade PPE was uncommon (2% vs 4.5%) and was not cumulative. In addition, neuropathy, a noted adverse event of paclitaxel, appeared to be enhanced and cumulative (grade 2 or higher) when combined with bevacizumab. Some additional toxicities (such as hypertension and neuropathy) represented the longer exposure of therapy due to lack of progression. In all, the trial demonstrates that bevacizumab can enhance the efficacy of standard, single-agent, platinum-resistant chemotherapy. The data now join three previous Phase 3 trials reporting the same findings, increased PFS and objective response without an improvement in OS, and highlight the robust efficacy signal of the agent.4-6 However, the burden of investigation in this disease is on OS, an endpoint that remains elusive in all-comer designed trials.

References

  1. Stockler MR, et al. Patient-reported outcome results from the open-label phase III AURELIA trial evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer. J Clin Oncol 2014;32:1309-1316.
  2. Coleman RL, et al. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol 2013;10:211-224.
  3. Pujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 2014;32:1302-1308.
  4. Aghajanian C, 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;30:2039-2045.
  5. Perren TJ, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365:2484-2496.
  6. Burger RA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-2483.