Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group (GOG) study

Reporter: Arpi D. Thukral, MD MPH
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2010

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Presenter: Robert Burger, MD for the Gynecologic Oncology Group and Fox Chase Cancer Center, Philadelphia, PA

Background

  • Ovarian cancer is the most common gynecologic cancer, and is the 4th leading cause of cancer death in women.
    • Annually, 22, 000 women are diagnosed with ovarian cancer and 15,000 women die of this disease per year.
    • Advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC) are all part of the spectrum of diagnoses named ovarian cancer.
  • Standard chemotherapy for ovarian cancer patients consists of a Carboplatin and Paclitaxel based regimen. However, outcomes in these patients are poor and survival remains dismal.
  • Previous research has demonstrated that vascular endothelial growth factor (VEGF) and angiogenesis are drivers of disease progression in these patients.
  • Bevacizumab (B) is a humanized monoclonal antibody that inhibits VEGF, a known central mediator of angiogenesis.
  • Previous Phase II trials by Burger et. al. (JCO 2007) and Cannistra et. al. (2007) have shown single-agent activity of B in patients with recurrent ovarian cancer.
  • However, there is currently a lack of evidence supporting the use of B in the front-line setting for patients with EOC, PPC or FTC.
  • This GOG 218 study is an international, double-blinded, placebo-controlled randomized Phase III trial that was designed to investigate the therapeutic impact of concurrent +/- maintenance B with standard chemotherapy.

Methods

  • Eligibility criteria:
    • Patients with newly diagnosed, previously treated EOC, PPC, or FTC following abdominal surgery for staging and maximal effort at tumor debulking were eligible for enrollment on this trial. Other criteria included:
      • No prior chemotherapy.
      • Surgery fewer than weeks prior to enrollment.
      • ECOG Performance Status 0-2
      • Stage III (macroscopic residual disease) or stage IV disease
      • No prior history of vascular events.
      • No evidence of intestinal obstruction.
  • Patients were randomized to one of 3 arms:
    • R1) Chemotherapy (CT): (IV paclitaxel 175 mg/m2 + carboplatin AUC 6 cycles 1-6) + placebo cycles (C) 2-22
    • R2) CT (as above) + concurrent B (15mg/kg) during courses 2-6 + placebo during courses 7-22
    • R3) CT (as above) + concurrent B during courses 2-6 + maintenance B during courses 7-22
  • Infusions were administered on Day 1 of a 21 day cycle. B was initiated at cycle 2 rather than cycle 1 to reduce risk of surgical wound complications.
  • Primary endpoint: Progression-free survival (PFS)
  • Secondary endpoints: Overall survival (OS), safety/toxicity, quality of life (QOL)
  • This study was designed to enroll 1800 patients for a 90% power to detect PFS with HR < 0.77.
  • Disease progression was defined based on imaging (RECIST criteria), clinical evaluation, or CA-125.

Results

  • 1873 patients in 336 sites in 4 countries (United States, Canada, Japan, South Korea) were enrolled on this study.
  • Patient baseline characteristics were well-balanced between the three arms.
    • Median age: 60 years
    • Stage III optimally debulked (34%); Stage III sub-optimally debulked (40%), and stage IV (26%) with similar distribution in each group (67% of patients in each arm had suboptimally debulked Stage III or Stage IV disease)
  • Median f/up: 17.4 months
  • Over 50% of patients had discontinued treatment by the end of the study, mostly due to disease progression. However, more patients in arms 1 and 2 discontinued treatment compared to arm 3.
  • PFS:
    • The control arm (arm 1) had PFS of 10.3 months. There was no difference in PFS seen between arms 1 (control arm) and 2 (concurrent arm).
    • However, a statistically significant difference between arms 1 and 3 was seen with a HR of 0.77 (p<0.0001). This was seen as an absolute improvement in PFS of 3.8 months.
  • OS:
    • No difference in OS was seen between the 3 study arms.
    • Analysis was limited by a 24% death rate.
    • Cross-over may have occurred when patients progressed, and patients in the control arm may have received B once they were off-trial.
  • Toxicity:
    • The majority of adverse events were seen during the chemotherapy part of treatment.
    • No differences were seen in neutropenia or thromboembolic events between the 3 arms.
    • GI events were experienced approximately twice as often in the 2 experimental arms (arms 2 &3), however the overall rate of GI events was still <3% in each arm, similar to previous studies in GI cancers.
    • Hypertension:
      • Any Hypertension: 7.2% in R1 group; 16.5% in R2 group; 22.9% in R3 group (p = sig)
      • Grade III-IV Hypertension: 1.6% in R1 group; 5.4% in R2 group; 10.0% in R3 group (p = sig)

Authors' conclusions

  • The addition of B to chemotherapy regimens used in 1st line treatment of EOC, PPC and FTC led to statistically significant improvements in PFS when comparing the control arm to arm III (concurrent + maintenance B).
  • Patients with no maintenance B (arm II) did not show a statistically significant improvement in PFS.
  • There was no difference seen in OS with the addition of B.
  • The treatment with B was well-tolerated with adverse events similar to previous studies.
  • B is the first anti-angiogenic agent to demonstrate benefit in this population.
  • Chemotherapy with concurrent and maintanace B should be considered as a standard option for these patients.

Clinical Implications

  • Ovarian cancer is a leading cause of death in women and, despite advances in chemotherapy, survival is poor. Therefore, novel therapeutic agents are needed in the management of this disease to improve the quality and quantity of survival for these patients.
  • This study is the first randomized phase III trial demonstrating the efficacy and safety of adding bevacizumab, a VEGF targeted antibody, with 1st line chemotherapy for ovarian cancer.
  • Strengths of this trial:
    • Large, well-conducted randomized study
    • Adequately powered for PFS and OS
    • Double-blinded
    • Standard GCIG definitions of progression were used
    • Evaluated both concurrent and maintenance B
  • GOG 218 met its primary endpoint of PFS (assessed by the investigator only) compared to chemotherapy alone, but only when comparing the control arm (arm 1) to the concurrent + maintanance B arm (arm 3).
    • An improvement in PFS was not seen for the conucrrent B arm. It is unclear why this effect was not seen. It is possible that the PFS benefit is due to solely to use of maintanance B, and not to concurrent use.
    • B was well-tolerated and safety appeared acceptable.
    • B did not, however, improve OS in either the concurrent or the concurrent + maintenance arms.
  • Several questions are prompted by the results of this study, namely, should B be implemented in practice for this population?
    • Although this study was powered to assess OS, this endpoint was not met. It begs the question: Does PFS benefit translate to OS benefit? If there is no OS benefit, is the cost of bevacizumab in this clinical situation appropriate? Does improvement in PFS lead to improvement in QOL? Are delayed symptoms related to increased QOL?
    • More mature data may be needed to assess for OS differences and impact on QOL.
  • From the results of this well-designed Phase III trial, we can conclude from that B is likely be an important component for treatment in ovarian cancer patients in the future, but more mature data is needed to examine impact on OS.
  • Other interesting questions which should be addressed in future studies include:
    • Does the choice of chemotherapy matter in the setting of B and other targeted agents?
    • Are there biomarkers available to test the efficacy of B in this population? Have these studies been done?
    • What is the cost-effectiveness of using B?
  • Further study of B in ovarian cancer patients should be performed, as it is a promising agent that shows potential to provide benefit in this setting.