CD31 Potential Biomarker for Bevacizumab in Ovarian Cancer

Michael J. Birrer, MD, PhD, from Mass General

Michael J. Birrer, MD, PhD

The glycoprotein CD31 was associated with improvements in overall survival (OS) and progression-free survival (PFS) for patients with advanced ovarian cancer treated with frontline bevacizumab plus chemotherapy in a retrospective analysis of the phase III GOG-0218 presented at the 2015 ASCO Annual Meeting.

"CD31 findings are consistent with smaller samples from two trials in colorectal cancer but contrast with observations in glioblastoma. So, perhaps the predictive effect of CD31 should not be extrapolated across indications," explained lead investigator Michael J. Birrer, MD, PhD, director of Medical Gynecologic Oncology at the Massachusetts General Hospital. "The effect of bevacizumab on PFS and OS appeared most pronounced in patients with high CD31."

In the phase III GOG-0218 trial, 1873 patients with untreated stage III/IV ovarian cancer were treated with carboplatin (AUC 6) and paclitaxel (175 mg/m2) with placebo (n = 625), bevacizumab-initiation from cycle 2 through 7 (n = 625), or bevacizumab-continuation starting at cycle 2 and continuing throughout the study (n = 623). Bevacizumab was administered at 15 mg/kg every 3 weeks.

An initial analysis of the GOG-0218 study was published inThe New England Journal of Medicinein 2011. At this analysis, the median PFS with bevacizumab-continuation was 14.1 months compared with 10.3 months with chemotherapy alone (HR = 0.717; 95% CI, 0.625-0.824;P<.001). The bevacizumab-initiation arm did not demonstrate a statistical difference compared with placebo (HR = 0.908;P= .16). A significant difference in OS was not observed between the arms.

"GOG-0218 did not demonstrated an overall survival difference in any of the arms, but we wanted to see if analyzing the individual biomarkers could tease out a patient population for which a particular treatment improved overall survival," Birrer noted.

For the retrospective analysis, tumor samples were available for 1455 patients treated in the study: 483 from the placebo arm, 475 in the bevacizumab-initiation arm, and 497 in the bevacizumab-continuation group. Outcomes in these patients were similar to those in the full intent-to-treat population, Birrer noted.

For patients with high CD31 expression, the median PFS was 19.9 months with bevacizumab versus 9.8 months with placebo (HR = 0.40; 95% CI, 0.29-0.54;P= .0025). In the CD31 low group, the median PFS with bevacizumab was 18.0 versus 13.4 months with placebo (HR = 0.80; 95% CI, 0.59-1.07). Other biomarkers were not associated with a significant impact on PFS.

The median OS with bevacizumab was 45.6 months compared with 35.9 months with placebo, for those with CD31 high expression (HR = 0.68; 95% CI, 0.52-0.89;P= .0155). In the CD31 low group, the HR was 1.13.

Higher levels of CD31 expression were associated with greater improvements in OS and PFS in patients treated with bevacizumab. In patients with the highest CD31 expression, the median OS was 45.6 months with bevacizumab compared with 34.1 months with placebo (HR = 0.57; 95% CI, 0.39-0.83;P= .0084).

"There is a direct linear relationship between the microvascular density and the impact of bevacizumab," noted Birrer. "The potential predictive value of CD31 microvascular density for PFS and OS benefit and certainly for tumor-associated VEGF-A for overall survival requires further validation in other relevant datasets."

In November 2014, the FDA approved bevacizumab in combination with chemotherapy for patients with platinum-resistant recurrent ovarian cancer. It is also indicated as a treatment for patients with metastatic colorectal cancer, metastatic non-squamous non-small cell lung cancer, persistent, recurrent, or metastatic cervical cancer, recurrent glioblastoma, and metastatic renal cell carcinoma.

References

1. Birrer MJ, Choi YJ, Brady MF, et al. Retrospective analysis of candidate predictive tumor biomarkers (BMs) for efficacy in the GOG-0218 trial evaluating front-line carboplatin—paclitaxel (CP) with or without bevacizumab (BEV) for epithelial ovarian cancer (EOC).J Clin Oncol. 2015;33 (suppl; abstr 5505).
2. Burger RA, Brady MF, Bookman MA, et al. Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer.N Engl J Med. 2011; 365:2473-2483.