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Original Investigation
October 10, 2019

Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial

Author Affiliations
  • 1Division of Gynecologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 2Division of Breast Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 3Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 4Department of Medical Oncology, Massachusetts General Hospital, Boston
  • 5Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 6Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 7Department of Medical Oncology, Lifespan Cancer Institute, Rhode Island Hospital, Providence
JAMA Oncol. 2019;5(12):1731-1738. doi:10.1001/jamaoncol.2019.3343
Key Points

Question  What is the clinical activity associated with the combination treatment of nivolumab and bevacizumab in women with relapsed epithelial ovarian cancer?

Findings  In this single-arm, phase 2 trial of 38 women, 28.9% experienced an objective confirmed response after combination therapy with nivolumab and bevacizumab by Response Evaluation Criteria in Solid Tumors 1.1, meeting the threshold for further exploration of the combination in this setting. The response rate was 40.0% in platinum-sensitive patients and 16.7% in platinum-resistant patients.

Meaning  Further exploration of the nivolumab with bevacizumab combination in relapsed ovarian cancer is warranted.

Abstract

Importance  To date, single-agent programmed cell death 1 protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint blockade has shown limited activity in recurrent epithelial ovarian cancer. Combination strategies of PD-1/PD-L1 inhibition with antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a potential therapeutic opportunity in this disease.

Objective  To evaluate the activity of combined nivolumab and bevacizumab in women with relapsed ovarian cancer.

Design, Setting, and Participants  A single-arm, phase 2 study enrolled patients between February 8, 2017, and December 29, 2017, at 2 sites in the United States; the primary data analysis was completed July 27, 2018. Thirty-eight women with relapsed epithelial ovarian cancer were enrolled in this study. Participants had disease recurrence within 12 months of their last platinum-based therapy and had received between 1 and 3 lines of prior therapy.

Interventions  Participants received intravenous nivolumab and intravenous bevacizumab once every 2 weeks.

Main Outcome and Measures  The primary end point was objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors 1.1. Secondary end points included evaluation of the ORR by platinum sensitivity, assessment of progression-free survival, assessment of safety data, and investigation of the association of tumor PD-L1 with response to therapy.

Results  Of the 38 women enrolled, 18 had platinum-resistant and 20 had platinum-sensitive disease; mean (SD) age was 63.0 (9.1) years. Eleven patients experienced a confirmed response to nivolumab with bevacizumab (ORR, 28.9%; 95% exact binomial CI, 15.4%-45.9%), with 1 additional unconfirmed response. The ORR was 40.0% (19.1%-64.0%) in platinum-sensitive and 16.7% (95% CI 3.6%-41.4%) in platinum-resistant participants. Thirty-four participants (89.5%) experienced at least 1 treatment-related adverse event; 9 participants (23.7%) experienced a grade 3 or higher treatment-related adverse event. Median progression-free survival was 8.1 months (95% CI, 6.3-14.7 months). In 36 histologic samples for which PD-L1 testing could be performed, 22 samples (61.1%) had a PD-L1 tumoral percentage less than 1, and 14 samples (38.9%) had a PD-L1 tumoral percentage of 1 or greater. Ten responses occurred in patients with PD-L1 tumor percentage less than 1, and 2 in patients with PD-L1 tumor percentages of 1 or greater.

Conclusions and Relevance  The nivolumab with bevacizumab combination appeared to show activity in patients with relapsed ovarian cancer, with greater activity in the platinum-sensitive setting. Alternative combinational strategies may be necessary in the platinum-resistant setting.

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