Results of a phase 2 clinical trial suggest that the addition of bevacizumab potentiates the activity of the programmed cell death-1 (PD-1) inhibitor, nivolumab, in the setting of recurrent ovarian cancer.

Thus far, results of studies of single-agent anti–PD-1 or anti-programmed cell death-ligand 1 (PD-L1) immunotherapy have shown only limited activity in the setting of recurrent ovarian cancer (ie, overall response rates [ORRs] of 15% or less). Hence, there is increased interest in evaluating whether the effectiveness of immunotherapy can be synergized by combining it with targeted agents such as inhibitors of the vascular endothelial growth factor receptor (VEGFR) pathway, particularly since signaling through that pathway has been identified as a potential mechanism of immune suppression. 

In this nonrandomized, single-arm, open-label, phase 2 study ( Identifier: NCT02873962), 38 patients with recurrent ovarian cancer that had relapsed within 12 months of receiving prior platinum-based therapy were treated with the PD-l inhibitor, nivolumab, in combination with bevacizumab, a monoclonal antibody that targets VEGF-A, a ligand for VEGFR. The primary study end point was ORR.

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Patients were eligible for the study if they had received up to 3 prior lines of therapy, including previous bevacizumab therapy, but excluding all other previous immunotherapy. Of the enrolled patients, 16 and 22 had recurrent disease following treatment of stage I or stage II ovarian cancer, respectively, only 2 were identified as having a deleterious BRCA1/2 germline mutation, and 47.4% and 52.6% had platinum-resistant disease (ie, relapse within 6 months following treatment with platinum-based therapy) and platinum-sensitive disease (ie, relapse within 6 months to 12 months of receiving platinum-based therapy), respectively.

The confirmed ORR was 28.9%, including 40% of patients with platinum-sensitive disease and 16.7% of patients with platinum-resistant disease. An additional 30% of patients with platinum-sensitive disease and 16.7% with platinum-resistant disease achieved stable disease as best response to treatment.

Notably, 10 of the 12 confirmed responses occurred in patients with tumor tissue characterized by a PD-L1 level of less than 1%.

Median progression-free survival, including clinical progression, was 8.1 months, 9.4 months, and 5.3 months for all patients, patients with platinum-sensitive disease, and those with platinum-resistant disease, respectively.

At least 1 treatment-related adverse events occurred in nearly 90% of patients, with 23.7% of patients experiencing a grade 3/4 treatment-related adverse event. These included 7 grade 3 adverse events involving hypertension, myalgia, arthralgia, and elevations in serum amylase, aspartate aminotransferase, and alanine aminotransferase levels, as well as 3 grade 4 elevations in either serum amylase or lipase level. No grade 5 adverse events occurred.

In their concluding remarks, the study authors commented that “examination of the response rates by platinum status suggests that this combination strategy may have the greatest promise in platinum-sensitive disease, while alternative strategies to enhance immunotherapy may still be required in the platinum-resistant setting.”

Disclosure: This trial was supported by Bristol-Myers Squibb, and some of the authors reported financial relationships with various companies in the health industry. For a full list of disclosures, please refer to the original study.


Liu JFHerold CGray KP, et al. Assessment of combined nivolumab and bevacizumab in relapsed ovarian cancer: A phase 2 clinical trial. JAMA Oncol. doi: 10.1001/jamaoncol.2019.3343