Dr Colombo on the Rationale for Evaluating Pembrolizumab Plus Paclitaxel With/Without Bevacizumab in PROC

“When we started this study, we decided to specifically use one type of chemotherapy, which was weekly paclitaxel. This could be the reason why our study is positive compared with others, because there was previous evidence that the use of metronomic chemotherapy together with pembrolizumab and bevacizumab [could] enhance the immune response.”

Nicoletta Colombo, MD, PhD, an associate professor of obstetrics and gynecology at the University of Milan and director of the Gynecologic Oncology Program at the European Institute of Oncology IRCCS in Milan, Italy, discussed the biological and clinical rationale for conducting the phase 3 ENGOT-ov65/KEYNOTE-B96 study (NCT05116189), which evaluated pembrolizumab (Keytruda) vs placebo in combination with weekly paclitaxel with or without bevacizumab (Avastin) for patients with platinum-resistant, recurrent ovarian cancer.

KEYNOTE-B96 was designed to explore the potential immunologic synergy between checkpoint inhibition and metronomic chemotherapy in a population with limited treatment options, Colombo began. Prior immunotherapy trials in platinum-resistant ovarian cancer tested various chemotherapy backbones and failed to show significant benefit, but the decision in this trial to utilize weekly paclitaxel was based on strong biological and clinical reasoning. Colombo explained that metronomic paclitaxel, administered in low, continuous doses, can modulate the tumor microenvironment by stimulating dendritic cell activation, enhancing antigen presentation, and decreasing immunosuppressive regulatory T cells—all of which may bolster the activity of PD-1 blockade.

In addition to pembrolizumab, bevacizumab was included in select treatment arms to target VEGF-mediated angiogenesis, which has been associated with immunosuppression within the tumor microenvironment, Colombo stated. By normalizing tumor vasculature and improving T-cell infiltration, bevacizumab was hypothesized to further enhance immune activation when combined with pembrolizumab and paclitaxel.

Colombo noted that this study’s rationale also stemmed from prior clinical data supporting the use of metronomic chemotherapy with immunotherapy. Although the phase 3 AGO-OVAR 2.29/ENGOT-ov34 study (NCT03353831) failed to meet its primary end point in recurrent ovarian cancer, investigators observed a trend toward improved efficacy with the addition of atezolizumab to chemotherapy in a prespecified subgroup of patients who received weekly paclitaxel, she reported. These findings provided early evidence that paclitaxel-based regimens may be particularly effective at amplifying the immune response when used in combination with checkpoint blockade, Columbo concluded.