Understanding KEYNOTE-B96

Treatment options for patients with platinum resistant ovarian cancer are quite limited and have a poor overall prognosis. Platinum resistance is typically defined as progression within 6 months of receiving platinum based chemotherapy. The KEYNOTE-B96 Trial (also called ENGOT-ov65) sought to incorporate immunotherapy with standard second line chemotherapy regimen in these patients.  Dr. Premal Thaker, a gynecologic oncologist at Washington University, recalls “we all know, checkpoint inhibitors have made a big splash in many cancers and we have been trying so hard in ovarian cancer to try to use these immune checkpoint inhibitors…” In this article, will discuss the key facets of KEYNOTE-B96 trial and the implications for treatment in the future, with FDA approval for this new regimen expected by late February, 2026.

Eligibility Criteria

• Adult patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer

• Platinum-resistant disease, defined as progression ≤6 months after last platinum therapy

• 1–2 prior systemic treatment lines, including platinum-based chemotherapy

• ECOG performance status 0–1

• Measurable or evaluable disease per RECIST 1.1

• Adequate organ function

• Excluded: non-epithelial histology, more than two prior regimens, active CNS metastases, prior progression on weekly paclitaxel alone

Randomization & Endpoints

• Randomization: 1:1

  • Pembrolizumab + weekly paclitaxel ± bevacizumab

  • Placebo + weekly paclitaxel ± bevacizumab

• Stratification factors: PD-L1 status, planned bevacizumab use, geographic region

• Primary endpoint: Progression-free survival (PFS)

• Key secondary endpoints: Overall survival (OS), safety, tolerability, quality of life

Key Findings

• Progression-Free Survival (PFS):

  • In patients with PD-L1 CPS ≥ 1, median PFS was 8.3 months with pembrolizumab vs 7.2 months with placebo (HR ≈ 0.72; statistically significant improvement).

  • The regimen improved PFS regardless of PD-L1 expression across the overall population.

• Overall Survival (OS):

  • Among the PD-L1 CPS ≥ 1 subgroup, median OS was 18.2 months with pembrolizumab vs 14.0 months with placebo (HR ≈ 0.76; P ≈ 0.0053), representing a clinically meaningful survival benefit.

  • In the all-comers population, the final analysis also showed a statistically significant OS improvement with pembrolizumab plus chemotherapy, making this the first immunotherapy regimen in this setting to demonstrate a survival benefit for all patients.

These results reflect some of the longest survival outcomes reported for platinum-resistant recurrent ovarian cancer to date.

Side Effects

The safety profile was consistent with known toxicities of pembrolizumab and paclitaxel. Immune-related adverse events included fatigue, rash, diarrhea, and thyroid dysfunction, while chemotherapy-related toxicities included neuropathy and myelosuppression. Dr. Robert Coleman, a gynecologic Oncologist at Texas Oncology in Houston, remarks, “we saw no new adverse events outside our expectations nor did we see an acceleration of adverse events with the combination, including the triplet.” 

Notable Advantages

A major strength of KEYNOTE-B96 is that it establishes immunotherapy as a viable strategy in platinum-resistant ovarian cancer, a space where prior checkpoint inhibitor trials had largely failed. The large, global, double-blind design strengthens confidence in the results, and the benefit across PD-L1 subgroups enhances clinical applicability. Dr. Thaker explains, “this regimen is pending FDA approval and we do believe a lot of us in the field that this will be a tumor-agnostic approval for patients, which is a great win for patients since all patients would be eligible as long as they do not have a contraindication to the receipt of bevacizumab.”

Shortcomings

Limitations include the need for full peer-reviewed publication with mature subgroup and quality-of-life data. As with all combination regimens, toxicity and cost considerations may limit real-world uptake. Additionally, regulatory approval and guideline integration are still pending despite positive survival results.

Could this Become the Preferred Regimen in Platinum Resistant Ovarian Cancer?

This new regimen represents a significant step forward in treatment-resistant ovarian cancer, providing much-needed improvements in overall and progression-free survival. Dr. Coleman explains, “In the platinum-resistant setting, I believe these will be favored regimens, so as a second-line therapy…Ultimately, cross-trial comparisons will drive some of the influence of those trials and the sequencing of therapy. This will likely be further augmented by biomarker expression, which we expect to be more robust as time goes on.” With regard to how this treatment may fit in with other systemic options, such as antibody drug conjugates, Dr. Dana Chase, a professor of gynecologic oncology at UCLA Health, explains, “The sequencing of the treatment is really dependent on the patient’s tumor biomarker profile.  We will need to take into consideration:  1) biomarker profile 2) prior toxicities 3) patient’s performance status, and/or goals of care/treatment.  Depending on these three factors, we may either treat with an ADC first or choose options like the B96 option first.” KEYNOTE-B96 not only represents significant progress in the ovarian cancer space but also adds to the ever-expanding range of cancers that can be treated with pembrolizumab either alone or in combination with other agents.