Why KEYNOTE-B96 Succeeded Where Single-Agent Pembrolizumab Did Not

The arrival of pembrolizumab (Keytruda) in platinum-resistant ovarian cancer followed years in which single-agent checkpoint inhibition produced little in this disease. Asked what changed, Ursula A. Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, described a convergence of 4 design decisions rather than any single biological insight.

The first was the patient population. The phase 3 ENGOT-ov65/KEYNOTE-B96 trial (NCT05116189), presented at the 2025 European Society for Medical Oncology (ESMO) Congress, limited eligibility to patients who had received up to 2 prior lines of treatment.¹ The second was the backbone. Matulonis characterized weekly paclitaxel in the recurrence setting, especially with bevacizumab (Avastin), as one of the most active regimens available in platinum-resistant disease.

The third came directly out of the phase 2 KEYNOTE-100 trial (NCT02674061), which tested single-agent pembrolizumab in recurrent ovarian cancer and produced 2 lessons that shaped what followed.² Objective response rates (ORRs) dropped off as the number of prior treatments climbed, particularly at 3 or 4 prior lines. And ORRs rose along with the PD-L1 combined positive score (CPS): roughly 4% when the CPS was less than 1, and 10% when the CPS was 10 or higher. KEYNOTE-B96 narrowed enrollment to patients with a CPS of 1 or higher.

The fourth was mechanistic. Matulonis noted that chemotherapy can improve the immunogenicity of a cancer and improve how checkpoint inhibitors work, and pointed to substantial preclinical data showing that paclitaxel can drive T cells into ovarian cancer cells, making the immune environment more conducive to immunotherapy. A phase 2 trial (NCT02440425) run by her colleagues at Moffitt Cancer Center combined weekly dose-dense paclitaxel with pembrolizumab and produced impressive response rates.³ Taken together, she said, those factors set the trial up to succeed.

Transcript:

CancerNetwork: Why was the KEYNOTE-B96 trial successful?

Why was [KEYNOTE-B96] positive? I think there are a number of reasons why [the trial] ended up being a positive trial. One is that the patient population who were eligible for that trial were up to 2 prior lines of previous treatment. You're taking patients whose ovarian cancer is not particularly heavily pretreated. Secondly, we know that weekly paclitaxel in the recurrence setting, especially with bevacizumab, is one of the most active regimens that we have for platinum-resistant ovarian cancer. So you're starting with a foundational, highly active regimen.

We did learn from KEYNOTE-100. KEYNOTE-100 was single-agent pembrolizumab in recurrent ovarian cancer, and we learned that one, the number of prior treatments—the more heavily pretreated the patient was, especially 3 or 4 prior lines—the response rates dropped off. Then importantly, as the [combined positive score (CPS)] rose, the response rates went up. If the CPS score was less than 1, the response rates of single-agent pembrolizumab were about 4%, but if the CPS score was 10 or higher, it was 10%.

So [in KEYNOTE-B96] you really narrow the patient population down to folks who are not particularly heavily pretreated, whose cancers have a [CPS] of 1 or higher, and you've added pembrolizumab to weekly paclitaxel with or without bevacizumab. We know that certainly chemotherapy can improve the immunogenicity of the cancer and improve how immunotherapy, or specifically checkpoint inhibitors, may be working. Certainly with weekly [paclitaxel] there's pretty substantial preclinical data that shows that paclitaxel can drive T cells into cancer cells, ovarian cancer cells, and make that immune environment more conducive to an immunotherapy. [There was also] a phase 2 trial led by my colleagues at [Moffitt Cancer Center] that combined weekly paclitaxel with pembrolizumab, really showing pretty impressive response rates. All of those factors really set up this [KEYNOTE-B96] to be a successful trial.

References

1. Colombo N, Zsiros E, Sebastianelli A, et al. Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: results from the randomized, double-blind phase 3 ENGOT-ov65/KEYNOTE-B96 study. Presented at: 2025 European Society for Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA3.
2. Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019;30(7):1080-1087. doi:10.1093/annonc/mdz135
3. Wenham RM, Buras AL, Gordon SW, et al. A phase 2 study of pembrolizumab and weekly paclitaxel for platinum-resistant epithelial ovarian cancer. Int J Gynecol Cancer. 2025;36(6):102856. doi:10.1016/j.ijgc.2025.102856