Keytruda Combo Extends Survival in Ovarian Cancer Trial: Expert Insights

In the phase 3 KEYNOTE-B96 trial, Keytruda (pembrolizumab) combined with weekly paclitaxel, with or without Avastin (bevacizumab), improved outcomes for patients with platinum-resistant ovarian cancer, showing benefits in both progression-free survival and overall survival.

In an interview, Dr. Nicoletta Colombo, faculty at the University of Milan-Bicocca and Director of the Gynecologic Oncology Program at the European Institute of Oncology in Milan, discussed what the results mean for patients. She explained that the randomized phase 3 study met both major endpoints, providing solid data that this combination could represent a new treatment option for patients with platinum-resistant ovarian cancer, a population with significant unmet need.

Colombo noted that the trial showed an improvement in overall survival, particularly among patients with PD-L1–expressing tumors. She also highlighted that this is the first phase 3 trial in ovarian cancer to demonstrate improvements in both progression-free survival and overall survival with an immune checkpoint inhibitor.

According to Colombo, the weekly paclitaxel chemotherapy backbone may help enhance the immune response, potentially improving the effectiveness of immunotherapy in this setting.

CURE: The phase 3 KEYNOTE-B96 trial showed that Keytruda plus paclitaxel, with or without bevacizumab, improved overall survival in platinum-resistant ovarian cancer. What do you see as the most important takeaway from these results for patients?

Colombo: The study is quite important because it is a randomized phase 3 trial achieving not only the endpoint of progression-free survival, but also overall survival. That means we now have solid data that patients may have another option for treating their platinum-resistant ovarian cancer, which is a very high unmet need for this population. Now we have another option to offer to these patients.

The study reported an 18% reduction in risk of death and a median overall survival improvement of 3.7 months in the overall population. How meaningful are these outcomes in the context of platinum-resistant ovarian cancer, where treatment options can often be limited?

We first analyzed overall survival in the PD-L1–expressing patients, meaning patients with a CPS score of 1 or higher. In this population, we achieved an improvement in overall survival with a difference in the median of more than four months.

This is the label population, because this regimen has been approved by the FDA, However, this is for the population with CPS 1 and higher. Even though we also achieved a positive overall survival improvement in the overall population, this is very important.

First of all, this is one of the longest overall survivals ever reported in patients with platinum-resistant recurrent ovarian cancer — 18 months in the CPS 1-or-higher population and 17.7 months in the overall population. That is unprecedented. Second, this improvement in overall survival was demonstrated against a very highly performing control arm. Our control arm in both the CPS 1-or-higher population and the overall population was 14 months. It is very important to stress that not only did we have a clinically meaningful and statistically significant improvement in overall survival, but this was also relative to a very highly performing control arm.

The regimen also improved progression-free survival in the overall study population and in patients with PD-L1–positive tumors. How do these results build on what we already know about immunotherapy in ovarian cancer?

This is the first phase 3 trial showing a significant improvement in progression-free survival and overall survival with an immune checkpoint inhibitor in ovarian cancer. This is really the first time that this has happened. All the prior trials were negative, and many people are asking why this one is positive.

We believe that there was a strong rationale behind this study and some preliminary clinical data supporting this trial design. The chemotherapy backbone of weekly paclitaxel is the key to the success. We know how important metronomic administration is to modulate the microenvironment and increase immunogenicity and therefore increase the possible activity of immunotherapy in this population.

We believe that weekly paclitaxel together with Keytruda, and also, if possible, Avastin — because Avastin was left to the investigator’s choice — played an important role. Whenever feasible, Avastin was added to the regimen. Altogether, these three components are very important to achieve the final results.

Even in patients not eligible for Avastin, we observed improvement in progression-free survival and overall survival with the addition of Keytruda to weekly paclitaxel.

Can you walk us through the design of the trial and the types of patients who were included in the study?

To be eligible for the study, patients had to have a confirmed histologic diagnosis of epithelial ovarian cancer, fallopian tube cancer or primary peritoneal carcinoma. They could have had one or two prior lines of therapy. Prior anti-PD-1 therapy and prior bevacizumab were allowed. Patients also had to have radiographic progression within six months after the last dose of platinum-based chemotherapy. However, patients with primary refractory or platinum-refractory disease were excluded.

Randomization was 1 to 1 to Keytruda or placebo together with weekly paclitaxel, with or without Avastin at the discretion of the investigator. The primary endpoint was progression-free survival. The key secondary endpoint was overall survival, and the trial was powered to demonstrate an improvement in overall survival.

The overall alpha was assigned to test the superiority of progression-free survival in the CPS 1-or-higher population and then in the intention-to-treat population. Alpha could then be reallocated to test the two hypotheses for overall survival. The study was considered positive if PFS superiority was demonstrated in the CPS 1-or-higher population or in the intention-to-treat population.

Altogether, we randomized 643 patients across 187 sites in 25 countries. A total of 322 patients were allocated to Keytruda and 321 to placebo. At the time of this final analysis — and I want to underline that the final analysis occurred with a median follow-up of 33 months — 96% of patients had discontinued treatment, mainly due to disease progression.

The safety profile was reported to be consistent with previous studies of Keytruda. What side effects should patients and caregivers be aware of when considering this treatment approach, and when should these side effects raise concern?

If we look at the adverse events, we may say that the addition of Keytruda did not significantly increase the overall amount of side effects. Numerically, grade 3 (severe) adverse events and serious adverse events were a little bit higher in the Keytruda arm. However, treatment exposure to Keytruda and weekly paclitaxel was also longer compared with the control arm.

If you look particularly at the immune-mediated adverse events, they were typically low grade. Grade 3 events were only about 10%, and there was nothing unexpected. This was consistent with what we already know about the use of Keytruda.

However, we did have two deaths related to immune-mediated adverse events, one due to colitis and one due to pneumonitis.

Besides immune-mediated adverse events, if we look at the most frequent adverse events with this regimen, they were mainly related to chemotherapy. These included anemia, peripheral neuropathy and alopecia as the most frequent adverse events. However, most of them were low grade and were managed with established treatment algorithms.

Transcript has been edited for clarity and conciseness.

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