Perioperative Pembrolizumab Shows Activity in Advanced High-Grade Serous Carcinoma

Isabelle Ray-Coquard, MD, PhD

Adding pembrolizumab (Keytruda) to perioperative treatment of chemotherapy and bevacizumab (Avastin) for the treatment of advanced high-grade serous carcinoma deemed non-optimally resectable is safe, according to the phase 2 NEOPEMBROV study.¹

The randomized, open-label, multicentric NEOPEMBROV study (NCT03275506) had an estimated enrollment of 91 patients. All patients included in the study were women between 18 and 75 years of age with a confirmed diagnosis of epithelial ovarian carcinoma, fallopian tube carcinoma, or peritoneal carcinoma with the exception of mucinous histology. All patients had advanced to stage IIIC to IV cancer and are not able to receive primary debulking surgery for which chemotherapy with carboplatin and paclitaxel is recommended.²

The primary end point of the study was complete resection rate after interval debulking surgery. Secondary end points include rate of pathologic complete response, objective response rate, best overall response, progression-free survival, and overall survival.

During the study, patients in the intent to treat (ITT) population were randomized to receive either pembrolizumab, chemotherapy and bevacizumab or chemotherapy with or without bevacizumab alone.

In an interview with Targeted Oncology™, Isabelle Ray-Coquard, MD, PhD, a medical oncologist in the Medical Oncology Department at the Institute for Clinical Sciences at the Centre Leon Berard and professor of medical oncology at the University of Claude Bernard Lyon, discussed the NEOPEMBROV study in greater detail and the benefits of adding pembrolizumab to perioperative treatment for serous carcinoma deemed non-optimally resectable.

TARGETED ONCOLOGY™: What are the standard methods of treating patients with advanced high-grade serous carcinoma?

RAY-COQUARD: Currently, the standard of care includes chemotherapy with paclitaxel and carboplatin, plus or minus bevacizumab. Now, close to s6 months or 1 years, we have a PARP inhibitor for maintenance therapy after chemotherapy. And the maintenance with the PARP inhibitor could be alone or in combination with bevacizumab if the patient was BRCA positive.

Was there any preclinical research that led to this NEOPEMBROV study that you'd like to highlight?

In fact, there is 2 populations of patients: the patient who can receive upfront surgery and patients where upfront surgery is not feasible for this patient because there is a very aggressive disease, because of the performance statues. In this case, the patient receives neoadjuvant chemotherapy. However, for all of these patients, the goal is to have a complete resection and upon complete resection of a patient who is not able to receive upfront surgery, neoadjuvant chemo and interval debulking surgery. This is where the complete resection rate is something important for the patient and for the prognosis. In this setting, we have the opportunity to explore new treatments such as checkpoint inhibitors, PD-1, or PD-L1 inhibitors in combination with chemo, and to explore the efficacy of such compound in the first line setting. And it is exactly the objective of the NEOPEMBROV trial to explore the impact of adding pembrolizumab in combination with chemotherapy on the efficacy in terms of surgical resection.

What was the study design? And was there any non-traditional inclusion and exclusion criteria for this study?

The clinical trial includes I grid serous carcinoma. In terms of histology, stage 3C and 4 of the seagull classifications, and patient not able to receive an f1 surgery with complete resection. In this case, the patients were randomized to receive the standard of care including paclitaxel plus carboplatin versus the same chemotherapy plus pembrolizumab for 4 cycles. After 4 cycles, the patient has an interval debulking surgery. After surgery, they continue to receive chemotherapy plus bevacizumab for the standard of care arm versus this combination, plus bevacizumab, plus pembrolizumab for 2 years. In this clinical trial, bevacizumab is optional after surgery and because this trial was conducted before 2019, there is no PARP inhibitor in this clinical trial.

What are the study results?

In terms of results, the primary end point of this clinical trial is the complete resection rate at the interval debulking surgery. This trial met his primary endpoint with a complete resection rate of close to 74% in the experimental arm, and we observe 70% of complete resection in the control arm. That is a little bit highest that we anticipated in the statistical plan. In terms of response rate, after 4 cycles of neoadjuvant chemotherapy, we observed a little bit more of an objective response rate in the experimental arm with 73.3% objective response versus a 62% in the standard arm. In terms of progression free survival, the median PFS of this combination plus pembrolizumab is 19 months for the combination, versus 20 months in the standard arm. So, we don't observe any difference in terms of progression free survival by adding pembrolizumab to a standard of care in the ITT population.

We don't see any safety issues adding pembrolizumab to neoadjuvant chemotherapy. And we can also mention that there is more of dose reduction in the standard versus the experimental arm. In terms of adjuvant treatment, we also did not report more safety issues using pembrolizumab in addition to the standard off care, chemotherapy, and bevacizumab versus chemotherapy plus bevacizumab. And so, we can mention in terms of summary, that pembrolizumab may be safely added to preoperative treatment in patients deemed non optimally resectable.

The primary end point of the NEOPEMBROV study was met with close to 74% of complete rejection rates in the experimental arm. However, the complete reduction rate in the control group was higher than anticipated. Also, there was a small increase of objective response in the experimental arm was observed compared to the standard of care. We don't see any benefit at the time of the analysis for the PFS. And so, we can see there that survival data in frontline research including, among other PD-L1, TMB/BRCA status and tumor human context here, are fundamental to identify the real place of PD-1 inhibitor in such a setting

Could you give a key takeaway from this research?

This research report measures important results. First, it is a great opportunity to have access to tumor tissue before and after neoadjuvant chemotherapy to explore the mechanics of efficacy but also resistance to a new agent. The second point is that adding a PD-1 inhibitor to chemotherapy is completely safe for the patient. However, the results in terms of complete resection rate, but also PFS is not positive in the ITT tradition. And so, we can't consider that PD-1 inhibitor could be sn interesting new treatment for all advanced, I grade a serous carcinoma. We have to look in the detail of the subgroups.

What is planned for the future of this trial?

It is a randomized phase 2 study dedicated to transnational research because the huge interest is to have access to the tumor block. Due to the results, and also the low number of patients included in the trial, that can be something able to change clinical practice. But it is not the objective of the trial. The objective is to understand the safety of the adding pembrolizumab to chemotherapy, and also to have tissue material to understand how immune therapy can be of interest in ovarian cancer.

_REFERENCES:

_{Ray-Coquard, Savoye A, Mouret-Reynier, et al. Efficacy and safety results from neopembrov study, a randomized phase II trial of neoadjuvant chemotherapy (CT) with or without pembrolizumab (P) followed by interval debulking surgery and standard systemic therapy ± P for advanced high-grade serous carcinoma (HGSC): A GINECO study. J Clin Oncol. 2021;39(15):5500. doi: 10.1200/JCO.2021.39.15_suppl.5500}

_{PEMBRO with chemo in neo adj treatment of ovarian cancer. (NEOPEMBROV). ClincialTrials.gov. Accessed August 19, 2021. https://bit.ly/3D2rdJZ.}