Eskander Highlights PFS Outcomes With Pembrolizumab in dMMR/pMMR Advanced Endometrial Cancer

Recent data have demonstrated that adding pembrolizumab (Keytruda) to standard-of-care (SOC) chemotherapy followed by pembrolizumab maintenance for patients with mismatch repair–deficient (dMMR) and mismatch repair–proficient (pMMR) advanced or recurrent endometrial cancer improved survival. The combination shows potential to shift the treatment paradigm as a new SOC if approved, according to Ramez N. Eskander, MD.¹

Data from the phase 3 NRG GY018 trial (NCT03914612), which were presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, showed that median progression-free survival (PFS) for patients in the dMMR cohort (n=225) was not reached (NR; 95% CI, 30.6-NR) in the pembrolizumab arm (n = 112) vs 7.6 months (95% CI, 6.4-9.9) for those in the placebo plus chemotherapy arm (n = 113; HR, 0.30; 95% CI, 0.19-0.48). Patients in the pMMR cohort (n=591) experienced a median PFS of 13.1 months (95% CI, 10.5-18.8) in the pembrolizumab arm (n = 290) vs 8.7 months (95% CI, 8.4-10.7) in the placebo arm (n = 292; HR, 0.54; 95% CI, 0.41-0.71).²

In terms of safety, patients in dMMR cohort experienced adverse effects (AEs) of any grade at a rate of 98.2% in the pembrolizumab arm compared with 99.1% in the placebo arm. Grade 3 or greater AEs were reported in 63.3% and 47.2% of patients, respectively.²

In the pMMR cohort, any grade AEs were present in 93.5% and 93.4% of patients in the pembrolizumab and placebo arms, respectively. AEs of grade 3 or higher severity occurred at a rate of 55.1% and 45.3% of patients, respectively.²

“It was quite reassuring data confirming the efficacy of this combination strategy and then pembrolizumab as maintenance,” Eskander said. “Our hope is that this is going to usher in a new SOC for patients with both dMMR and pMMR endometrial cancer in the adjuvant setting or in the recurrent setting in patients who are chemotherapy naïve.”

In an interview with OncLive^®, Eskander, a gynecologic oncologist and assistant professor of obstetrics, gynecology, and reproductive sciences at UC San Diego Health, highlighted the potential implications of NRG GY018 as well as additional safety and efficacy results from the trial.

What was the rationale for initiating NRG GY018?

NRG GY018 was a prospective randomized phase 3 placebo-controlled and blinded clinical trial designed to help us answer whether the addition of pembrolizumab to chemotherapy followed by pembrolizumab maintenance would be of benefit to patients with advanced stage or recurrent endometrial cancer. Importantly, the trial was designed looking at 2 separate patient populations: patients who have dMMR endometrial cancer and those with pMMR endometrial cancer. The premise behind that is there is data that shows that dMMR cancers respond well to immune checkpoint inhibition, but to date that’s [only] been examined in patients who have progressed after prior systemic chemotherapy.

In the pMMR population when we look at immunotherapy alone there have been more modest results. We wanted to ask 2 questions. In the patients with dMMR [tumors] if we moved immune checkpoint inhibition [with] pembrolizumab to the frontline with chemotherapy and then as maintenance, could we elicit a beneficial response and then subsequently improve cancer outcomes? In the patients with pMMR [disease], could we add chemotherapy to pembrolizumab to improve the response rate to pembrolizumab? Historically, single-agent checkpoint inhibitors [have not] benefited pMMR cohorts.

What were the key findings from NRG GY018 presented during SGO?

This study was designed with a prespecified interim efficacy analysis at the time in which both cohorts completed accrual and we had at least half of the information fraction. We presented the interim efficacy analysis, which was dated December 6, 2022, for the pMMR population and December 16, 2022, for the dMMR population.

We saw that in the dMMR cohort the median PFS was not reached in patients treated with pembrolizumab and it was 7.6 months in patients treated with placebo. That [resulted in] a HR of 0.30, a P value of less than .00001, [and] a 70% reduction in the risk of disease progression or death. In those same dMMR patients, at 12 months, 74% of patients who were treated with pembrolizumab were without evidence of disease, progression, or death, compared with 38% of those who received placebo.

In the pMMR population, we saw consistent benefit. The median PFS in the pembrolizumab arm was 13.1 months vs 8.7 months in the placebo arm of the trial; [the] HR was 0.54, [there was] a 46% reduction in the risk of disease progression or death, [and the] P value was less than .00001 as well.

What is the safety profile of pembrolizumab plus chemotherapy?

What we saw was quite reassuring. We looked at the AEs that had an incidence of 15% or greater in both the pMMR and the dMMR populations and we compared pembrolizumab with placebo and saw no new safety signals. We saw similar rates of AEs of grade 3 or 4 frequency in both patient populations with pembrolizumab or placebo.

We also looked specifically at AEs of interest, which were defined as those with a potential immune-related etiology. We saw what we might anticipate with immune checkpoint inhibition; [AEs were] slightly more frequent in pembrolizumab, but no new safety signals.

We were able to show that when we add pembrolizumab to chemotherapy there didn’t appear to be an increase in the frequency of AEs that we associate with immunotherapy alone based on prior trials or an increase in the frequency of AEs that we see with carboplatin and paclitaxel.

What are the next steps for this research?

This motivates us to ask the next question. If this is approved, these patients are now going to receive chemotherapy and immunotherapy in the front line.What are we going to use at the time of recurrence for those patients who do have an episode of disease recurrence? How can we improve outcomes for those patients? We’re going to have to think critically about appropriate study designs knowing that endometrial cancer is a heterogeneous group of diseases with various molecular characteristics.

What is your main takeaway message for your colleagues regarding this research?

Endometrial cancer was commonly neglected or not considered a gynecologic malignancy that needed to be prioritized with respect to drug development and drug discovery. We’ve clearly shown that that’s not the case. It is a cancer with a domestic national burden and global burden, it has a rising incidence and mortality, and we were able to complete these clinical trials in the context of a global pandemic, which highlights the motivation behind drug discovery for these patients, but also the importance of making a difference.

It's a testament to the collective efforts of all the investigators, the site personnel, and the patients and their families that invested the time in this trial. It shows that we were able to identify an effective treatment strategy that we believe will hopefully change the SOC, and in parallel confirms to us that we can continue and need to study treatment opportunities in these patients.

References

1. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab versus placebo in addition to carboplatin and paclitaxel for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: the phase 3, NRG GY018 study. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL.
2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2302312