Pembrolizumab Plus Chemo Could Represent a New SOC in Advanced/Recurrent Endometrial Cancer

Data derived from the phase 3 NRG-GY018/KEYNOTE-868 trial (NCT03914612) could establish pembrolizumab (Keytruda) plus chemotherapy as a new standard of care for patients with advanced or recurrent endometrial cancer, if the combination is approved by the FDA, according to Ramez N. Eskander, MD.

Updated findings from the study presented at the 2024 SGO Annual Meeting on Women’s Cancer showed that although overall survival (OS) data were immature, a favorable trend was observed for pembrolizumab plus chemotherapy vs chemotherapy plus placebo in both the mismatch repair–proficient (pMMR) population (HR, 0.79; 95% CI, 0.53-1.17; P = .1157) and the mismatch repair–deficient (dMMR) population (HR, 0.55; 95% CI, 0.25-1.19; P = .0617).¹

Furthermore, progression-free survival (PFS) benefits were observed with the combination in both the pMMR and dMMR patient populations, irrespective of PD-L1 combined positive score (CPS). A strong concordance between blinded independent central review (BICR)– and investigator-assessed PFS was also seen in both the pMMR and dMMR populations.

In February 2024, the FDA granted priority review to the supplemental biologics license application seeking the approval of pembrolizumab plus standard-of-care chemotherapy, followed by pembrolizumab monotherapy, for the treatment of patients with primary advanced or recurrent endometrial carcinoma, based on results from NRG-GY018/KEYNOTE-868. The Prescription Drug User Fee Act (PDUFA) target action date is June 21, 2024.²

“There is a PDUFA date in June to adjudicate whether we're going to have an approval for the combination in the all-comer patient population, meaning [patients with] pMMR or dMMR [disease],” Eskander said in an interview with OncLive^®. “If that approval is secured, that could change the landscape of how we treat advanced-stage or recurrent endometrial cancer and set a new standard.”

In the interview, Eskander, a gynecologic oncologist and assistant professor of obstetrics, gynecology, and reproductive sciences at Moores Cancer Center of the University of California, San Diego Health, highlighted the updated data and expanded on the potential implications of the findings.

OncLive: Regarding the NRG GY-018/KEYNOTE-868 trial, could you provide an overview of the rationale and design of this trial?

Eskander: NRG GY018 was designed as a randomized, phase 3, international clinical trial to look at the clinical benefit of adding immunotherapy—pembrolizumab, a checkpoint inhibitor—to chemotherapy—carboplatin and paclitaxel—and then [pembrolizumab monotherapy] continued as maintenance in patients who had advanced-stage metastatic or recurrent endometrial cancer.

The premise was to try to identify if there was therapeutic benefit to this combination in patients with endometrial carcinoma, recognizing that there are 2 distinct molecular populations: the dMMR [population] and the pMMR [population]. The trial was really 2 separate trials in 1 in an effort to identify the therapeutic efficacy of this approach vs placebo [plus chemotherapy] in the dMMR and pMMR populations.

Before we discuss the updated findings presented at the 2024 SGO Annual Meeting on Women’s Cancer, what data were previously derived from this study?

In March 2023, we reported the primary efficacy analysis. That [analysis included] the PFS difference, and we did see a clinically meaningful and statistically significant benefit with an improvement in median PFS with the addition of pembrolizumab to carboplatin and paclitaxel, then continued as maintenance. There was a 70% reduction in the risk of disease progression or death in the dMMR population [HR, 0.30; 95% CI, 0.19-0.49; P < .001] and a 46% risk reduction in the risk of disease progression or death in the pMMR population [HR, 0.54; 95% CI, 0.41-0.71; P < .001]. [The trial] met its primary end point, and there were no concerning safety signals.

At the 2023 ESMO Congress, we also reported that the addition of pembrolizumab to chemotherapy resulted in an improvement in both the overall response rate and the median duration of response. We saw a provocative doubling of the complete responses in the dMMR and pMMR populations with the addition of pembrolizumab to chemotherapy.

What updated OS and PFS data were presented at the 2024 SGO Annual Meeting on Women’s Cancer?

At the 2024 SGO Annual Meeting, we reported on key prespecified secondary end points. We presented the OS [data] at the [first] interim analysis data cutoff. We also reported on PFS based on PD-L1 expression status, as defined by the CPS, as well as BICR- and investigator-assessed PFS.

With respect to OS, there was a numerical and directionally favorable improvement in both the dMMR and pMMR populations when we added pembrolizumab to chemotherapy and continued pembrolizumab maintenance. That was despite 45% of [patients in the pMMR population in the control arm] and 54.5% of [patients in the dMMR population in the control arm] receiving immunotherapy after trial. It was a positive signal that we saw with respect to OS.

Interestingly and importantly, when we looked at PD-L1 expression status, we could identify that the benefit of pembrolizumab with chemotherapy was noted irrespective of whether patients had a PD-L1 CPS score of 1 or greater, or less than 1, meaning it benefitted either population.

Lastly and importantly, we saw a very strong and consistent finding with respect to BICR- and investigator-assessed PFS, adding a lot of confidence to the primary efficacy end point.

What is the safety profile of pembrolizumab plus chemotherapy in this population?

When we presented the data initially and published it, we reported on the safety of the combination, and what we saw was there were no new safety signals. The addition of immunotherapy to chemotherapy did not increase the frequency of adverse effects [AEs] normally noted with cytotoxic chemotherapy via carboplatin and paclitaxel, nor did we see an increase of immune-related AEs.

References

1. Eskander RN, Sill M, Miller A, et al. Overall survival, progression-free survival by PD-L1 status, and blinded independent central review results with pembrolizumab plus carboplatin/paclitaxel (CP) versus placebo plus CP in patients with endometrial cancer: results from the NRG GY018 trial. Presented at: 2024 SGO Annual Meeting for Women's Cancer; March 15-18, 2024; San Diego, CA.
2. FDA grants priority review to Merck’s application for Keytruda (pembrolizumab) plus chemotherapy as treatment for primary advanced or recurrent endometrial carcinoma. News release. February 20, 2024. Accessed April 24, 2024. https://www.merck.com/news/fda-grants-priority-review-to-mercks-application-for-keytruda-pembrolizumab-plus-chemotherapy-as-treatment-for-primary-advanced-or-recurrent-endometrial-carcinoma/