First-line Pembrolizumab Plus Chemo Meets PFS End Point in Advanced or Recurrent Endometrial Carcinoma

The combination of pembrolizumab (Keytruda) plus carboplatin and paclitaxel demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs chemotherapy alone in the first-line treatment of patients with stage III/IV or recurrent endometrial cancer, meeting the primary end point of the phase 3 NRG-GY018 trial (NCT03914612).¹

Notably, the benefit of pembrolizumab plus chemotherapy was observed both in patients with mismatch repair–proficient (pMMR) endometrial carcinoma and those with mismatch repair–deficient (dMMR) disease. Full data from the prespecified interim analysis will be presented at an upcoming medical meeting and shared with regulatory authorities.

“Patients with advanced stage or recurrent endometrial cancer, the most common type of gynecologic cancer in the U.S., face a poor prognosis with limited treatment options. This is particularly notable in patients who progress after prior platinum-based adjuvant therapy with disease not amenable to curative surgery or radiation,” Ramez Eskander, MD, the trial’s principal investigator and a gynecologic oncologist at the University of California, San Diego, stated in a news release. “In this study, pembrolizumab in combination with carboplatin and paclitaxel resulted in a statistically significant and clinically meaningful improvement in progression-free survival in both the dMMR and pMMR study populations.”

Pembrolizumab is currently approved in two indications for endometrial cancer in the United States. In March 2022, the FDA approved pembrolizumab for use as a single agent in the treatment of patients with advanced endometrial carcinoma that is microsatellite instability–high (MSI-H) or dMMR, and who experienced disease progression following previous systemic therapy in any setting and are not candidates for curative surgery or radiation.²

Additionally, in July 2021, the FDA granted regular approval to pembrolizumab plus lenvatinib (Lenvima)for the treatment of patients with advanced endometrial carcinoma that is not MSI-H) or dMMR, who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation.³

The randomized, blinded, placebo-controlled NRG-GY018 trial enrolled patients who were at least 18 years of age with stage III, IVA, IVB, or recurrent endometrial cancer in pMMR and dMMR cohorts.⁴ Patients were required to undergo MMR testing by immunohistochemistry and have an ECOG performance status of 0 to 2. Patients were allowed to have no prior chemotherapy for endometrial cancer or prior adjuvant chemotherapy that was completed at least 12 months prior to enrollment. Prior radiation was permitted up to 4 weeks prior to step 2 registration, and prior hormonal therapy was allowed up to 3 weeks before step 2 registration.

Interval or cytoreductive surgery after the start of study treatment on this trial and prior to documentation of disease progression was not permitted. Other key exclusion criteria included any prior anti–PD-1, anti–PD-L1, or anti–CTLA-4 treatment; a diagnosis of immunodeficiency, or systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of step 2 registration; or active autoimmune disease or history of autoimmune disease that might recur.

Patients with treated brain metastases were eligible if follow-up brain imaging after central nervous system–directed therapy showed no evidence of progression.

The trial enrolled 819 patients who were randomly assigned to receive pembrolizumab plus chemotherapy or chemotherapy alone. Those in the experimental arm received intravenous (IV) pembrolizumab over 30 minutes on day 1, IV paclitaxel for 3 hours on day 1, and IV carboplatin over 30 minutes on day 1 of each 21-day cycle during the combination phase. Treatment continued for 6 cycles or until disease progression or unacceptable toxicity, and patients with stable disease or a partial response who still had measurable disease were allowed to continue treatment for up to 10 cycles. In the maintenance phase, those in the experimental arm were given IV pembrolizumab for 30 to 60 minutes on day 1 of each 6-week cycle for up to 14 cycles.

In the control arm, patients received the same chemotherapy regimen plus placebo during the combination phase, followed by placebo alone in the maintenance phase.

Approximately 70% of patients enrolled were pMMR, and about 30% were dMMR.¹

No new safety signals were identified, and findings were consistent with safety data observed in previous studies.

“In certain patients with advanced endometrial cancer who have progressed following prior systemic therapy and are not candidates for surgery or radiation, [pembrolizumab] has become an important treatment option, both as monotherapy and in combination,” Eliav Barr, MD, senior vice president, head of Global Clinical Development and chief medical officer of Merck Research Laboratories, said. “These latest results in the first-line setting are very encouraging and show the potential of [pembrolizumab] plus chemotherapy for patients with stage III to IV or recurrent disease, regardless of MRR status. We thank our collaborators for their partnership on this study, and we are grateful to the patients and investigators for their participation.”

Pembrolizumab is also being investigated in the first-line setting for advanced endometrial cancer both as monotherapy in the phase 3 KEYNOTE-C93/ENGOT-en15/GOG-3064 trial (NCT05173987) and in combination with lenvatinib in the phase 3 LEAP-001/ENGOT-en9 trial (NCT03884101). Furthermore, adjuvant pembrolizumab plus chemotherapy with or without radiotherapy is being evaluated in the phase 3 KEYNOTE-B21/ENGOT-en11/GOG-3053 trial (NCT04634877) in patients with newly diagnosed endometrial cancer after surgery with curative intent.

References

1. Merck’s Keytruda® (pembrolizumab) plus chemotherapy met primary endpoint of progression-free survival (PFS) as first-line therapy for advanced or recurrent endometrial carcinoma. News release. Merck. February 3, 2023. Accessed February 3, 2023. https://www.merck.com/news/mercks-keytruda-pembrolizumab-plus-chemotherapy-met-primary-endpoint-of-progression-free-survival-pfs-as-first-line-therapy-for-advanced-or-recurrent-endometrial-carcinoma/
2. FDA approves Merck’s KEYTRUDA (pembrolizumab) for patients with MSI-H/dMMR advanced endometrial carcinoma, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. News release. Merck. March 21, 2022. Accessed February 3, 2023. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-for-patients-with-msi%E2%80%91h-dmmr-advanced-endometrial-carcinoma-who-have-disease-progression-following-prior-systemic-therapy-in-any-se/
3. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed February 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pembrolizumab-and-lenvatinib-advanced-endometrial-carcinoma
4. Testing the addition of the immunotherapy drug pembrolizumab to the usual chemotherapy treatment (paclitaxel and carboplatin) in stage III-IV or recurrent endometrial cancer. ClinicalTrials.gov. Updated January 30, 2023. Accessed February 3, 2023. https://clinicaltrials.gov/ct2/show/NCT03914612