Phase 3 Trial of Pembrolizumab Meets Primary PFS End Point in Endometrial Cancer

Ramez Eskander, MD

Pembrolizumab (Keytruda) combined with carboplatin and paclitaxel showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients with stage III to IV or recurrent endometrial carcinoma regardless of mismatch repair status, meeting the primary end point of the phase 3 NRG-GY018/KEYNOTE-868 trial (NCT03914612).¹

The combination of pembrolizumab plus the standard of care chemotherapy was given every 3 weeks for approximately 6 cycles followed by pembrolizumab as a single agent every 6 weeks for up to 14 cycles. At a pre-specified interim analysis review conducted by an independent Data Monitoring Committee, patients with endometrial carcinoma who had mismatch repair proficient (pMMR) or mismatch repair deficient (dMMR) proved to be more effective by producing a statistically significant PFS rate vs chemotherapy alone.

In this study, the safety profile of pembrolizumab was also consistent with what has been observed in previous studies. No new safety signals were identified.

“Endometrial cancer is the only gynecologic cancer with a rising incidence and mortality.Importantly, metastatic, recurrent endometrial cancer remains a difficult to treat disease with limited therapeutic options. Pembrolizumab monotherapy has established efficacy in the treatment of patients with dMMR endometrial cancer, and in combination with lenvatinib in the pMMR population, both following progression on prior chemotherapy,” Eskander Ramez, MD, Ramez Eskander, MD, principal investigator and gynecologic oncologist, University of California, San Diego, told Targeted Oncology^TM. “This study was designed to determine if pembrolizumab given in combination with chemotherapy, followed by maintenance pembrolizumab in patients with newly diagnosed dMMR and pMMR EC could improve outcomes. As noted in the press release, the study met its primary endpoint in both patient populations. We look forward to sharing the study results at an upcoming scientific congress.”

The randomized, blinded, placebo-controlled, phase 3 NRG-GY018 trial is examining the combination of pembrolizumab with the standard of care chemotherapy, paclitaxel, and carboplatin, compared with placebo plus standard of care chemotherapy for the treatment of measurable stage III, IVA, IVB or recurrent endometrial cancer in patients with both pMMR and dMMR.

In the trial, 819 patients were enrolled and randomized to receive either the combination phase of pembrolizumab plus chemotherapy every 3 weeks for approximately 6 cycles followed by pembrolizumab as a single agent every 6 weeks for up to 14 cycles, or the control of placebo plus chemotherapy.

Patients aged 18 years and older with measurable stage III, measurable stage IVA, stage IVB or recurrent endometrial cancer were eligible for enrollment.² A pathology report showing results of institutional MMR IHC testing, histologic confirmation of the original primary tumor, submission of tumor specimens for centralized MMR IHC testing, and an ECOG performance status of 0,1, or 2, were required for all patients enrolled. Further, patients must have not received any prior chemotherapy for the treatment of their endometrial cancer.

Among patients enrolled, all were required to have MMR testing prior to randomization. Approximately 70% of patients were pMMR, and 30% were dMMR.¹ The primary end point of the trial was PFS with secondary end points of overall survival, objective response rate, duration of response and safety.

The complete results from the trial are expected to be presented at an upcoming medical meeting and discussed with regulatory authorities.

In addition to this study, pembrolizumab is also being evaluated by MERCK in first-line advanced endometrial cancer as a monotherapy in KEYNOTE-C93/ENGOT-en15/GOG-3064 (NCT05173987) and in combination with lenvatinib (Lenvima) in the LEAP-001/ENGOT-en9 (NCT03884101). The agent is also being evaluated in the adjuvant setting in the KEYNOTE-B21/ENGOT-en11/GOG-3053 trial (NCT04634877).

“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, Merck Research Laboratories. “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 mismatch repair status. We thank our collaborators for their partnership on this study, and we are grateful to the patients and investigators for their participation.”

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://bit.ly/3l9DkAw

2. 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