Pembro Monotherapy Boosts PFS Vs Chemo in dMMR Endometrial Cancer

Pembrolizumab (Keytruda) became the first and only PD-1 inhibitor to demonstrate a statistically significant and clinically meaningful progression-free survival (PFS) benefit as monotherapy over platinum doublet chemotherapy in the frontline treatment of patients with mismatch repair deficient (dMMR) advanced or recurrent endometrial cancer, according to top-line results from the phase 3 KEYNOTE-C93 trial (NCT05173987).¹

At a prespecified interim analysis, KEYNOTE-C93 met its primary end point of PFS, with blinded independent central review (BICR)-assessed PFS significantly favoring pembrolizumab monotherapy over carboplatin plus paclitaxel in patients with dMMR advanced or recurrent endometrial cancer who had not previously received systemic chemotherapy or who experienced disease recurrence more than 6 months after completing prior adjuvant therapy.

A trend toward improvement in overall survival (OS), the trial's other primary end point, was observed for pembrolizumab; however, the OS data were not mature at the time of this analysis. A clinically meaningful objective response rate (ORR), complete response rate (CRR), and duration of response (DOR) were also observed with pembrolizumab monotherapy. Full results will be presented at an upcoming medical meeting and shared with regulatory authorities, according to Merck.

The KEYNOTE-C93 safety analysis showed a profile consistent with that previously observed with pembrolizumab, with no new safety signals identified.

"This is the first phase 3 trial of a PD-1 inhibitor to show improved PFS compared to platinum doublet chemotherapy when given as monotherapy in the frontline setting for these patients, potentially providing a chemo-free option," Brian Slomovitz, MD, director of Gynecologic Oncology and deputy director of the Braman Comprehensive Cancer Center at Mount Sinai Medical Center in Miami Beach, Florida, and the study's overall principal investigator, stated in a news release.¹

KEYNOTE-C93 is a randomized, open-label, phase 3 trial enrolling 299 patients with dMMR advanced or recurrent endometrial cancer who had not previously received systemic chemotherapy for their disease. Patients were randomized to receive either pembrolizumab 400 mg intravenously every six weeks for up to 18 cycles, or carboplatin (AUC 5 or 6) plus paclitaxel (175 mg/m²) every three weeks for six cycles. The trial's dual primary end points were BICR-assessed PFS per RECIST v1.1 and OS; a key secondary endpoint was ORR.¹

Clinical Context

The KEYNOTE-C93 findings build on prior study results supporting pembrolizumab in endometrial cancer across several settings and combinations. In the phase 3 NRG-GY018/KEYNOTE-868 trial (NCT03914612), pembrolizumab added to carboplatin and paclitaxel followed by single-agent pembrolizumab demonstrated a 70% reduction in the risk of progression or death in patients with dMMR advanced or recurrent endometrial cancer compared with chemotherapy alone at the primary analysis (HR, 0.30; 95% CI, 0.19-0.48; P <.001), with the median PFS not yet reached in the pembrolizumab arm vs 8.3 months with placebo.² At a median follow-up of approximately 49 months, updated data from KEYNOTE-868 showed pembrolizumab plus chemotherapy reduced the risk of death by 44% in the dMMR cohort (HR, 0.56; 95% CI, 0.34-0.92; log-rank P =.0124).³

These data supported the FDA's June 2024 approval of pembrolizumab in combination with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for adults with primary advanced or recurrent endometrial carcinoma, which includes both dMMR and pMMR disease.⁴

KEYNOTE-C93 now builds on that combination data by testing whether pembrolizumab monotherapy, without the toxicity burden of platinum doublet chemotherapy, can produce superior PFS in the dMMR population specifically. For patients who are eligible for and willing to receive chemotherapy in the combination regimen, the question becomes whether the addition of chemotherapy to pembrolizumab provides meaningful incremental benefit over pembrolizumab alone for dMMR tumors, which are among the most immunologically responsive tumor subtypes. The OS endpoint of KEYNOTE-C93, though currently immature, will be critical to answering that question definitively.

Pembrolizumab currently holds three approved indications in endometrial cancer in the United States: in combination with carboplatin and paclitaxel followed by single-agent pembrolizumab for primary advanced or recurrent endometrial carcinoma; in combination with lenvatinib (Lenvima) for advanced pMMR or non-MSI-H endometrial carcinoma following prior systemic therapy; and as a single agent for previously treated MSI-H or dMMR advanced endometrial carcinoma in patients not candidates for curative surgery or radiation.¹

"These findings build upon the well-established role of KEYTRUDA in endometrial cancer, one of the few cancers with rising incidence rates," Gursel Aktan, MD, vice president of global clinical development at Merck Research Laboratories, stated in the news release. "We are committed to helping women facing this disease by advancing potential treatment options. We thank the patients and investigators for their important contributions to this study and look forward to sharing these results with the medical community."¹

REFERENCES

1. KEYTRUDA (pembrolizumab) as monotherapy significantly improved progression-free survival (PFS) in certain patients with advanced or recurrent endometrial cancer with mismatch repair deficient (dMMR) tumors compared to chemotherapy. News release. Merck. July 15, 2026. Accessed July 15, 2026. https://tinyurl.com/mv6nrh5p

2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312

3. 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 versus placebo plus carboplatin/paclitaxel in patients with endometrial cancer: results from the NRG GY018 trial. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2026; Chicago, IL. Abstract 5503.

4. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. News release. US Food and Drug Administration. June 17, 2024. Accessed July 15, 2026. https://tinyurl.com/bdfkwhfd