Merck's Keytruda Meets Primary Endpoint in Phase 3 Frontline Endometrial Cancer Trial

Merck announced that the Phase 3 KEYNOTE-C93 trial evaluating

pembrolizumab (Keytruda) monotherapy met its primary endpoint of progression-free survival (PFS) in patients with mismatch repair deficient (dMMR) advanced or recurrent endometrial cancer who had not previously received systemic chemotherapy.¹ The trial compared Keytruda alone against platinum doublet chemotherapy (carboplatin plus paclitaxel), and Keytruda is now the first and only PD-1 inhibitor to show a statistically significant and clinically meaningful PFS improvement as monotherapy compared with chemotherapy in this frontline setting.¹

The study also showed an immature trend toward improved overall survival (OS), although follow-up is continuing and the available report did not establish a statistically significant survival benefit. Brian Slomovitz, MD, principal investigator of the study at Mount Sinai Medical Center, described pembrolizumab as a potential "new chemo-free option" for first-line dMMR disease.¹ Merck said it plans to submit the findings to regulatory authorities.¹

“These findings build upon the well-established role of Keytruda in endometrial cancer, one of the few cancers with rising incidence rates,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories.

What did the KEYNOTE-C93 study show?

KEYNOTE-C93 enrolled patients with dMMR advanced or recurrent endometrial cancer who had received no systemic chemotherapy or whose disease recurred more than 6 months after completion of adjuvant therapy. Keytruda monotherapy was compared with platinum-based chemotherapy.¹

PFS and OS were dual primary end points. Keytruda met the PFS end point, producing a statistically significant improvement over chemotherapy, according to Merck's announcement.¹ However, neither the company announcement nor published news coverage provided a hazard ratio, confidence interval, median PFS, subgroup findings, or absolute difference between treatment groups.¹˒²

OS data were immature at the interim analysis but trended in favor of pembrolizumab. The trial remains ongoing for further survival assessment.¹ No detailed adverse-event results, treatment-discontinuation rates, or immune-mediated toxicity findings were reported in the available top-line disclosure.¹

These omissions limit assessment of the magnitude and clinical relevance of the PFS benefit. Full presentation or publication will be needed to determine whether Keytruda delays progression without compromising quality of life and whether selected patients experience durable treatment-free intervals.

How could Keytruda affect first-line endometrial cancer care?

PD-1 inhibitors already have established roles in dMMR endometrial cancer, including previously approved monotherapy indications after prior treatment and first-line combination regimens with carboplatin and paclitaxel.³˒⁴

Dostarlimab initially received US approval with chemotherapy for newly diagnosed advanced or recurrent dMMR endometrial cancer in 2023. Keytruda and dostarlimab subsequently received broader first-line approvals in combination with carboplatin and paclitaxel.³˒⁴ Unlike those regimens, KEYNOTE-C93 evaluated checkpoint inhibition without concurrent cytotoxic chemotherapy.

Keytruda is a PD-1-blocking antibody. Inhibiting this immune checkpoint can restore antitumor T-cell activity, an approach that has demonstrated particular relevance in tumors with deficient DNA mismatch repair. The potential clinical distinction in KEYNOTE-C93 is therefore not introduction of a new drug class, but possible movement of single-agent immunotherapy into an earlier treatment setting for a molecularly selected population.

Treatment competition will depend partly on mature survival evidence. In the phase 3 RUBY program, dostarlimab plus chemotherapy produced a statistically significant OS benefit, whereas the pembrolizumab-plus-chemotherapy KEYNOTE-868 program had not established an OS benefit in the cited analysis.³˒⁴ Cross-trial comparisons remain inappropriate because study populations, treatment strategies, follow-up, and statistical plans may differ.

What uncertainties remain for Keytruda?

KEYNOTE-C93 is a top-line trial update rather than a regulatory decision. Keytruda is not yet approved for first-line monotherapy in this setting, and any future indication would depend on regulatory review.¹

Key unanswered questions include the size and durability of the PFS effect, mature OS results, patient-reported outcomes, and the comparative burden of immune-related toxicity versus chemotherapy-associated adverse events. Additional details are also needed regarding subsequent therapies, crossover, and outcomes among patients whose cancers recurred after adjuvant treatment.

The findings apply specifically to dMMR tumors and should not be extrapolated to mismatch repair-proficient endometrial cancer. Until full data are available, the result supports a potentially treatment-sparing strategy but does not establish that Keytruda monotherapy should replace existing first-line chemoimmunotherapy regimens.

References

1. Keytruda (pembrolizumab) as monotherapy significantly improved progression-free survival in certain patients with advanced or recurrent endometrial cancer with mismatch repair-deficient disease. (2026 Jul 15). Merck. https://www.merck.com/news/keytruda-pembrolizumab-as-monotherapy-significantly-improved-progression-free-survival-pfs-in-certain-patients-with-advanced-or-recurrent-endometrial-cancer-with-mismatch-repair-deficient-d/
2. Liu A. (2026 Jul 15). Merck touts Keytruda front-line win in endometrial cancer subtype. Fierce Pharma. https://www.fiercepharma.com/pharma/merck-touts-keytruda-front-line-win-endometrial-cancer-subtype-pd-1-first
3. Eskander RN, et al. (2025 Mar 5). Pembrolizumab plus chemotherapy in advanced endometrial cancer (KEYNOTE-868/NRG-GY018). Nature Medicine.
4. Liu A. (2023 Jul 31). GSK beats Merck to first PD-1 approval in newly diagnosed endometrial cancer. Fierce Pharma. https://www.fiercepharma.com/pharma/gsk-beats-merck-first-pd-1-approval-newly-diagnosed-endometrial-cancer