Immunotherapy has transformed the treatment landscape of endometrial cancer, particularly for tumors with deficient mismatch repair (dMMR). Although immune checkpoint inhibitors have already become standard in combination with chemotherapy for advanced disease, an important question has remained unanswered: Can immunotherapy alone replace chemotherapy in the first-line setting for patients with dMMR tumors?
New findings from the Phase III KEYNOTE-C93 trial suggest the answer may be yes.
According to Merck’s announcement, KEYTRUDA® (pembrolizumab) became the first PD-1 inhibitor to demonstrate a statistically significant and clinically meaningful improvement in progression-free survival compared with platinum-doublet chemotherapy as first-line monotherapy for patients with advanced or recurrent dMMR endometrial cancer.
Why This Study Matters
Patients with dMMR endometrial cancer have highly immunogenic tumors characterized by a large number of mutations that generate neoantigens capable of stimulating an immune response. These tumors are particularly sensitive to PD-1 blockade, making them ideal candidates for immunotherapy.
While pembrolizumab has already shown substantial benefit in previously treated MSI-H/dMMR disease and in combination with chemotherapy in the frontline setting, KEYNOTE-C93 is the first Phase III study designed to determine whether chemotherapy can be omitted entirely in this biomarker-selected population.
About KEYNOTE-C93
KEYNOTE-C93 (NCT05173987) is a randomized, open-label, Phase III trial evaluating pembrolizumab monotherapy versus standard platinum-doublet chemotherapy in patients with advanced or recurrent dMMR endometrial cancer who had:
- not received prior systemic chemotherapy for advanced disease, or
- experienced recurrence more than six months after completing adjuvant therapy.
Study Design
A total of 299 patients were randomized to receive either:
- Pembrolizumab 400 mg intravenously every six weeks for up to 18 cycles, or
- Paclitaxel plus carboplatin every three weeks for six cycles.
Endpoints
The study included two co-primary endpoints:
- Progression-free survival (PFS)
- Overall survival (OS)
Key secondary endpoints included:
- Overall response rate (ORR)
- Complete response rate (CRR)
- Duration of response (DOR).
Primary Results
At the planned interim analysis, pembrolizumab successfully met its primary endpoint.
Compared with platinum-doublet chemotherapy, pembrolizumab monotherapy demonstrated:
- Statistically significant improvement in progression-free survival
- Clinically meaningful overall response rate
- Encouraging complete response rate
- Durable responses
- A favorable safety profile consistent with previous pembrolizumab studies
- No new safety signals.
Overall survival also showed a positive trend in favor of pembrolizumab, although the data remain immature and continued follow-up is ongoing.
Safety
No unexpected toxicities were identified.
The safety profile was consistent with the well-established adverse-event spectrum of pembrolizumab, including immune-related toxicities that are familiar to oncologists using PD-1 inhibitors across multiple tumor types.
Clinical Implications
The importance of KEYNOTE-C93 extends beyond another positive immunotherapy trial.
Until now, frontline treatment for advanced endometrial cancer has relied largely on chemotherapy, even in tumors known to be highly responsive to immunotherapy. These results suggest that selected patients with dMMR disease may be able to receive effective treatment without upfront cytotoxic chemotherapy, potentially reducing chemotherapy-associated toxicity while maintaining—or even improving—disease control.
Although the detailed efficacy data have not yet been presented, the trial establishes proof of principle that biomarker-driven immunotherapy alone may become a new frontline option for this molecular subgroup.
The results also reinforce the growing importance of universal mismatch repair testing in endometrial cancer, as treatment decisions are increasingly guided by tumor biology rather than histology alone.
Looking Ahead
The complete efficacy analyses from KEYNOTE-C93—including hazard ratios, median progression-free survival, overall survival, subgroup analyses, and response durability—are expected to be presented at an upcoming scientific meeting and submitted to regulatory authorities.
If confirmed by the full dataset, KEYNOTE-C93 could redefine the first-line treatment paradigm for patients with advanced or recurrent dMMR endometrial cancer, introducing a chemotherapy-free immunotherapy strategy for a population whose tumors are particularly susceptible to PD-1 blockade.
FDA Approves Pembrolizumab with Paclitaxel for Platinum-Resistant Ovarian Cancer