Chemotherapy-Free First Line: Pembrolizumab Delays Progression In MMR-Deficient Endometrial Cancer

Can Endometrial Cancer Treatment Start Without Chemotherapy? First Results From KEYNOTE-C93

The phase 3 KEYNOTE-C93 trial, presented on October 26 at the ESMO 2026 Congress, shows that in mismatch repair–deficient (dMMR) advanced or recurrent endometrial cancer, pembrolizumab (Keytruda) alone, without chemotherapy, clearly delayed disease progression in the first line compared with carboplatin + paclitaxel (HR 0.57; median 38.2 vs 8.4 months) and reduced severe adverse events. The difference in overall survival is not yet significant. The results are summarized in the Merck announcement and published in The Lancet. We have previously covered pembrolizumab and its uses, dMMR immunotherapy in colon cancer through the ATOMIC trial, and dostarlimab approval in dMMR rectal cancer.

Why does this matter?

Endometrial (uterine lining) cancer is one of the most common gynecologic cancers in developed countries. In advanced or recurrent disease, the standard first-line treatment was for a long time carboplatin and paclitaxel chemotherapy; in recent years, adding an immunotherapy drug (pembrolizumab or dostarlimab) to this chemotherapy has become the new standard.

In a substantial share of endometrial cancers, the system that repairs DNA copying errors (mismatch repair) does not work; these tumors are called dMMR or microsatellite instability–high (MSI-H). Some are linked to hereditary Lynch syndrome. Because they carry many mutations, these tumors are easily recognized by the immune system and are especially sensitive to immunotherapy.

The question of KEYNOTE-C93 was this: in this sensitive group, can starting with immunotherapy alone, without chemotherapy, give better results than standard chemotherapy?

Can pembrolizumab alone replace chemotherapy in dMMR endometrial cancer?

In KEYNOTE-C93, chemotherapy-free pembrolizumab gave longer progression-free survival than carboplatin + paclitaxel as first-line treatment of dMMR advanced or recurrent endometrial cancer (median 38.2 vs 8.4 months; HR 0.57) and reduced severe adverse events (18.1% vs 50.7%). The overall survival difference is not yet significant; the decision should be individualized.

Trial design: KEYNOTE-C93

Results

Progression-free survival

By blinded independent central review, median progression-free survival was 38.2 months in the pembrolizumab arm and 8.4 months in the chemotherapy arm. The risk of progression or loss of life fell by 43% (HR 0.57; 95% CI 0.42–0.79). At 36 months, the share of patients progression-free was 52.8% vs 30.0%; that is, about 23 of every 100 patients stayed progression-free longer than would be expected with chemotherapy. The curves crossed at about 6 months: chemotherapy controlled disease faster early on, but the benefit of pembrolizumab then separated durably.

Overall survival

In overall survival the trend favors pembrolizumab but is not statistically significant: the median was not reached in either arm; loss of life was recorded in 43 patients (28.9%) in the pembrolizumab arm and 54 (36.0%) in the chemotherapy arm (HR 0.77; 95% CI 0.52–1.15). Overall survival was 79.0% vs 73.2% at 24 months and 70.7% vs 62.0% at 36 months. According to the investigators, an important reason is crossover: 85.2% of patients who progressed in the chemotherapy arm later received pembrolizumab or another PD-1/PD-L1 inhibitor. The trial therefore in practice compares pembrolizumab in the first line with pembrolizumab in the second line.

Response rates and durability of response

The objective response rate was similar in the two arms (64.1% vs 62.1%). The complete response rate was higher with pembrolizumab (33.8% vs 26.2%). The clearest difference was in durability of response: the share of patients still responding at 24 months was 77.0% vs 41.3%. In other words, chemotherapy often produces a response, but for many patients those responses were short-lived.

Safety and quality of life

Grade 3 or higher treatment-related adverse events were reported in 18.1% of patients on pembrolizumab and 50.7% on chemotherapy. At week 12, global health status and quality-of-life scores favored pembrolizumab (between-group difference of 7.02 points).

This result suggests that avoiding the known burden of chemotherapy can be a concrete benefit for patients. On the other hand, immunotherapy can cause immune-related adverse events that affect the thyroid and other hormone glands and can become permanent (side effects of immunotherapy, kidney side effects). Detailed rates of these events are not included here because the full text was not accessible.

How should the results be read?

Strengths

• A large phase 3 trial in a biomarker-selected (dMMR), centrally confirmed patient group.
• The primary endpoint was measured by blinded independent central review; the risk of progression or loss of life fell by 43%.
• Not only progression-free survival but also durability of response (77.0% vs 41.3% at 24 months) and quality of life favor pembrolizumab.
• Grade 3 or higher adverse events fell by about two thirds (18.1% vs 50.7%).

Points of caution

• The overall survival difference is not significant: HR 0.77 (one-sided p=0.1000) did not cross the interim boundary (0.0189); the picture may change as follow-up lengthens.
• Crossover effect: 85.2% of patients who progressed in the chemotherapy arm later received a PD-1/PD-L1 inhibitor; this may have narrowed the overall survival difference.
• Open-label design: Patients and physicians knew the treatment; however, the primary endpoint was measured by blinded independent review.
• Interim analysis and short follow-up: Median follow-up is about 36.7 months; the upper limit of the confidence interval for median progression-free survival was not reached (17.9 months–not reached).
• Early-period curve: The progression-free survival curves cross at about 6 months; in the first months chemotherapy may control disease faster.
• The comparator: The control arm received chemotherapy alone; there was no direct comparison with chemotherapy + immunotherapy, the standard in many centers today.

What does it mean in practice?

• Mismatch repair testing in every endometrial cancer: Immunohistochemical staining for the MLH1, MSH2, MSH6, and PMS2 proteins (or MSI testing) is essential for treatment selection; if the result is dMMR, this trial comes into play as an option.
• Who it may suit: dMMR patients who wish to avoid chemotherapy or who would not tolerate it well; quality of life and the burden of side effects carry more weight in the decision.
• Who needs caution: In patients with extensive, symptomatic disease who need rapid control, the speed of chemotherapy in the first months may matter; there is no comparison with chemotherapy + immunotherapy.
• Lynch syndrome assessment: In dMMR patients, hereditary Lynch syndrome should be investigated; this is also important for screening relatives (hereditary variant analysis).
• Shared decision: The rise of median progression-free survival to 38.2 months, the reduction in severe adverse events, and the still nonsignificant overall survival difference should be discussed together with the patient.

Practical tips for patients and relatives

• If you have endometrial cancer, ask whether mismatch repair (dMMR/MSI) testing was done on your tumor and what the result is.
• If your tumor is dMMR, tell your team whether there is colon, uterine, or ovarian cancer in your family; genetic counseling may be needed.
• Ask for the benefits and risks of chemotherapy, chemotherapy + immunotherapy, and immunotherapy alone in numbers.
• During treatment, contact your team right away if you have diarrhea, abdominal pain, shortness of breath, cough, marked fatigue, dizziness, skin rash, or jaundice.
• Regular monitoring of thyroid hormones, blood sugar, and liver and kidney values is important; do not miss your lab appointments.
• At the decision stage, do not hesitate to get a second opinion and to ask whether a suitable clinical trial exists.

Frequently asked questions

What did the KEYNOTE-C93 trial show?

In advanced or recurrent endometrial cancer with centrally confirmed dMMR, pembrolizumab without chemotherapy prolonged progression-free survival compared with carboplatin + paclitaxel (median 38.2 vs 8.4 months; HR 0.57) and reduced severe adverse events. The overall survival difference is not yet significant.

Can pembrolizumab replace chemotherapy?

In selected dMMR patients it is a promising option, but the results come from an interim analysis and the overall survival difference is not significant. The decision should be made with the oncologist, based on disease burden, ability to tolerate chemotherapy, and patient preference.

How long does the treatment last?

In the pembrolizumab arm, 400 mg was given intravenously every 6 weeks for up to 18 cycles (about 2 years). In the control arm, carboplatin + paclitaxel was given every 3 weeks for 6 cycles.

Can this treatment be used in Türkiye?

Pembrolizumab is licensed in Türkiye, but licensing and SGK reimbursement for chemotherapy-free first-line use based on this trial could not be confirmed; this use may require off-label approval. The up-to-date situation must be confirmed.

Glossary

dMMR / MSI-H

Tumors in which the mismatch repair system that corrects DNA copying errors does not work (dMMR) and, as a result, repeated sequences in tumor DNA are unstable (MSI-H).

Lynch syndrome

A syndrome in which an inherited change in mismatch repair genes raises the risk of colon, uterine, ovarian, and other cancers.

Pembrolizumab

An immunotherapy drug that blocks the PD-1 protein and helps the immune system become active against cancer cells.

Progression-free survival

The time from the start of treatment until disease progression or loss of life.

Overall survival

The time from the start of treatment until loss of life from any cause.

BICR

Blinded independent central review: imaging is read by independent experts who do not know the treatment arm.

Crossover

Patients in the control arm moving to a new treatment (here immunotherapy) after disease progression; it can narrow the overall survival difference.