Pembrolizumab Alone Beat Chemotherapy First Line in dMMR Endometrial Cancer. A New ADC Extended Survival After It.
Pembrolizumab alone cut progression risk 43 percent over chemotherapy in KEYNOTE-C93; sacituzumab tirumotecan added 6.9 months of survival in TroFuse-005.
Idea in Brief
The News
Two Merck phase 3 trials in advanced endometrial cancer were presented Oct. 26 at ESMO and published in The Lancet.
The Evidence
First-line pembrolizumab alone beat carboplatin-paclitaxel on progression-free survival in dMMR disease (HR 0.57); sacituzumab tirumotecan improved overall survival after platinum and immunotherapy (HR 0.68).
The Caveats
KEYNOTE-C93 has not shown a survival benefit and did not compare against chemoimmunotherapy; sacituzumab tirumotecan is not approved, with an FDA action date of June 15, 2027.
Pembrolizumab alone beat carboplatin and paclitaxel on progression-free survival as first-line treatment for mismatch repair-deficient (dMMR) advanced or recurrent endometrial cancer in the phase 3 KEYNOTE-C93 trial, presented Oct. 26 at the ESMO Congress in Madrid.
The same Presidential Symposium of the European Society for Medical Oncology (ESMO) carried a second Merck endometrial trial, TroFuse-005, in which the TROP2-directed antibody-drug conjugate sacituzumab tirumotecan improved overall survival over chemotherapy in patients whose disease had progressed after platinum and anti-PD-1 or PD-L1 therapy. Both results were published simultaneously in The Lancet, according to Merck's announcements of KEYNOTE-C93 and TroFuse-005. Together they address two different decision points in the same disease.
What did KEYNOTE-C93 show?
Pembrolizumab alone cut the risk of progression or death by 43 percent but has not yet shown an overall survival benefit. The open-label trial (NCT05173987) randomized 299 patients with centrally confirmed dMMR disease, in the first-line setting, to pembrolizumab 400 mg every six weeks for up to 18 cycles or six cycles of carboplatin (AUC 5 or 6) plus paclitaxel 175 mg/m2. Crossover was allowed after progression, Targeted Oncology reported from the presentation by Brian M. Slomovitz, M.D., of Mount Sinai Medical Center in Miami Beach and the GOG Foundation.
At a median follow-up of 36.7 months, median progression-free survival was 38.2 months with pembrolizumab versus 8.4 months with chemotherapy (HR 0.57; 95% CI, 0.42 to 0.79; P=.0002), and 36-month progression-free survival was 52.8 versus 30.0 percent. Overall survival, the second dual primary endpoint, did not reach significance (HR 0.77; 95% CI, 0.52 to 1.15; P=.10); median survival was not reached in either arm and 36-month survival was 70.7 versus 62.0 percent. Response rates were similar, 64.1 versus 62.1 percent, but responses lasted longer: an estimated 70.7 percent of pembrolizumab responders were still in response at 36 months versus 40.0 percent with chemotherapy.
Toxicity favored pembrolizumab. Grade 3 or higher treatment-related adverse events occurred in 18.1 versus 50.7 percent, and grade 3 or higher anemia in 2.0 versus 18.1 percent. Grade 3 or higher immune-mediated events and infusion reactions were more common with pembrolizumab, 7.4 versus 3.5 percent, Merck said.
KEYNOTE-C93 shows that chemotherapy can be deferred in dMMR disease without losing ground on progression, but it has not yet shown that patients live longer, and its comparator was chemotherapy alone, not chemotherapy plus a checkpoint inhibitor.
What did TroFuse-005 show?
Sacituzumab tirumotecan extended median overall survival by 6.9 months in previously treated disease. The open-label trial (NCT06132958) randomized 776 patients who had received platinum chemotherapy and an anti-PD-1 or PD-L1 agent, with no more than three prior lines, to sacituzumab tirumotecan 4 mg/kg every two weeks or physician's choice of doxorubicin or weekly paclitaxel. Domenica Lorusso, M.D., Ph.D., of Humanitas University in Milan presented the results. At a median follow-up of 14.0 months, median overall survival was 19.0 versus 12.1 months (HR 0.68; 95% CI, 0.55 to 0.84) and median progression-free survival 7.2 versus 3.9 months (HR 0.59; 95% CI, 0.50 to 0.70). The response rate was 35.1 versus 17.3 percent.
The conjugate was harder on blood counts and mucosa. Grade 3 or higher treatment-related events occurred in 54.4 versus 41.4 percent; the most common grade 3 or higher events with sacituzumab tirumotecan were anemia (23.7 percent), neutropenia (20.1 percent) and stomatitis or oral mucositis (9.9 percent). Discontinuation for adverse events was low, 3.1 versus 4.9 percent, and three treatment-related deaths occurred in each arm. The Food and Drug Administration has accepted a Biologics License Application for priority review in this setting with a target action date of June 15, 2027, Merck said. The drug, developed by Kelun-Biotech, is not approved in the United States.
Clinical Pearls
- KEYNOTE-C93 randomized 299 patients with centrally confirmed dMMR disease to pembrolizumab 400 mg every six weeks or carboplatin plus paclitaxel.
- Median progression-free survival was 38.2 versus 8.4 months (HR 0.57; 95% CI, 0.42 to 0.79).
- Overall survival in KEYNOTE-C93 was not significantly different at this analysis (HR 0.77; 95% CI, 0.52 to 1.15).
- Grade 3 or higher treatment-related adverse events occurred in 18.1 percent with pembrolizumab versus 50.7 percent with chemotherapy.
- TroFuse-005 randomized 776 previously treated patients; median overall survival was 19.0 versus 12.1 months with sacituzumab tirumotecan versus chemotherapy.
- Grade 3 or higher anemia (23.7 percent) and neutropenia (20.1 percent) were the most common severe events with sacituzumab tirumotecan.
How big are the gains?
By The Script Pad's arithmetic from the published figures, pembrolizumab added 29.8 months of median progression-free survival in KEYNOTE-C93, and at three years about 23 more patients per 100 were alive without progression. It also spared about 33 patients per 100 a grade 3 or higher treatment-related event. In TroFuse-005 the gains were smaller in absolute terms, 6.9 months of median survival and 3.3 months of progression-free survival, in a population that had already received platinum and immunotherapy, and the cost was about 13 more patients per 100 with a grade 3 or higher event. These are unadjusted calculations from reported medians and rates, not trial analyses.
The comparison KEYNOTE-C93 did not make matters in practice. Pembrolizumab is already approved in the United States with carboplatin and paclitaxel, followed by pembrolizumab alone, for primary advanced or recurrent endometrial carcinoma, the regimen studied in KEYNOTE-868, and as a single agent for MSI-H or dMMR disease after prior systemic therapy, Merck notes. KEYNOTE-C93 compared single-agent immunotherapy with chemotherapy alone, so it does not show whether dropping chemotherapy from a chemoimmunotherapy regimen is equivalent. Merck said results will be shared with regulators; it did not announce a U.S. filing date.
What it means in clinic
Two points apply now. First, MMR status drives the first-line choice, so mismatch repair immunohistochemistry should be on every newly diagnosed advanced or recurrent endometrial cancer, the same biomarker that now steers immunotherapy in rectal cancer and adjuvant treatment in colon cancer. Second, for patients with dMMR disease who want to avoid chemotherapy, the chemotherapy-free option now has phase 3 progression data behind it, though not yet survival data or a label in this setting. For previously treated disease, sacituzumab tirumotecan remains investigational until the FDA acts; watch for that decision, for mature KEYNOTE-C93 survival data and for other ESMO Presidential Symposium results moving toward labels.
Reported, fact-checked and edited by The Script Pad's editorial staff. See How we use AI.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
