Sac-TMT Improves Survival vs Chemotherapy in Pretreated Endometrial Cancer

At the 2026 European Society for Medical Oncology (ESMO) Congress, results from the phase 3 TroFuse-005/ENGOT-en23/GOG-3095 trial (NCT06132958) showed that sacituzumab tirumotecan (sac-TMT) significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs treatment of physician’s choice (TPC) in patients with advanced or recurrent endometrial cancer who had received platinum-based chemotherapy and immunotherapy.¹ Sac-TMT is a TROP2-directed antibody-drug conjugate (ADC) with a topoisomerase I inhibitor payload.

How did sac-TMT perform vs chemotherapy in endometrial cancer?

At a median follow-up of 14.0 months (range, 6.2-26.6), median PFS by blinded independent central review (BICR) was 7.2 months (95% CI, 5.6-7.6) with sac-TMT vs 3.9 months (95% CI, 3.7-5.3) with TPC (HR, 0.59; 95% CI, 0.50-0.70; P <.0001). Median OS was 19.0 months (95% CI, 16.1-not reached) vs 12.1 months (95% CI, 11.0-15.2), respectively (HR, 0.68; 95% CI, 0.55-0.84; P = .0001). Twelve-month OS rates were 63.4% vs 50.8%. “The curves separate early and remain separated over time, suggesting consistent benefit,” said presenting study author Domenica Lorusso, MD, PhD, director of the Gynecological Oncology Unit at Humanitas Hospital San Pio X, Milan, and professor of Obstetrics and Gynecology, Humanitas University, Rozzano (MI). Investigators noted that OS favored sac-TMT even though more patients in the TPC arm received subsequent therapy (49.0% vs 35.0%), including ADCs (12.1% vs 4.9%).

The ORR was 35.1% (95% CI, 30.3%-40.2%) with sac-TMT vs 17.3% (95% CI, 13.6%-21.6%) with TPC (difference, 17.8 percentage points; 95% CI, 11.6-23.9; P <.00001). Complete responses were observed in 6.1% vs 4.5%. Median duration of response was 11.1 months (95% CI, 9.2-13.0) vs 6.9 months (95% CI, 5.4-9.1).

How did outcomes differ across subgroups?

PFS and OS HRs favored sac-TMT in most prespecified subgroups, including patients with mismatch repair–proficient (pMMR) disease (PFS HR, 0.57; 95% CI, 0.47-0.69; OS HR, 0.62; 95% CI, 0.49-0.78) and medium-to-high TROP2 expression (PFS HR, 0.54; 95% CI, 0.44-0.65; OS HR, 0.58; 95% CI, 0.45-0.74). Estimates were less clear in patients with mismatch repair–deficient (dMMR) disease (PFS HR, 0.72; 95% CI, 0.47-1.09; OS HR, 0.99; 95% CI, 0.60-1.63), low TROP2 expression (PFS HR, 0.84; 95% CI, 0.60-1.20; OS HR, 1.07; 95% CI, 0.72-1.60), and carcinosarcoma (PFS HR, 1.52; 95% CI, 0.80-2.90; OS HR, 2.27; 95% CI, 1.09-4.71).

“The interpretation of this exploratory analysis in the smaller subgroups should be cautious, considering the limited number of patients, the wide confidence intervals, and the absence of a formal treatment-by-subgroup interaction analysis,” Lorusso said.

What was the safety profile of sac-TMT?

Median treatment duration was 31 weeks with sac-TMT vs 15 weeks with TPC. Grade 3 or higher treatment-related adverse effects (AEs) occurred in 54.4% vs 41.4% of patients, and serious treatment-related AEs in 12.0% vs 13.6%. Treatment-related AEs led to dose interruption in 44.5% vs 21.5%, dose reduction in 29.2% vs 18.8%, and discontinuation in 3.1% vs 4.9%; 3 patients (0.8%) in each arm died of treatment-related AEs. Anemia (any grade, 62.5% vs 39.8%; grade 3, 20.3% vs 13.4%) was the most common hematologic AE, and stomatitis (any grade, 54.9% vs 14.4%; grade 3, 9.9% vs 1.6%) was the most common nonhematologic AE. Dry eye occurred in 18.5% vs 3.0%, and interstitial lung disease or pneumonitis in 1.8% vs 0.5% (regardless of attribution).

Stomatitis incidence and severity declined after a protocol amendment in late 2024 recommended prophylactic steroid mouthwash. Health-related quality of life was maintained in both arms, with no between-group difference in change from baseline to week 12 (0.02; 95% CI, −3.11 to 3.15). “Quality of life was not impacted,” Lorusso said.

What is the design of TroFuse-005?

The trial randomly assigned 776 patients at 242 sites in 31 countries and regions 1:1 to sac-TMT at 4 mg/kg intravenously every 2 weeks (n = 386) or TPC (n = 390), consisting of doxorubicin at 60 mg/m² every 3 weeks or paclitaxel at 80 mg/m² on days 1, 8, and 15 of each 28-day cycle. Patients had received prior platinum-based chemotherapy and anti–PD-1/PD-L1 therapy and no more than 3 prior lines of systemic therapy; carcinosarcoma was capped at 4% by central histology. The dual primary end points were PFS by BICR and OS, and ORR was a key secondary end point. Randomization was stratified by mismatch repair status, TROP2 expression, prior lines of therapy, and measurable vs nonmeasurable disease. The data cutoff was March 23, 2026, and this was the first interim analysis and the final formal analysis for PFS, OS, and ORR.

What did the investigators and discussant conclude?

“For all these reasons, we believe that sac-TMT should be considered a new standard of care for patients who have failed [chemotherapy] and immunotherapy and have very limited treatment options,” Lorusso said.

Invited discussant Joyce F. Liu, MD, MPH, said the toxicity profile still matters. “Even though this is an ADC, and our hope for these is they have reduced toxicity, they are still targeted chemotherapies, and chemotherapy by any other name will have chemotherapy [AEs],” she said.² Liu noted that only about one-third of patients with carcinosarcoma in the study had high TROP2 expression, and asked whether biology explains the lack of benefit in that small subgroup. She added that sac-TMT is 1 of 7 ADCs in phase 3 development in endometrial cancer, all with topoisomerase I inhibitor payloads. “We don’t need just antigen diversity; we need payload diversity,” Liu said. Liu is associate chief and director of Clinical Research in the division of Gynecologic Oncology at Dana-Farber Cancer Institute.

Lorusso reported advisory board roles with AstraZeneca, AbbVie, Clovis Oncology, Corcept, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Oncoinvest, Novocure, Regeneron, Seagen, and Sutro; speaker, consulting, institutional funding, and travel support from multiple companies including AstraZeneca, GSK, MSD, and Genmab.

References

1. Lorusso D, Martin-Babau J, Backes F, et al. Sacituzumab tirumotecan in previously treated advanced or recurrent endometrial cancer: results from the phase 3 TroFuse-005/ENGOT-en23/GOG-3095 study. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA11.
2. Liu JF. Discussion of LBA11. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain.