The trophoblast cell-surface antigen 2 (TROP2)-directed antibody–drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) significantly improves survival outcomes in advanced or recurrent endometrial cancer previously treated with platinum-based chemotherapy and immunotherapy, according to the phase III TroFuse-005 trial.
TroFuse-005 met its dual primary endpoints of progression-free (PFS) and overall survival (OS), reported Dr Domenica Lorusso from IRCCS Humanitas Research Hospital in Milan, Italy, at the annual ESMO Congress.
Over a median follow-up of 14 months, the median PFS was 7.2 months with sac-TMT vs 3.9 months with treatment of physician’s choice (TPC), while the median OS was 19 vs 12.1 months, respectively, Lorusso continued. [ESMO 2026, abstract LBA11]
Compared with TPC, sac-TMT reduced the risk of progression or death by 41 percent (hazard ratio [HR] for PFS, 0.59, 95 percent confidence interval [CI], 0.50–0.70; p<0.0001) and the risk of death by 32 percent (HR for OS, 0.68, 95 percent CI, 0.55–0.84; p=0.0001).
“Furthermore, sac-TMT doubled the objective response rate (ORR) and improved disease control rate (DCR),” Lorusso noted.
ORR was 35.1 percent with sac-TMT vs 17.3 percent with TPC (p<0.00001), and DCR was 74.5 percent vs 57.3 percent, respectively. The median duration of response was 11.1 vs 6.9 months, respectively.
“Efficacy with sac-TMT was observed across most prespecified subgroups,” Lorusso said.
TroFuse-005
Conducted across 31 countries and regions, TroFuse-005 included 776 adult patients (median age 65 years, 60.2 percent White) with histologically confirmed advanced or recurrent endometrial carcinoma or carcinosarcoma received up to two (75 percent) or three (25 percent) previous lines of therapy, including systemic platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 therapy.
Of the patients, 84.3 percent had mismatch repair-proficient (pMMR) disease, 79.5 percent had medium-to-high TROP2 expression, 55.3 percent had endometrioid histology, and 96.9 percent had measurable disease at baseline.
The patients were randomly assigned to receive intravenous sac-TMT (4 mg/kg on days 1 and 15 of each 28-day cycle; n=386) or TPC (intravenous doxorubicin 60 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle; n=390).
Patients in the sac-TMT group had a median of 16 treatment cycles, while those in the TPC group had a median of five. The median duration of treatment was 31 weeks and 15 weeks in the respective treatment groups.
Grade 3 or higher adverse events (AEs) occurred 69 percent of patients in the sac-TMT group and 57 percent in the TPC group. Serious AEs were reported in 35 percent and 32 percent of patients in the respective groups. Treatment-related AEs led to death in three (<1 percent) patients in the sac-TMT group and three (<1 percent) in the TPC group.
Anaemia was the most common haematological treatment-related AE (62.5 percent in the sac-TMT group vs 39.8 percent in the TPC group), while stomatitis was the most common non-haematological treatment-related AE (54.9 percent in the sac-TMT group vs 14.4 percent in the TPC group). Treatment-emergent AEs of special interest for sac-TMT included stomatitis and ocular surface toxicity.
Lorusso noted that quality of life, as evaluated according to EORTC QLQ-C30, remained stable over time in both treatment groups, with no between-group difference noted in change from baseline to week 12.
“In conclusion, sac-TMT is the first ADC to show statistically significant and clinically meaningful improvements in the dual primary endpoints of PFS and OS and the key secondary endpoint of ORR compared with TPC in previously treated advanced endometrial cancer,” Lorusso said.
“These findings support sac-TMT as a new standard of care for patients with endometrial cancer who have received platinum-based chemotherapy and immunotherapy and have limited effective treatment options,” she added.
The ADC Era
“Endometrial cancer really has entered its ADC era,” noted study discussant Dr Joyce Liu from the Dana Farber Cancer Institute in Boston, Massachusetts, US, who congratulated Lorusso and colleagues for “bringing ADCs fully into our present.”
“TroFuse-005 validates the clinical activity of a TROP2-targeting topoisomerase I (Topo1) inhibitor payload ADC in advanced endometrial cancer,” Liu said.
However, she emphasized that sac-TMT was only one of seven ADCs currently being evaluated in phase III studies of advanced endometrial cancer, with every one of them having shown promising early-phase data. The ADCs target four different antigens—TROP2, HER2, B7-H4, and foliate receptor alpha—but all of them are Topo1 inhibitor payload ADCs.
According to Liu, clinicians would have to navigate ADC selection by considering target expression overlap and correlation with ADC activity. Questions including whether antigen target profile guide ADC selection, whether one ADC would be better if multiple target antigens are highly expressed, and whether an ADC targeting a more highly expressed antigen would be more active if expression of one target antigen is low should be consistently asked in trials, she added.
Additionally, “side effect and safety profiles will shape patient and clinician preferences for ADCs, especially when efficacy is similar,” Liu said.