Sac-TMT Improves PFS and OS, Is Under FDA Priority Review in Previously Treated Endometrial Cancer

Sacituzumab tirumotecan (sac-TMT; SKB264/MK-2870) improved progression-free survival (PFS) and overall survival (OS) vs treatment of physician’s choice in patients with advanced or recurrent endometrial cancer previously treated with platinum-based chemotherapy and immunotherapy, according to findings from the phase 3 TroFuse-005/ENGOT-en23/GOG-3095 trial (NCT06132958) presented at the 2026 ESMO Congress.¹

At a median follow-up of 14.0 months (range, 6.2-26.6), the median PFS by blinded independent central review (BICR) was 7.2 months (95% CI, 5.6-7.6) with sac-TMT (n = 386) vs 3.9 months (95% CI, 3.7-5.3) with treatment of physician’s choice (n = 390; HR, 0.59; 95% CI, 0.50-0.70; P < .0001). The median OS values were 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).

The confirmed objective response rate (ORR) by BICR, a key secondary end point, was 35.1% (95% CI, 30.3%-40.2%) with sac-TMT vs 17.3% (95% CI, 13.6%-21.6%) with treatment of physician’s choice (P < .00001), with complete responses reported in 6.1% and 4.5% of patients, respectively.¹

“We believe that sac-TMT should be considered a new standard of care for patients who have [progressed on chemotherapy] and immunotherapy and have limited treatment options,” Domenica Lorusso, MD, PhD, of the Department of Biomedical Sciences at Humanitas University and the Division of Gynecologic Oncology at IRCCS Humanitas Research Hospital in Milan, Italy, stated in a presentation of the data.

Based on these findings, the FDA has accepted for priority review a biologics license application seeking the approval of sac-TMT for the treatment of adult patients with endometrial cancer who have previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor; the Prescription Drug User Fee Act target action date is June 15, 2027.²

How was the TroFuse-005 trial of sac-TMT in endometrial cancer designed?

Sac-TMT is an antibody-drug conjugate (ADC) that targets TROP2, a protein that is overexpressed in more than 90% of endometrial cancers.¹

To be eligible for enrollment on the trial, patients had to have advanced or recurrent endometrial carcinoma, including carcinosarcoma, have received platinum and an anti–PD-1/PD-L1 agent in any setting, and have received no more than 3 prior lines of systemic therapy. A total of 776 patients were randomly assigned 1:1 to receive sac-TMT at 4 mg/kg intravenously every 2 weeks or treatment of physician’s choice, which was either doxorubicin at 60 mg/m² every 3 weeks (up to a lifetime cumulative dose of 450 mg/m²) or paclitaxel at 80 mg/m² on days 1, 8, and 15 of 28-day cycles.

Randomization was stratified by mismatch repair status (deficient [dMMR] vs proficient [pMMR]), TROP2 expression (low vs medium-high), number of prior lines of therapy, and the presence of measurable disease at baseline. The dual primary end points were PFS by BICR and OS. Secondary end points included ORR and duration of response (DOR) by BICR, patient-reported outcomes, and safety. This first interim analysis served as the final formal analysis for PFS, OS, and ORR.

Baseline characteristics were balanced between the arms; 84.5% of patients in the sac-TMT arm and 84.1% of those in the treatment of physician’s choice arm had pMMR disease, and 79.5% of patients in each arm had medium-high TROP2 expression.

What did landmark survival and response data show for sac-TMT in endometrial cancer?

The 12-month PFS rates were 29.4% with sac-TMT vs 12.4% with treatment of physician’s choice, and the 12-month OS rates were 63.4% vs 50.8%, respectively. The respective disease control rates were 74.5% vs 57.3%. The median DOR was 11.1 months (95% CI, 9.2-13.0) with sac-TMT vs 6.9 months (95% CI, 5.4-9.1) with treatment of physician’s choice.

ORRs favored sac-TMT in patients with non-endometrioid (sac-TMT arm, 41.3%; treatment of physician’s choice arm, 15.9%), endometrioid (34.1%; 19.1%), and carcinosarcoma histologies (14.8%; 9.5%).

Did sac-TMT benefit pMMR, dMMR, and TROP2-low endometrial cancer subgroups?

In patients with pMMR disease (n = 654), the OS outcomes favored sac-TMT (HR, 0.62; 95% CI, 0.49-0.78); in those with dMMR disease (n = 122), the OS outcomes were slightly less favorable (HR, 0.99; 95% CI, 0.60-1.63). The OS outcomes favored sac-TMT in patients with medium-high TROP2 expression (n = 617; HR, 0.58; 95% CI, 0.45-0.74) and treatment of physician’s choice in those with low expression (n = 159; HR, 1.07; 95% CI, 0.72-1.60). In the carcinosarcoma subgroup by local histology (n = 48), the OS outcomes favored treatment of physician’s choice (HR, 2.27; 95% CI, 1.09-4.71). Lorusso cautioned that outcomes in smaller subgroups should be interpreted carefully given limited patient numbers, wide 95% CIs, and no formal treatment-by-subgroup interaction analysis.

Overall, the OS benefit was observed with sac-TMT even though more patients in the treatment of physician’s choice arm received any subsequent anticancer therapy (49.0% vs 35.0% with sac-TMT), including ADCs (12.1% vs 4.9%, respectively).

What was the safety profile of sac-TMT in TroFuse-005? What does the future look like for developing this agent?

The median treatment duration was 31 weeks (range, 0.1-97) with sac-TMT vs 15 weeks (range, 0.1-94) with treatment of physician’s choice. In the safety population (sac-TMT arm, n = 384; treatment of physician’s choice arm, n = 367), grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 54.4% vs 41.4% of patients, and serious TRAEs were seen in 12.0% vs 13.6% of patients, respectively. TRAEs led to dose interruption in 44.5% vs 21.5% of patients, dose reduction in 29.2% vs 18.8% of patients, and discontinuation in 3.1% vs 4.9% of patients. TRAEs led to death in 3 patients in each arm (0.8% each).

Anemia was the most frequent hematologic TRAE (sac-TMT arm, 62.5% vs treatment of physician’s choice arm, 39.8%; grade 3, 20.3% vs 13.4%). Stomatitis was the most frequent nonhematologic TRAE (54.9% vs 14.4%; grade 3, 9.9% vs 1.6%), and dry eye occurred in 18.5% vs 3.0% of patients. After adjustment for exposure, only the rates of oral mucositis/stomatitis and ocular surface AEs remained higher with sac-TMT. Both the incidence and severity of stomatitis fell after a late-2024 trial protocol amendment added prophylactic steroid mouthwash, and 1% of patients discontinued sac-TMT because of oral mucositis/stomatitis. Quality of life, assessed with the EORTC QLQ-C30, remained stable in both arms.

Disclosures: Lorusso reported serving on advisory boards for AstraZeneca, AbbVie, Clovis Oncology, Corcept, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Oncoinvest, Novocure, Regeneron, Seagen, and Sutro; serving as an invited speaker for AstraZeneca, Clovis Oncology, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Novocure, and Seagen; serving as a consultant for AstraZeneca, AbbVie, Genmab, GSK, MSD, Pfizer, and Pharma&; receiving institutional funding, grants, or contracted research from AstraZeneca, Clovis Oncology, Pharma&, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, Pharmamar, Roche, Seagen, Alkermes, and Corcept; and receiving travel grants from AstraZeneca, AbbVie, GSK, and MSD.

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 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA11.
2. Sacituzumab tirumotecan (sac-TMT) reduced the risk of death by 32% and the risk of disease progression or death by 41% compared to chemotherapy in certain patients with advanced or recurrent endometrial cancer. News release. Merck. October 26, 2026. Accessed October 26, 2026. https://www.merck.com/news/sacituzumab-tirumotecan-sac-tmt-reduced-the-risk-of-death-by-32-and-the-risk-of-disease-progression-or-death-by-41-compared-to-chemotherapy-in-certain-patients-with-advanced-or-recurrent-endometrial/