A Phase 3, Randomized, Open-label Study of Sacituzumab Tirumotecan (MK-2870) Versus Investigator's Choice of Non-platinum Chemotherapy in Participants With Pretreated Locally Advanced/Metastatic Urothelial Carcinoma

Overview

Sacituzumab tirumotecan (sac-TMT; SKB264; MK-2870) is an investigational antibody–drug conjugate (ADC) being evaluated across multiple solid tumors. The most mature evidence comes from randomized studies in previously treated metastatic triple-negative breast cancer (TNBC) and EGFR-mutated non-small-cell lung cancer (NSCLC). Earlier-phase activity has also been reported in hormone-receptor-positive breast, urothelial, endometrial, ovarian, cervical, gastric and other cancers. (nature.com)

Mechanism of action

Sac-TMT consists of a humanized antibody targeting TROP2, a cell-surface protein frequently overexpressed by epithelial cancers, conjugated through a hydrolytically cleavable linker to KL610023, a belotecan-derived topoisomerase I inhibitor. Its average drug-to-antibody ratio is approximately 7.4. After TROP2 binding and internalization, KL610023 is released and inhibits topoisomerase I, causing DNA damage and tumor-cell death. (frontiersin.org)

Efficacy

• Metastatic TNBC: In the 263-patient phase 3 OptiTROP-Breast01 trial, sac-TMT improved median progression-free survival versus physician’s-choice chemotherapy: 6.7 vs 2.5 months (hazard ratio 0.32). Objective response rates were 45.4% vs 12.0%, and median response durations were 7.1 vs 3.0 months. At the interim overall-survival analysis, median survival was not reached with sac-TMT versus 9.4 months with chemotherapy (hazard ratio 0.53). (nature.com)
• EGFR-mutated NSCLC: In a randomized Chinese trial of 137 patients previously treated with an EGFR inhibitor and platinum chemotherapy, sac-TMT produced an objective response rate of 45%, compared with 16% for docetaxel. Median progression-free survival was 6.9 vs 2.8 months (hazard ratio 0.30), while 12-month overall survival was 73% vs 54%. (pubmed.ncbi.nlm.nih.gov)
• Other tumors: Preliminary single-arm studies have reported responses in urothelial cancer—confirmed response rates of 45.5% in second line and 26.3% in third or later lines—and in previously treated endometrial cancer, where the response rate was 34.1%**. These small, non-randomized cohorts require confirmation. (ascopubs.org)

Safety

Toxicity is predominantly hematologic. In the TNBC phase 3 trial, hematologic toxicity was the most common treatment-related adverse-event category. In an earlier 59-patient TNBC cohort, 57.6% experienced grade 3 or worse treatment-related events, most commonly decreased neutrophils (25.4%), decreased white-cell counts (23.7%), anemia (22.0%) and decreased platelets (16.9%); no treatment-related deaths, interstitial lung disease or grade 3 or worse diarrhea were reported. (nature.com)

In the randomized EGFR-mutated NSCLC study, grade 3 or worse treatment-related adverse events occurred in 56% of sac-TMT recipients versus 72% with docetaxel. Longer follow-up and broader international experience remain important for defining uncommon or delayed toxicities. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Phase 3 OptiTROP-Breast01 trial in metastatic TNBC
• Randomized trial versus docetaxel in EGFR-mutated NSCLC
• Phase 2 TNBC results
• Preclinical mechanism and pharmacology

Last updated: Sep 2026

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

* Has histologically documented locally advanced/metastatic urothelial cancer. Locally advanced disease must not be amenable to resection or radiation with curative intent per investigator assessment

* Has measurable disease per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as assessed by the investigator

* Has received treatment with anti-programmed cell death \[ligand\] 1 (anti-PD-\[L\]1) therapy, platinum-based chemotherapy, and enfortumab vedotin (EV)

* Prior therapy with disitamab vedotin (DV) is allowed but will not meet the requirement for prior treatment with EV, except in China, where participants may have received DV instead of EV before study entry

* Has received a maximum of 3 prior lines of therapy

* Has experienced radiographic disease progression on or after the immediate prior line of therapy before study entry

* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization

* Is eligible to receive at least one of the control arm nonplatinum chemotherapy options (paclitaxel, docetaxel, or vinflunine)

* Is able to provide archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously irradiated

* If human immunodeficiency virus (HIV) positive, has well-controlled HIV on antiretroviral therapy (ART)

* If hepatitis B surface antigen (HBsAg) positive, has received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and has undetectable HBV viral load

* If history of hepatitis C virus (HCV) infection, has undetectable HCV viral load

* Has adequate organ function

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

* Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing

* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease

* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease

* Has received prior systemic anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) and has not recovered to grade ≤ 1 or baseline from adverse event (AE) associated with anticancer therapy

* Has received prior therapy with trophoblast cell-surface antigen 2 (TROP2)-targeted antibody drug conjugate (ADC)

* Has received prior therapy with a topoisomerase 1 inhibitor-containing ADC

* Has completed prior external radiotherapy within 6 weeks or stereotactic radiotherapy within 4 weeks of start of study intervention, or has radiation related toxicities, requiring corticosteroids

* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed

* Has received prior chemotherapy for urothelial cancer with any of the study therapies in the control arm (paclitaxel, docetaxel, and vinflunine)

* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration

* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention

* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years

* Has a current or past history of central nervous system (CNS) metastases and/or carcinomatous meningitis

* Has an active infection requiring systemic therapy other than those permitted per protocol

* Has a history of stem cell/solid organ transplant

* Has not adequately recovered from major surgery, or has ongoing surgical complications