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 a TROP2-directed antibody–drug conjugate (ADC) that couples the same anti‑TROP2 monoclonal antibody used in sacituzumab govitecan to a belotecan‑derived topoisomerase I inhibitor payload (KL610023) via a sulfonyl‑pyrimidine–CL2A–carbonate linker; the average drug‑to‑antibody ratio (DAR) is ~7.4. Early- and late‑phase studies report antitumor activity across multiple solid tumors, most notably triple‑negative breast cancer (TNBC), hormone‑receptor–positive/HER2‑negative (HR+/HER2–) breast cancer, non–small cell lung cancer (NSCLC), and urothelial carcinoma. (jhoonline.biomedcentral.com)

Regulatory note: Sacituzumab tirumotecan received approval in China (November 2024) for pretreated advanced TNBC; it remains investigational in the United States with multiple ongoing phase 3 trials. (onclive.com)

Mechanism of action

• Target: TROP2, broadly expressed in epithelial cancers. (jhoonline.biomedcentral.com)
• Payload/linker: Belotecan‑derived topoisomerase I inhibitor (KL610023) linked via an irreversible methylsulfonyl‑pyrimidine chemistry designed to enhance conjugate stability and enable membrane‑permeable payload release (bystander effect). DAR ~7.4. (pmc.ncbi.nlm.nih.gov)

Efficacy

Breast cancer
- Phase 1/2 (first‑in‑human, MK‑2870‑001; data cutoff June 29, 2023):
- TNBC expansion: ORR 34.8% at 4 mg/kg (n=23) and 38.9% at 5 mg/kg (n=36). (jhoonline.biomedcentral.com)
- HR+/HER2– expansion: ORR 31.7% (n=41); median DOR 9.5 months; median PFS 8.0 months; median OS 13.9 months. (jhoonline.biomedcentral.com) - Phase 3 (OptiTROP‑Breast01; randomized vs physician’s‑choice chemotherapy; TNBC):
- PFS (BICR): 5.7 vs 2.3 months; HR 0.31 (95% CI 0.22–0.45).
- ORR: 43.8% vs 12.8%.
- Interim OS: HR 0.53 (95% CI 0.36–0.78). (ascopubs.org)

Lung cancer
- Phase 1b/2 (ASCO 2024; treatment‑naive metastatic NSCLC) sac‑TMT + KL‑A167 (anti‑PD‑1):
- Cohort 1A and 1B showed ORR 48.6% and 77.6%, respectively; 6‑month PFS rates 69.2% and 84.6%. A phase 3 study of sac‑TMT + pembrolizumab in first‑line PD‑L1 TPS ≥50% NSCLC is ongoing (NCT06170788). (ovid.com)
- Nature Medicine publications (April 2025) reported results in previously treated metastatic TNBC (phase 3) and advanced NSCLC (phase 1/2 and phase 2); DOIs: 10.1038/s41591‑025‑03630‑w (TNBC) and 10.1038/s41591‑025‑03638‑2 (NSCLC). (nature.com)

Urothelial carcinoma
- ASCO GU 2025 (MK‑2870‑001 cohort): sac‑TMT 5 mg/kg Q2W in previously treated unresectable/metastatic UC:
- Second‑line (n=11): ORR 45.5% (1 CR, 4 PR).
- Third‑line or later (n=38): ORR 26.3%.
- Median PFS ~5.0–5.8 months; median OS 11.5 months (3L+). (ascopubs.org)

Safety

Across studies, the most common treatment‑related grade ≥3 adverse events include myelosuppression (neutrophil count decreased, white blood cell count decreased) and anemia; dermatologic events and stomatitis occurred in early dose‑finding.

• Phase 1/2 (MK‑2870‑001): grade 3/4 TRAEs in 52% (4 mg/kg) and 67% (5 mg/kg) in TNBC expansion; no grade 5 TRAEs. HR+/HER2– cohort: grade 3/4 TRAEs in 54%; no grade 5 TRAEs. Reported DLTs included grade 3 stomatitis and rash; MTD 5.5 mg/kg; recommended expansion doses 4 and 5 mg/kg. (jhoonline.biomedcentral.com)
• Phase 3 TNBC (OptiTROP‑Breast01): common grade ≥3 TRAEs with sac‑TMT were neutrophil count decreased (32.3%), anemia (27.7%), and white blood cell count decreased (25.4%); rates were comparable or lower than chemotherapy for hematologic events; no new safety signals reported. (ascopubs.org)
• Urothelial carcinoma (ASCO GU 2025): treatment‑related grade ≥3 AEs in 59.2%; most common were anemia (38.8%) and decreased neutrophil count (28.6%); no treatment‑related deaths reported at cutoff. (ascopubs.org)

Further reading

• Journal article: Phase 1/2 MK‑2870‑001 results (design, TNBC and HR+/HER2– expansions, dosing, safety). Journal of Hematology & Oncology, 2025. (jhoonline.biomedcentral.com)
• Preclinical characterization of SKB264 (payload/linker chemistry, DAR, stability, bystander effect). Cancer Biol Med (PMC), 2022. (pmc.ncbi.nlm.nih.gov)
• ASCO 2024 phase 3 TNBC (OptiTROP‑Breast01) abstract. Journal of Clinical Oncology. (ascopubs.org)
• ASCO 2024 NSCLC combination cohort abstract (sac‑TMT + anti‑PD‑1). Journal of Clinical Oncology. (ovid.com)
• ASCO GU 2025 urothelial carcinoma cohort abstract. Journal of Clinical Oncology. (ascopubs.org)
• Nature Medicine (April 2025) articles: phase 3 TNBC and NSCLC trials (publication DOIs listed by Nature Index). (nature.com)

Notes: Dosing, efficacy, and safety data reflect study‑specific populations and cutoffs (e.g., June 29, 2023 for MK‑2870‑001 expansions; June 21/Nov 30, 2023 for interim PFS/OS in OptiTROP‑Breast01; June 30/May 21, 2024 for ASCO GU 2025 UC efficacy/safety). Cross‑trial comparisons should be made cautiously. (jhoonline.biomedcentral.com)

Last updated: Oct 2025

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