Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 3
Start date: April 14, 2024
Planned enrollment: 1200
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)
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)
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)
Last updated: Sep 2026
Goal: Determine whether sacituzumab tirumotecan alone or with pembrolizumab improves progression-free survival compared with physician’s-choice chemotherapy in HR+/HER2− unresectable locally advanced or metastatic breast cancer.
Patients: Patients have centrally confirmed HR+/HER2− disease that progressed after at least one endocrine-therapy regimen for advanced disease, including a CDK4/6 inhibitor combination. They must be chemotherapy candidates with ECOG performance status 0–1 and adequate organ function. Prior chemotherapy for advanced disease, rapidly threatening symptomatic visceral disease, and active autoimmune disease requiring recent systemic treatment are among the exclusions.
Design: Open-label, randomized, three-arm phase 3 treatment study. The two primary comparisons are each investigational arm versus physician’s-choice chemotherapy; progression-free survival is assessed by blinded independent central review.
Treatments: Patients receive intravenous sacituzumab tirumotecan 4 mg/kg every 2 weeks, either alone or with intravenous pembrolizumab 400 mg every 6 weeks for up to approximately 2 years. The comparator is physician’s-choice paclitaxel, nab-paclitaxel, oral capecitabine, or liposomal doxorubicin. Sacituzumab tirumotecan is an investigational TROP2-directed antibody–drug conjugate that delivers a topoisomerase I inhibitor to tumor cells. In a separate phase 3 study in previously treated metastatic triple-negative breast cancer, median progression-free survival was 6.7 versus 2.5 months with physician’s-choice chemotherapy; efficacy in this trial’s HR+/HER2− population remains to be established. Pembrolizumab is a PD-1 inhibitor being evaluated for added benefit when combined with the conjugate.
Outcomes: The primary endpoint is RECIST 1.1 progression-free survival by blinded independent central review for each investigational arm versus chemotherapy. Secondary endpoints include overall survival, progression-free survival for the combination versus sacituzumab tirumotecan alone, objective response rate, duration of response, adverse events and treatment discontinuations, and patient-reported quality of life, functioning, fatigue, and diarrhea.
Burden on patient: Estimated moderate burden. Treatment requires intravenous visits every 2 weeks with sacituzumab tirumotecan, plus pembrolizumab every 6 weeks in the combination arm; comparator visit frequency depends on the selected chemotherapy. Imaging, safety monitoring, and repeated quality-of-life questionnaires add assessments, but no mandatory research biopsies or intensive pharmacokinetic sampling are specified.
Last updated: Sep 2026
Inclusion Criteria:
* Has unresectable locally advanced or metastatic centrally-confirmed hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer
* Has radiographic disease progression on one or more lines of endocrine therapy for unresectable locally advanced/metastatic HR+/HER2- breast cancer, with one in combination with a CDK4/6 inhibitor
* Is a chemotherapy candidate
* Has an eastern cooperative oncology group (ECOG) performance status of 0 to 1 assessed within 7 days before randomization
* Has adequate organ function
* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy
* Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load
* Participants with a history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable
Exclusion Criteria:
* Has breast cancer amenable to treatment with curative intent
* Has experienced an early recurrence (\<6 months after completing adjuvant/neoadjuvant chemotherapy) and therefore is eligible to receive second-line (2L) treatment
* Has symptomatic advanced/metastatic visceral spread at risk of rapidly evolving into life-threatening complications
* Has received prior chemotherapy for unresectable locally advanced or metastatic breast cancer
* Active autoimmune disease that has required systemic treatment in the past 2 years
* History of (noninfectious) pneumonitis/interstitial lung disease that requires steroids, or has current pneumonitis/interstitial lung disease
* Has an active infection requiring systemic therapy
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Baton Rouge, Louisiana, 70817, United States
No email / 888-501-4763
Status: Recruiting
Baltimore, Maryland, 21201, United States
No email / 410-328-6373
Status: Recruiting
Silver Spring, Maryland, 20910, United States
No email / 301-754-7000
Status: Recruiting
Boston, Massachusetts, 02215, United States
No email / 857-215-3246
Status: Recruiting
Detroit, Michigan, 48202, United States
No email / 313-916-2576
Status: Recruiting
Kansas City, Missouri, 64111, United States
No email / 816-932-2677
Status: Recruiting
St Louis, Missouri, 63110, United States
No email / 314-454-8313
Status: Recruiting
Nyack, New York, 10960, United States
No email / 845-362-1750
Status: Recruiting
New York, New York, 10016, United States
No email / 212-731-6000
Status: Recruiting
Brooklyn, New York, 11220, United States
No email / 212-731-6000
Status: Recruiting
Mineola, New York, 11501, United States
No email / 212-731-6000
Status: Recruiting
Stony Brook, New York, 11794, United States
No email / 631-444-4392
Status: Recruiting
Charlotte, North Carolina, 28204, United States
No email / 980-442-2000
Status: Recruiting
Columbus, Ohio, 43219, United States
No email / 614-383-6000
Status: Recruiting
Portland, Oregon, 97213, United States
No email / 503-215-2619
Status: Recruiting
Portland, Oregon, 97225, United States
No email / 503-215-2619
Status: Recruiting
Philadelphia, Pennsylvania, 19107, United States
No email / 215-955-8874
Status: Recruiting
Dallas, Texas, 75235, United States
No email / 214-590-8000
Status: Recruiting
San Antonio, Texas, 78240, United States
No email / 212-241-0493
Status: Recruiting
Dallas, Texas, 75231, United States
No email / 214-265-2080
Status: Recruiting
Fort Worth, Texas, 76104, United States
No email / 817-759-7000
Status: Recruiting
Tyler, Texas, 75701, United States
No email / 903-595-7093
Status: Recruiting
Dallas, Texas, 75390, United States
No email / 214-648-3111
Status: Recruiting
Midlothian, Virginia, 23114, United States
No email / 804-594-7300
Status: Recruiting
Fairfax, Virginia, 22031, United States
No email / 571-472-4724
Status: Recruiting
Roanoke, Virginia, 24014, United States
No email / 844-482-4812
Status: Recruiting
Richmond, Virginia, 23219, United States
No email / 877-462-7739
Status: Recruiting
Madison, Wisconsin, 53792, United States
No email / 800-622-8922
Status: Recruiting
Newmarket, Ontario, L3Y 2P9, Canada
No email / No phone
Status: Active, not recruiting
San Pedro Garza García, Nuevo León, 66278, Mexico
No email / No phone
Status: Active, not recruiting
Monterrey, Nuevo León, 64460, Mexico
No email / No phone
Status: Active, not recruiting
Auckland, 1023, New Zealand
No email / No phone
Status: Active, not recruiting
Lima, 15036, Peru
No email / No phone
Status: Active, not recruiting
Arequipa, Ariqipa, 15036, Peru
No email / No phone
Status: Active, not recruiting
Jesús María, Lima, 18, Peru
No email / No phone
Status: Active, not recruiting
Lima, Muni Metro de Lima, 15036, Peru
No email / No phone
Status: Active, not recruiting
Wieliszew, Masovian Voivodeship, 05-135, Poland
No email / No phone
Status: Active, not recruiting
Gdynia, Pomeranian Voivodeship, 81-519, Poland
No email / No phone
Status: Active, not recruiting
Poland, West Pomeranian Voivodeship, 75-581, Poland
No email / No phone
Status: Active, not recruiting
Kielce, Świętokrzyskie Voivodeship, 25-734, Poland
No email / No phone
Status: Active, not recruiting
Seoul, 03080, South Korea
No email / No phone
Status: Active, not recruiting
La Jolla, California, 92093-0698, United States
No email / No phone
Status: Active, not recruiting
Frankston, Victoria, 3199, Australia
No email / No phone
Status: Completed
Santa Ana, Provincia de San José, 10903, Costa Rica
No email / No phone
Status: Completed
Mumbai, Maharashtra, 400053, India
No email / No phone
Status: Completed
Szczecin, West Pomeranian Voivodeship, 71-730, Poland
No email / No phone
Status: Completed
Hato Rey, 00917, Puerto Rico
No email / No phone
Status: Completed
Changhua, 50006, Taiwan
No email / No phone
Status: Completed
Istanbul, 34722, Turkey (Türkiye)
No email / No phone
Status: Completed
Baltimore, Maryland, 21202, United States
No email / No phone
Status: Completed