A Phase 3, Randomized, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of Sacituzumab Tirumotecan Maintenance Treatment With or Without Bevacizumab Versus Standard of Care After Second-line Platinum-based Doublet Chemotherapy in Participants With Platinum-sensitive Recurrent Ovarian Cancer (TroFuse-022/ENGOT-ov84/GOG-3103)

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:

* Has histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

* Has received 4 or more cycles of platinum-based doublet chemotherapy in first-line and a total of 6 cycles of carboplatin-based doublet chemotherapy in second-line setting for ovarian cancer (OC).

* Has platinum-sensitive epithelial OC,

* Has provided tissue of a tumor lesion that was not previously irradiated

* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy

* Participants who are hepatitis B surface antigen positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to allocation (Part 1) or randomization (Part 2)

* Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening

* Has an ECOG performance status of 0 to 1 assessed within 7 days before allocation (Part 1) or randomization (Part 2)

Exclusion Criteria:

* Has nonepithelial cancers (germ cell tumors and sex cord-stromal tumors), borderline tumors (low malignant potential), mucinous, seromucinous that is predominantly mucinous, malignant Brenner's tumor and undifferentiated carcinoma

* Has platinum-resistant OC or platinum-refractory OC

* 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 active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis, or chronic diarrhea)

* 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 more than 2 prior lines of systemic therapy for OC.

* Has received prior systemic anticancer therapy within 3 weeks or 5 half-lives (whichever is shorter) before allocation (Part 1) or randomization (Part 2)

* Has received prior radiotherapy within 2 weeks of allocation (Part 1) or randomization (Part 2), or has radiation related toxicities, requiring corticosteroids

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

* Has active central nervous system (CNS) metastases and/or carcinomatous meningitis

* Has an active infection requiring systemic therapy