On June 24, 2026, the U.S. Food and Drug Administration (FDA) approved sacituzumab govitecan-hziy (Trodelvy, Gilead Sciences, Inc.) for two new first-line indications in adults with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) as a single agent for patients who are not candidates for PD-1 or PD-L1 inhibitor-based therapy, and in combination with pembrolizumab (Keytruda, Merck & Co., Inc.) for patients whose tumors express PD-L1 (CPS ≥ 10). The approvals were supported by data from the ASCENT-03 and ASCENT-04/KEYNOTE-D19 trials, respectively, and were conducted under Project Orbis.

Clinical Takeaway

Sacituzumab govitecan-hziy now has two FDA-approved first-line roles in metastatic TNBC. For patients ineligible for checkpoint inhibitor therapy, the antibody-drug conjugate (ADC) monotherapy demonstrated a significant PFS benefit over standard chemotherapy. For PD-L1–positive patients (CPS ≥ 10), combining the ADC with pembrolizumab further improved outcomes versus chemotherapy plus pembrolizumab, establishing a new combination standard of care in this biomarker-selected population.

Drug Profile & Mechanism

  • Drug name: Sacituzumab govitecan-hziy (Trodelvy)
  • Class: Antibody-drug conjugate (ADC) targeting Trop-2, a cell-surface glycoprotein overexpressed in TNBC
  • Payload: SN-38, the active metabolite of irinotecan, a topoisomerase I inhibitor, delivered via a hydrolyzable linker enabling both intracellular and bystander cytotoxic activity
  • Sponsor: Gilead Sciences, Inc.
  • Combination partner (Indication 2): Pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex), both from Merck & Co., Inc. — anti-PD-1 checkpoint inhibitors

Approved Indications & Target Populations

  • Indication 1 (Monotherapy — ASCENT-03):
    • Adults with unresectable locally advanced or metastatic TNBC who have received no prior systemic therapy for advanced disease
    • Restricted to patients who are not candidates for PD-1 or PD-L1 inhibitor-based therapy
  • Indication 2 (Combination — ASCENT-04/KEYNOTE-D19):
    • Adults with unresectable locally advanced or metastatic TNBC who have received no prior systemic therapy for advanced disease
    • Tumors must express PD-L1 (CPS ≥ 10) as determined by an FDA-authorized test (PD-L1 IHC 22C3 pharmDx assay was used in the trial)

Study Design

  • ASCENT-03 (NCT05382299):
    • Design: Multicenter, open-label, randomized phase 3 trial
    • Enrollment: 558 patients with unresectable locally advanced or metastatic TNBC, treatment-naïve in the advanced setting, ineligible for PD-1/PD-L1 inhibitor therapy
    • Randomization: 1:1 to sacituzumab govitecan-hziy vs. investigator’s choice of chemotherapy (treatment of physician’s choice [TPC]): nab-paclitaxel, paclitaxel, or gemcitabine + carboplatin AUC2
    • Sacituzumab govitecan-hziy dosing: Days 1 and 8 of a 21-day cycle
  • ASCENT-04/KEYNOTE-D19 (NCT05382286):
    • Design: Multicenter, open-label, randomized phase 3 trial
    • Enrollment: 443 patients with locally advanced or metastatic TNBC, treatment-naïve in the advanced setting, with PD-L1 CPS ≥ 10
    • Randomization: 1:1 to sacituzumab govitecan-hziy + pembrolizumab vs. TPC (nab-paclitaxel, paclitaxel, or gemcitabine + carboplatin) + pembrolizumab
    • Sacituzumab govitecan-hziy: Days 1 and 8 of a 21-day cycle; pembrolizumab: Day 1 of a 21-day cycle

Endpoints

  • Primary endpoint (both trials): Progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR) per RECIST v1.1
  • Secondary endpoints (both trials):
    • Overall survival (OS)
    • Confirmed objective response rate (ORR)

Efficacy Outcomes

  • ASCENT-03 (Monotherapy vs. TPC):
    • Median PFS: 9.7 months (95% CI: 8.1–11.1) vs. 6.9 months (95% CI: 5.6–8.2) with TPC
    • Hazard ratio: 0.62 (95% CI: 0.50–0.77); p < 0.0001
    • Confirmed ORR: 50% (95% CI: 44–56) vs. 47% (95% CI: 41–53)
    • OS: Data immature at time of approval
  • ASCENT-04/KEYNOTE-D19 (Combination vs. TPC + Pembrolizumab):
    • Median PFS: 11.2 months (95% CI: 9.3–16.7) vs. 7.8 months (95% CI: 7.3–9.3) with TPC + pembrolizumab
    • Hazard ratio: 0.65 (95% CI: 0.51–0.84); p = 0.0009
    • Confirmed ORR: 61% (95% CI: 55–68) vs. 55% (95% CI: 48–62)
    • OS: Data immature at time of approval

Safety

The prescribing information for sacituzumab govitecan-hziy carries a boxed warning for the following:

  • Severe diarrhea
  • Severe neutropenia

Additional warnings and precautions for sacituzumab govitecan-hziy include:

  • Hypersensitivity and infusion-related reactions
  • Nausea and vomiting
  • Increased toxicity risk in patients with reduced UGT1A1 activity (relevant to SN-38 metabolism)
  • Embryo-fetal toxicity

The prescribing information for pembrolizumab includes warnings and precautions for:

  • Immune-mediated adverse reactions
  • Infusion-related reactions
  • Complications of allogeneic hematopoietic stem cell transplantation
  • Embryo-fetal toxicity

Recommended Dosage

  • Sacituzumab govitecan-hziy: 10 mg/kg administered as an intravenous infusion on Days 1 and 8 of each 21-day cycle, whether used as monotherapy or in combination with pembrolizumab
  • Treatment should be continued until disease progression or unacceptable toxicity
  • Refer to the full prescribing information for recommended dosing of pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex)

Key Clinical Implications

✔ Sacituzumab govitecan-hziy is now an FDA-approved first-line option for metastatic TNBC, expanding its role beyond the previously approved second-line setting and offering a chemotherapy-based ADC alternative for patients who cannot receive checkpoint inhibitor therapy.

✔ PD-L1 testing (CPS ≥ 10) is required prior to initiating the combination regimen with pembrolizumab; clinicians should ensure tumor biomarker status is assessed with an FDA-authorized assay at the time of diagnosis of advanced disease.

✔ The ADC plus pembrolizumab combination demonstrated superiority over the current standard of chemotherapy plus pembrolizumab in PD-L1–positive TNBC, with a median PFS of 11.2 vs. 7.8 months and an ORR of 61% vs. 55%, providing a meaningful clinical advance in this population.

✔ UGT1A1 genotyping should be considered given the known increased risk of toxicity from SN-38 accumulation in patients with reduced UGT1A1 activity; this information should inform monitoring and dose management strategies.

✔ OS data remain immature from both trials; longer follow-up will be needed to determine whether the PFS benefit translates into an overall survival advantage.

✔ This approval was reviewed under Project Orbis, with regulatory reviews ongoing in Australia, Israel, Brazil, Canada, and Switzerland — facilitating broader global access to this therapy for patients with TNBC.

Bottom Line

The dual approval of sacituzumab govitecan-hziy — as monotherapy for checkpoint inhibitor-ineligible patients and in combination with pembrolizumab for PD-L1–positive patients — marks a significant shift in the first-line treatment landscape for metastatic TNBC. Driven by statistically significant and clinically meaningful PFS improvements in both ASCENT-03 and ASCENT-04/KEYNOTE-D19, these approvals position the Trop-2–directed ADC as a cornerstone of frontline therapy. Clinicians should integrate PD-L1 biomarker testing and UGT1A1 assessment into their evaluation workflows to guide appropriate regimen selection and proactive toxicity management.

Sources:

  • U.S. Food and Drug Administration. (2026). FDA approves sacituzumab govitecan-hziy monotherapy and combination with pembrolizumab for first-line treatment of adults with unresectable locally advanced or metastatic TNBC. FDA Drugs Resources — Approved Drugs. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sacituzumab-govitecan-hziy-monotherapy-and-combination-pembrolizumab-first-line