Post–T-DXd Sacituzumab Govitecan Plus Trastuzumab Yields Low ORR in HER2+ Metastatic Breast Cancer

The combination of sacituzumab govitecan-hziy (Trodelvy) and trastuzumab (Herceptin) elicited an overall response rate (ORR) of 3.7% (95% CI, 0.1%-19%) in patients with HER2-positive metastatic breast cancer who had previously received fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), failing to meet the primary end point of the phase 2 SATEEN trial (NCT05113251) presented at the 2026 ESMO Breast Cancer Congress.¹

One confirmed partial response was observed among 27 evaluable patients, and the clinical benefit rate among these patients for 18 weeks or longer was 14.8% (95% CI, 4%-33%). Due to these results, the trial was stopped for futility after the first stage of the Simon’s 2-stage design.

“This constitutes the first prospective data for sacituzumab govitecan plus trastuzumab in HER2-positive disease,” Paolo Tarantino, MD, PhD, a clinical fellow at Dana-Farber Cancer Institute in Boston, Massachusetts, stated in a presentation of the data.

What was the rationale for investigating sacituzumab govitecan after T-DXd in patients with HER2-positive metastatic breast cancer?

Although T-DXd is a standard therapy for HER2-positive metastatic breast cancer, Tarantino explained that no prospective data currently exist to guide treatment selection following progression on the agent. He also noted that research has shown that HER2 is often downregulated following T-DXd treatment, whereas TROP2 is highly expressed in HER2-positive breast cancer, supporting the potential of TROP2-targeted therapy in this setting.

Sacituzumab govitecan is a TROP2-directed antibody-drug conjugate (ADC) featuring a topoisomerase-1 (TOPO1) inhibitor payload that is FDA approved for the treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received at least 2 prior systemic therapies, with at least 1 of them for metastatic disease; and for the treatment of patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have previously received endocrine therapy and at least 2 additional systemic therapies in the metastatic setting.² Although this ADC has generated survival benefits in these patient populations, it had not been previously tested in the HER2-positive setting or specifically after T-DXd, Tarantino contextualized.¹

What was the design of the SATEEN trial?

SATEEN was a single-arm, investigator-initiated, multicenter trial. Using a Simon’s 2-stage design, the trial required a minimum of 3 responders among the first 27 patients in stage 1 to proceed to stage 2. The trial was powered to distinguish an ORR of 25% from a null ORR of 10%.

Patients received sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles in combination with trastuzumab every 3 weeks (administered intravenously or subcutaneously).

What were the baseline characteristics of the SATEEN trial patient population?

The 27 patients enrolled in the first stage had a median age of 55 years. The population was heavily pretreated, with a median of 5 prior anti-HER2 lines for metastatic disease (range, 1-17). All patients had previously received trastuzumab and pertuzumab (Perjeta), 70% of patients had received ado-trastuzumab emtansine (T-DM1; Kadcyla), and 74% of patients had received a HER2-directed TKI like tucatinib (Tukysa), neratinib (Nerlynx), or lapatinib (Tykerb).

Regarding prior T-DXd treatment, 81% of patients had discontinued the agent due to disease progression, whereas 15% of patients had discontinued the agent without progression. The median time spent on prior T-DXd was 12 months (range, 2-35). At enrollment, 70% of patients had visceral metastases, and 33% of patients had brain metastases (18% active and 15% stable).

What survival outcomes were observed in the SATEEN trial?

The median progression-free survival for the total population was 2.3 months (95% CI, 2.0-3.5). The median overall survival was 9.2 months (95% CI, 7.6-not reached).

What was the safety profile of sacituzumab govitecan plus trastuzumab in T-DXd–pretreated HER2-positive metastatic breast cancer?

Treatment-related adverse effects (TRAEs) of grade 2 or higher occurred in 85% of patients. Grade 3 TRAEs were reported in 48% of patients, and grade 4 TRAEs occurred in 26% of patients. Dose modifications due to AEs were required for 33% of patients in the population.

The most common grade 2 or higher TRAEs included:

• Anemia (grade ≥ 2, 59%; grade 3, 26%; grade 4, 0%)
• Neutropenia (59%; 30%; 30%)
• Diarrhea (30%; 19%; 0%)
• Fatigue (26%; 4%; 0%)

Notably, there was 1 grade 5 TRAE involving neutropenic sepsis with multi-organ failure. Following this event, the study investigators implemented mandatory growth factor support after day 8 of each cycle.

“Safety was consistent with prior sacituzumab govitecan trials, although these data do emphasize the importance of growth factor support, especially in heavily pretreated patients receiving sacituzumab govitecan,” Tarantino concluded. “Biomarker analyses are ongoing to understand the reasons why tumors become resistant to TOPO1-directed ADCs to guide sequential ADC treatment and optimize treatment beyond ADCs.”

Disclosures: Tarantino reported performing consultant/advisory roles for AstraZeneca, Daiichi Sankyo, Gilead, Eli Lilly, Menarini/Stemline, Novartis, Roche/Genentech, and Sanofi; performing speaking roles for AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, and Roche/Genentech; and receiving institutional research funding from AstraZeneca and Ignite Proteomics.

References

1. Tarantino P, Yu L, Faggen M, et al. Efficacy and safety of sacituzumab govitecan (SG) plus trastuzumab in patients with HER2+ metastatic breast cancer after prior trastuzumab deruxtecan (T-DXd): results from the phase II SATEEN trial. Presented at: 2025 ESMO Breast Cancer Congress. May 6-8, 2026; Berlin, Germany. Abstract LBA4.
2. Trodelvy. Prescribing information. Gilead; March 2025. Accessed May 8, 2026. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.pdf