In early February this year, the U.S. Food and Drug Administration (FDA) approved  sacituzumab govitecan-hziy (Trodelvy®; Gilead Sciences) for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) metastatic breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.[1]

Sacituzumab govitecan is a first-in-class Trop-2 directed antibody-drug conjugate designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Sacituzumab govitecan gained the approval by outperforming traditional chemotherapies in this patient group shown in the Phase 3 TROPiCS-02 study, which demonstrated a statistically significant and clinically meaningful progression-free survival and overall survival.

Based on the outcomes in the study, sacituzumab govitecan is now also recommended as a Category 1, preferred treatment for metastatic HR+/HER2- breast cancer by the National Comprehensive Cancer Network® (NCCN®) as defined in the Clinical Practice Guidelines in Oncology (NCCN Guidelines®).

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According to analysts at GlobalData, the drug is expected to become a standard of care for these breast cancer patients, who have had limited treatment options.

Commercial impact
This is sacituzumab govitecan’s second approval for breast cancer patients after it started being marketed for triple-negative breast cancer in 2021. Sales of the drug rose 79% from US $ 380 million in 2021 to US $ 680 million in 2022. A consensus forecasts by analysts at GlobalData project sales for sacituzumab govitecan to reach US $ 2.8 billion by 2028.

“Patients with HR+/HER2- metastatic breast cancer who are treated with hormone therapy and chemotherapy often develop resistance to these treatments. sacituzumab govitecan, an antibody-drug conjugate (ADC) that targets the Trop-2 protein found on the surface of most breast cancer cells, presents a statistically significant improvement in overall survival compared to retreating with chemotherapy,” said Israel Stern, Oncology & Hematology Analyst at GlobalData,

In the Phase 3 TROPiCS-02 study, sacituzumab govitecan showed a superior overall survival (OS) of 3.2 months (hazard ratio [HR]: 0.79) as well as a higher median progression-free survival (PFS) compared to those who were treated with chemotherapy.

“A challenge for sacituzumab govitecan’s market penetration is trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo/AstraZeneca) for the treatment of HER2-low metastatic breast cancer, which was approved in 2022. One reason is that the majority of HER2-negative patients display some HER2 expression making them (potentially) good candidates for treatment with trastuzumab deruxtecan. Aside from being first-to-market, trastuzumab deruxtecan may be more active than sacituzumab govitecan and reported impressive results in both OS (median 23.4 months) and PFS in a comparable trial of patients who received prior lines of chemotherapy,” Stern continued.

Topoisomerase I inhibitor payload
Although the two drugs target different receptors on the cancer cells, they both include a topoisomerase I inhibitor payload aimed at interrupting DNA replication resulting in cell death. If a patient develops resistance to one of the drugs due to antigen loss, they may be eligible to receive the other treatment in succession.

Gilead hopes to withstand the challenge of trastuzumab deruxtecan by developing sacituzumab govitecan in other indications such as first-line therapy in triple-negative breast cancer (TNBC), and non-small cell lung cancer. Sacituzumab govitecan represents a foundational piece for Gilead’s oncology pipeline and the company will seek every opportunity to utilize the drug in different cancer types,” Stern said.

“The company acquired Immunomedics, the developer of sacituzumab govitecan, for US $ 21 billion in 2020, and they’re relying on the success of this asset to justify this acquisition,” Stern concluded.

Clinical trials
Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Participants With HR+/HER2- Metastatic Breast Cancer (TROPiCS-02) – NCT03901339
Trial of Sacituzumab Govitecan in Participants With Refractory/Relapsed Metastatic Triple-Negative Breast Cancer (TNBC) (ASCENT) – NCT02574455

Highlights of Prescribing information
Sacituzumab govitecan-hziy (Trodelvy®; Gilead Sciences) [Prescribing Information]
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo/AstraZeneca)[Prescribing Information]

[1] Drug Description Sacituzumab govitecan. ADC Review | J. Antibody-drug Conjugates [Article]

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