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Real-World Data Show Improved Survival With Sacituzumab Govitecan as First-Line ADC in HER2-Low Breast Cancer
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Key Takeaways
- Sacituzumab govitecan (SG) as the first ADC improves TTF and rwOS compared to trastuzumab deruxtecan (T-DXd) in HER2-low mBC.
- HER2-low mBC, defined by low HER2 expression, constitutes nearly 55% of breast cancer diagnoses.
Sequencing of antibody-drug conjugates (ADCs) in HER2-mutated breast cancer is crucial for optimizing treatment outcomes.
Patients with human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC) experience longer time to treatment failure (TTF) and real-world overall survival (rwOS) when treated with sacituzumab govitecan (SG, Trodelvy; Gilead Sciences) as the first antibody-drug conjugate (ADC) compared with trastuzumab deruxtecan (T-DXd, Enhertu; Trodelvy, AstraZeneca) administered second. The authors’ findings suggest that the sequence in which the ADCs are administered can significantly impact treatment efficacy, with most patients achieving a better duration of response from ADC1 versus ADC2.
Concept image of an antibody drug conjugate | Image Credit: © AddMeshCube - stock.adobe.com
HER2 mutations have become an increasingly promising target for various cancers, including BC. HER2 proteins are responsible for controlling the healthy growth of breast cells; however, when over- or underexpressed, they can disrupt normal cell signaling, leading to uncontrolled cell proliferation and tumor development. There are multiple types of HER2 mutations, including HER2-positive, HER2-negative, HER2-low, and HER2-ultra low, which are each defined by their immunohistochemical (IHC) score. HER2-low and ultra-low have been defined more recently as clinical understanding of the disease’s pathology expands.1
Nearly 55% of all BC diagnoses are HER2-low, which is characterized by low levels of HER2 expression with an IHC score of 1+ and 2+. Until the notable DESTINY-Breast04 trial (NCT03734029), there were no agents capable of successfully targeting HER2 in this subgroup. In the trial, the HER2-targeting ADC T-DXd significantly improved survival compared with patients treated with chemotherapy. Additionally, the treatment yielded a 50% lower risk of disease progression. T-DXd received approval from the FDA in April 2024 for the treatment of adult patients with unresectable or metastatic HER2+ solid tumors based on promising survival and safety outcomes.1-3
SG is an ADC that targets Trop-2 and has been shown to dramatically enhance OS and PFS in patients with triple-negative breast cancer (TNBC). In 2021, it was initially authorized as a monotherapy for patients with unresectable locally advanced or metastatic TNBC who had received 2 or more previous systemic treatments. In 2023, clinically meaningful data from the TROPiCS-02 trial (NCT03901339) led to SG’s approval for HER2-negative, hormone receptor-positive (HR+) mBC.4-6
In a multicenter retrospective cohort study, investigators set out to determine how the sequential use of SG and T-DXd—in either order—impacts treatment outcomes in patients with HER2-low mBC. Their assessment involved a total of 84 patients with a median age of 60.4 years, of whom 56 had HR+/HER2-low MBC (66.7%) and 28 had HR-negative (HR-)/HER2-low MBC (33.3%). The primary measurements included TTF and rwOS, as well as real-world response rates.7
In the HR+/HER2-low mBC group (n = 56), 42.9% of patients received SG as ADC1 and T-DXd as ADC2. For evaluable patients, the real-world response rate was 77.3% for ADC1 and 34.8% for ADC2. There was a TTF of 6.3 months for the ADC1 compared with 3.6 months for the ADC2 and a median rwOS of 22.8 months and 7.8 months, respectively.7
There was a real-world response rate of 46.9% for ADC1 and 17.2% for ADC2 in the HR+/HER2-low mBC group receiving T-DXd as ADC1 and SG as ADC2 (57.1%). The rwOS was 17.7 months from the start of ADC1 and 5.8 months from the start of ADC2, the investigators reported. Additionally, the TTF for T-DXd as ADC1 was 5.3 months and 2.1 months for SG as ADC2.7
In the HR-/HER2-low mBC cohort, 89.3% of patients were treated with SG as ADC1 and T-DXd as ADC2. The real-world overall response rate was 68.0% for ADC1 and 33.3% for ADC2, with an rwOS of 16.5 months for ADC1 and 6.5 months for ADC2. There was a median TTF of 7.5 months and 2.8 months, respectively.7
Patients with HR-/HER2-low mBC receiving SG as ADC1 and T-DXd as ADC2 (10.7%), there was a real-world response rate of 68% for ADC1 and 33.3% for ADC2. The median TTF was 7.5 months and 2.8 months, respectively. The rwOS, as reported by the investigators, was 16.5 months and 6.5 months for ADC1 and ADC2, respectively. For those in that cohort receiving T-DXd as ADC1 and SG as ADC2 (10.7%), the real-world response rate was 33.3% for ADC1 and 0% for ADC2, and the TTF and rwOS were undetermined due to the smaller sample size.7
Age also played a factor in treatment response. In subgroup analyses by age, visceral disease, central nervous system (CNS) metastases, and de novo versus non-de novo mBC showed no significant differences in median TTF or rwOS among patients with HR+/HER2-low MBC treated with ADCs in either order—except for younger patients (less than or equal to 65) who received SG before T-DXd, who had longer rwOS (26.0 vs. 15.7 months, P = .05).7
In patients with HR-/HER2-low mBC treated with SG before T-DXd (n = 25), TTF and rwOS did not differ by age, disease status, or visceral metastases. However, those without CNS disease had longer TTF (7.9 vs. 5.2 months, P = .047) and rwOS (19.3 vs. 11.6 months, P < .0001). Subgroup analysis for the reverse sequence was not feasible due to small sample size (n = 3).7
Effective sequencing of ADCs in HR- and HER2-mutated mBC is critical to encourage optimal response rates. Continued research is needed to assess sequencing of other agents, but these data offer deeper insights into how sequencing impacts treatment outcomes.
