At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Professor Sara M. Tolaney from Dana-Farber Cancer Institute and Harvard Medical School, representing the research team, presented the latest exploratory analysis results of the ASCENT-04 study (NCT04612127). This analysis delved into the impact of biomarkers—Trop-2 expression levels, BRCA mutation status, and HER2 expression status—on the efficacy of Sacituzumab Govitecan (SG) combined with Pembrolizumab as a first-line treatment for PD-L1 positive metastatic triple-negative breast cancer (mTNBC), providing key evidence for the precise selection of benefited populations in clinical practice.01 Research Background: Treatment Challenges of 1L mTNBC and the Original Design of ASCENT-04
Triple-negative breast cancer (TNBC) has long been limited to chemotherapy due to the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Although immune checkpoint inhibitors (ICI) combined with chemotherapy have become the standard first-line treatment for PD-L1 positive mTNBC patients (based on the KEYNOTE-355 study), the prognosis for patients still needs further improvement. Sacituzumab Govitecan (SG) is an antibody-drug conjugate (ADC) targeting Trop-2. Through a high drug-to-antibody ratio (DAR 7.6) and a unique cleavable linker, it exerts a powerful bystander effect after releasing the active SN-38 component. ASCENT-04 is a randomized, open-label Phase III clinical trial designed to evaluate the efficacy of SG plus pembrolizumab compared to treatment of physician’s choice (TPC, including gemcitabine + carboplatin, paclitaxel, or nab-paclitaxel) plus pembrolizumab in previously untreated patients with PD-L1 positive (CPS≥10) mTNBC. Previously released primary analysis data showed that the SG combination regimen significantly reduced the risk of disease progression or death by 35% (HR=0.65). This subgroup analysis aimed to verify whether this clinical benefit is consistent across populations with different biomarker characteristics.
02 Trop-2 Expression Levels: Benefits from SG Combination Regimen Regardless of H-score
Trop-2 is expressed in over 90% of TNBC cases and is the core target for SG. In this subgroup analysis, researchers used immunohistochemistry (IHC) to test Trop-2 expression in archived tumor tissues and divided patients into four quartiles (Q1-Q4) based on the H-score, where Q1 was the lowest expression group and Q4 was the highest. Data Performance: In the overall population, the median progression-free survival (mPFS) of the SG plus pembrolizumab group was superior to that of the chemotherapy combination group. Specifically for Trop-2 expression subgroups: • In all four Trop-2 expression quartiles, the PFS of the SG combination group was longer than that of the chemotherapy combination group. • Kaplan-Meier curves showed that as Trop-2 expression levels increased (Q3, Q4 groups), the mPFS of the SG group showed a longer trend, and the separation between the two curves was more significant. • However, even in patients with low Trop-2 expression (Q1 group), the SG combination regimen still showed clinical benefit superior to the standard regimen. Expert Commentary: Professor Sara M. Tolaney pointed out that this result further confirms that the mechanism of action of SG does not only depend on high-level target binding on the membrane surface; its unique bystander effect may also play a killing role in tumors with low expression. Although Trop-2 expression levels show a trend related to the degree of efficacy, they should not be used as a limiting factor to exclude SG treatment.
03 BRCA Mutation Status: Consistency of Benefits in Mutant and Wild-type Populations
BRCA1/2 mutations account for about 10%-15% of TNBC patients and are important factors influencing treatment decisions (such as the use of PARP inhibitors). This analysis assessed the difference in benefits between BRCA mutant (including 1, 2, or both) and wild-type patients through whole exome sequencing (WES) of tumor tissues. Data Performance: • In the SG + pembrolizumab group, approximately 23% of patients carried BRCA mutations; in the chemotherapy + pembrolizumab group, approximately 20% carried mutations. • BRCA Wild-type Population: The mPFS of the SG combination group was significantly better than that of the chemotherapy combination group. • BRCA Mutant Population: A similar improvement in PFS brought by the SG regimen was observed. Notably, although the sample size of this subgroup was small (requiring cautious interpretation), the mPFS of both groups was longer than their corresponding wild-type subgroups. Data Granularity: Even in the BRCA mutant population with DNA damage repair (DDR) defects, the SG plus pembrolizumab group still showed advantages compared to the platinum-containing chemotherapy group (the TPC group mostly contained carboplatin). This means that the SG combination immunotherapy regimen has the potential to replace or supplement existing platinum-containing chemotherapy regimens in the BRCA mutant population.
04 HER2 Expression Status: Universal Benefits for HER2-Low and HER2-0 Populations
With the emergence of the HER2-Low definition, the subdivision of the mTNBC population has become more complex. In this ASCENT-04 subgroup, patients were divided into HER2-0 (IHC 0) and HER2-Low (IHC 1+ or IHC 2+/ISH negative). Data Performance: • HER2-0 Subgroup: SG plus pembrolizumab significantly prolonged PFS, with the HR value being highly consistent with the overall population. • HER2-Low Subgroup: The benefit was equally significant. Data showed that the hazard ratio (HR) of the SG combination group in HER2-Low patients was basically the same as that in HER2-0 patients. Statistical Observation: Kaplan-Meier curves showed that regardless of HER2 status, the curve of the SG + pembrolizumab group remained consistently above the control group, suggesting that the efficacy of SG in this population is not interfered with by HER2 expression. This provides a powerful alternative for patients who have failed to benefit from anti-HER2 ADC drugs or do not meet their medication criteria.
05 Conclusion and Clinical Significance: Reshaping First-line Treatment Regimens for mTNBC
Professor Sara M. Tolaney concluded that this exploratory subgroup analysis of the ASCENT-04 study provided the following key conclusions:
- Breadth of Efficacy: The benefit of SG plus pembrolizumab in 1L PD-L1+ mTNBC patients does not depend on Trop-2 score, BRCA mutation status, or HER2 expression level.
- Clinical Universality: This finding is highly consistent with the results of the ASCENT study conducted in second-line and later treatments, once again proving the stable position of SG as a Trop-2 ADC in the full-course management of TNBC.
- Regimen Prospect: Introducing the combination of ADC and immunotherapy early in the first-line treatment phase can more effectively delay disease progression (HR=0.65) compared to traditional chemotherapy + immunotherapy, which may change the sequencing of first-line treatments for PD-L1 positive patients in clinical practice.
Future Outlook:
Although the sample size of each subgroup (especially the BRCA mutant group) is limited and the subgroup analysis is exploratory in nature, the highly consistent data trends provide confidence for clinicians. In future clinical practice, for previously untreated mTNBC patients, the SG plus pembrolizumab regimen is expected to break through the limitations of biomarkers and become a more universal and powerful first-line choice. The research team will continue to follow up on long-term data to evaluate the final impact of this combination regimen on overall survival (OS).
