DESTINY-Breast06 continues to explore HR⁺, HER2-negative metastatic breast cancer beyond DESTINY-Breast04

Hormone receptor-positive HER2-negative (HR⁺/HER2⁻) is one of the most common subtypes in breast cancer (BC) (1). CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) have become the standard first-line treatment for HR⁺/HER2⁻ metastatic BC (mBC) achieving a median progression-free survival (mPFS) of 23.8–33.6 months (2-4). While first-line CDK4/6i treatment offers significant clinical benefits, drug resistance remains an important clinical challenge. Approximately, 30% of patients will experience disease progression within 1 year after receiving first-line ET + CDK4/6i treatment (5). For patients with first line ET + CDK4/6i treatment mPFS within 12 months will have a worse overall survival (OS), the median OS (mOS) is no more than 20 months, while those mPFS over 12 months achieved mOS of 27 months (6). A retrospective study from a multicenter in the United States showed that the OS of patients who received first-line CDK4/6i treatment mPFS within 12 months was 14.1 months, while the OS of patients with first-line CDK4/6i treatment mPFS more than 12 months was 29.2 months (7).

This suggested that the efficacy of CDK4/6i not only influences the current therapeutic outcomes but also plays a significant role in shaping the effectiveness of subsequent treatments. However, as therapy advances, resistance has increasingly become the predominant factor contributing to treatment failure.

Further now, there is no standard treatment for post CDK4/6i treatment, several emerging therapeutic strategies have been proposed in recent years, including novel ETs, phosphatidylinositol 3-kinase/AKT/mTOR (PAM) pathway-targeted therapies, chemotherapy and antibody-drug conjugates (ADCs). Multiple clinical trials evaluated the efficacy of CDK4/6i rechallenge, showing mPFS of approximately 4.6–6 months (8-10). In the development of oral selective oestrogen receptor degraders (SERDs) and PAM pathway-targeted therapies, the mPFS generally ranges between 3–5.5 months (11-13). Overall, the limited mPFS in post-CDK4/6i mBC indicated a significant unmet clinical need.

ADCs recognize specific tumor antigens through antibodies and precisely deliver chemotherapy drugs to tumor cells, thereby improving the selectivity of treatment and reducing toxic effects on normal cells (14). Recently, ADCs demonstrated significant potential in HR⁺/HER2⁻ mBC (Table 1), including the HER2-targeted trastuzumab deruxtecan (T-DXd) and the trophoblast cell surface antigen 2 (TROP2)-targeted sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd).

The DESTINY-Breast04 study, as the first successful III clinical trial, anti-HER2 therapy in HER2-low [defined as immunohistochemistry (IHC) 1+ or IHC 2+ with in situ hybridization negative (ISH⁻)] mBC who have received prior endocrine therapy and at least one previous line of chemotherapy [or have experienced progression within 6 months of (neo)adjuvant chemotherapy], pioneered and established the concept of HER2-low. In HR⁺ cohort, the mPFS assessed by blinded independent central review (BICR) was 10.1 months for the T-DXd group versus 5.4 months for the treatment of physician’s choice (TPC) group [hazard ratio (HR), 0.51, 95% confidence interval (CI): 0.40–0.64; P<0.0001] and the mOS was 23.9 months for the T-DXd group versus 17.5 months for the TPC group (16). Since the release of DESTINY-Breast04 trial findings in June 2022, European Society for Medical Oncology (ESMO) Metastatic Breast Cancer Living Guideline 2023, National Comprehensive Cancer Network (NCCN) guidelines for BC version 2, 2023, as well as Chinese Society of Clinical Oncology (CSCO) guideline 2024 recommended T-DXd for HR⁺/HER2-low BC patients after at least one line of chemotherapy.

TROPiCS-02 is a phase 3 study of SG versus TPC in patients with HR⁺, HER2⁻ mBC, the mPFS was 5.5 months for the SG group versus 4.0 months for the chemotherapy group (HR, 0.66, 95% CI: 0.53–0.83; P=0.0003) (17). TROPION-Breast01 study evaluating Dato-DXd versus TPC in HR⁺, HER2⁻ mBC, the mPFS was 6.9 months for the Dato-DXd group versus 4.9 months for the TPC group (HR, 0.63, 95% CI: 0.52–0.76; P<0.0001) (18).

DESTINY-Breast06 (15) is a phase 3 trial evaluating the efficacy and safety of T-DXd versus TPC in HR⁺, HER2-low or HER2-ultralow [defined as IHC 0 with membrane staining (IHC >0 and <1+)] mBC. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and either experienced disease progression within 6 months of starting first-line treatment with an endocrine therapy combined with a CDK4/6i or received at least two previous lines of ET in the metastatic setting, enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow).

In this trial, T-DXd demonstrated effectiveness as an earlier-line treatment for mBC after endocrine-based therapies. T-DXd demonstrated a statistically significant and clinically meaningful improvement in mPFS by BICR in the HER2-low cohort compared with TPC: 13.2 vs. 8.1 months (HR, 0.62, 95% CI: 0.51–0.74; P<0.0001). Similarly, in the ITT population (HER2-low and HER2-ultralow), median PFS by BICR was 13.2 months for T-DXd and 8.1 months for TPC (HR, 0.63, 95% CI: 0.53–0.75; P<0.0001). As a result, T-DXd offers an alternative treatment choice positioned between ET and TPC.

In the exploratory analysis of the HER2-ultralow cohort, median PFS by BICR was 13.2 and 8.3 months in the T-DXd and TPC groups, respectively (HR, 0.78, 95% CI: 0.50–1.21); 12-month OS rate was 84.0% and 78.7%, respectively (HR, 0.75, 95% CI: 0.43–1.29). Notably, PFS improvement in the HER2-ultralow cohort was consistent with HER2-low cohort. Moreover, the objective response rate (ORR) was significantly higher in the T-DXd group compared to the TPC group (57.3% vs. 31.2%), supporting its superior anti-tumor activity. It is estimated that approximately 60% to 65% of HR⁺, HER2-BC are HER2-low and approximately 20% to 25% are HER2-ultralow (19-23). DESTINY-Breast06 further establish T-DXd as a transformative treatment option for most patients with HR⁺, HER2-negative mBC.

Historically, the HER2 expression was classified as either HER2⁻ or HER2 positive (HER2⁺). With the demonstrated efficacy of novel ADCs in HER2-low (16), the CSCO guidelines had rapidly updated the HER2 classification system, adding a new category, HER2-low. T-DXd achieves a breakthrough in bystander effect, effectively eliminating the impact of intratumoral HER2 heterogeneity caused by the mixture of HER2⁺ and HER2⁻ cells. The cleavable linker and bystander effect endowed T-DXd with the ability to overcome the therapeutic barriers posed by low-level and heterogeneous HER2 expression (24).

DAISY trial demonstrated that T-DXd has activity in cancer with HER2 expression level lower than IHC 1+/2+. In cohort 3 [HER2-nonexpressing (IHC0) mBC], the confirmed ORR is 29.7% (95% CI: 15.9–47.0%) (25). After that, in DESTINY-Breast06, HER2-ultralow subgroup achieved comparable efficacy to the HER2-low cohort, this finding highlights that T-DXd has further expanded the lower boundary of HER2-targeted therapy, offering new hope to a broader range of mBC patients. Furthermore, the mPFS of 13.2 months provides a clinically meaningful benchmark for treatment options for post-CDK4/6i mBC. In the future, DESTINY-Breast15 (NCT05950945) is expected to further extend the therapeutic potential of T-DXd in redefining the boundaries of HER2 expression.

The treatment post-CDK4/6i continue to have significant unmet therapeutic needs, recent advancements include strategies such as CDK4/6i rechallenge, PAM-pathway target therapy, oral SERD, and ADCs. Notably, ADCs have demonstrated promising efficacy a through their specific targeting and effective drug delivery mechanisms, provide new therapeutic options for HR⁺/HER2⁻ mBC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Breast Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-51/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82172650) and Beijing Natural Science Foundation (No. 7222150).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-51/coif). The authors have no conflicts of interest to declare.

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