DESTINY-Breast09, new breakthroughs in first-line therapy for HER2-positive advanced breast cancer

Introduction

Human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer is a highly aggressive subtype of breast cancer, characterized by rapid proliferation, propensity for visceral and central nervous system metastasis, and poorer prognosis compared to other breast cancer types. Since the CLEOPATRA studies (1,2) and PUFFIN study (3) established the combination of taxanes, trastuzumab, and pertuzumab (THP regimen) as the standard first-line therapy, this regimen has significantly delayed disease progression. In MARIANNE study (4), trastuzumab emtansine (T-DM1) showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer. However, some patients would still experience rapid progression. In recent years, major advances have been made in HER2-targeted therapies, while there remains an unmet clinical need for more durable and effective first-line treatment approaches.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of a humanized anti-HER2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload. In posterior-line therapies, T-DXd has demonstrated encouraging efficacy, in the DESTINY Breast 03 trial (5), which successfully established T-DXd as the standard second-line therapy for advanced breast cancer. The DESTINY-Breast09 study (6) presented at the 2025 American Society of Clinical Oncology meeting, targeting patients with HER2-positive advanced breast cancer in the first-line setting, showed that the T-DXd plus pertuzumab regimen has for the first time challenged the THP regimen, emerging as a potential new standard of care for the future.

Transformation of first-line for HER2-positive advanced breast cancer

The CLEOPATRA study represents a milestone in the treatment of HER2-positive metastatic breast cancer, establishing the concept of dual HER2-targeted therapy by combining pertuzumab with the TH (taxane + trastuzumab) regimen. In this study, after a median follow-up of 50 months, the THP regimen prolonged the median progression-free survival (PFS) from 12.4 months with TH alone to 18.7 months (an increase of 6.3 months), with a hazard ratio (HR) of 0.62 [95% confidence interval (CI): 0.51–0.75], reducing the risk of recurrence by 38%. Following a median follow-up of 99 months, the median overall survival (OS) in the pertuzumab group reached 57.1 months (2), compared to 40.8 months in the control group (HR =0.69). Additionally, the 8-year survival rate in the pertuzumab group significantly improved to 37% (23% in the control group). Under this circumstance, THP has remained the standard first-line therapy since 2013.

Meanwhile, small-molecule tyrosine kinase inhibitors (TKIs) have also demonstrated promising efficacy in first-line therapy. Results from the PHILA study (7) showed that adding pyrotinib to the TH regimen significantly improved PFS in treatment-naive HER2-positive metastatic breast cancer patients. After a median follow-up of 15.5 months, the pyrotinib group continued to show a significant PFS benefit compared to the TH group: 22.1 months (95% CI: 19.3–27.8) vs. 10.5 months (95% CI: 9.5–12.4), with a HR of 0.44 (95% CI: 0.36–0.53) and one-sided P<0.0001, meeting the pre-specified statistical significance criteria. Although head-to-head studies comparing pertuzumab and pyrotinib are lacking, the TH + pyrotinib regimen has become a level I recommendation in domestic guidelines, considering multiple factors such as patient benefit and product accessibility (8).

Study design and the main result of DESTINY-Breast09

DESTINY-Breast09 (NCT04784715) is a randomized, open-label, multicenter, global phase III clinical trial that enrolled 1,160 patients with HER2-positive advanced/metastatic breast cancer (a/mBC). These patients had not received prior systemic therapy for advanced disease (first-line endocrine therapy was permitted). Participants were randomized 1:1:1 to receive: (I) T-DXd plus placebo; (II) T-DXd plus pertuzumab; or (III) the standard THP regimen. The study was stratified by disease type (de novo or recurrent), hormone receptor status, and phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA) mutation status. The primary endpoint was PFS assessed by blinded independent central review (BICR). Key secondary endpoints included investigator-assessed PFS, OS, objective response rate (ORR), duration of response (DOR), second PFS (PFS2), and safety outcomes, among others (Figure 1).

Figure 1 Trial design of DESTINY-Breast09 study (6). BICR, blinded independent central review; DOR, duration response rate; HER2, human epidermal growth factor receptor 2; HR, hormonal receptor; INV, investigator; mBC, metastatic breast cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PFS2, second PFS; T-DXd, trastuzumab deruxtecan; THP, taxanes, trastuzumab, and pertuzumab.

At the interim analysis (data cutoff: February 26, 2025), the T-DXd plus pertuzumab group demonstrated a statistically significant and clinically meaningful improvement in PFS. As assessed by BICR, the median PFS for the T-DXd plus pertuzumab group was 40.7 months (95% CI: 36.5 to not estimable), compared to 26.9 months (95% CI: 23.1–30.9) for the THP regimen, with a HR of 0.56 (95% CI: 0.44–0.71; P<0.00001) (Figure 2). Investigator-assessed results were similar, with the median PFS in the T-DXd plus pertuzumab group remaining at 40.7 months vs. 20.7 months in the THP group (HR: 0.49; 95% CI: 0.39–0.61). In terms of ORR, the experimental group also outperformed the control group (85.1% vs. 78.6%), including a complete response (CR) rate of 15.1% (8.5% in the THP group) (Figure 3). The median DOR in the experimental group exceeded three years. Subgroup analysis showed consistent benefits of T-DXd plus pertuzumab regardless of HR status, PIK3CA mutation status, or disease type (de novo or recurrent).

Figure 2 PFS by different regimens from selected phase III trials in first-line HER2-positive metastatic breast cancer (1-4,6,7). D, docetaxel; H, trastuzumab; mPFS, median progression-free survival; P, pertuzumab; Py, pyrotinib; T, taxane; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.

Figure 3 ORR by different regimens from selected phase III trials in first-line HER2-positive metastatic breast cancer (1-4,6,7). CR, complete response; D, docetaxel; H, trastuzumab; ORR, objective response rate; P, pertuzumab; Py, pyrotinib; T, taxane; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.

Safety assessments showed that toxicity in the T-DXd groups was generally manageable, consistent with the known side effects of T-DXd and pertuzumab as monotherapies. Nevertheless, interstitial lung disease (ILD) remained the primary risk of T-DXd treatment, with an incidence of 12.1%, including 0.5% grade 3 or higher events, accompanied by two fatal cases. Another aspect of note is treatment sustainability. The median duration of T-DXd + P treatment was 21.7 months, significantly longer than 16.9 months in the THP group, indicating that most patients could tolerate this regimen well.

Discussion

DESTINY-Breast09 represents a new milestone breakthrough in breast cancer therapy—as the first phase III study to validate head-to-head the efficacy of T-DXd plus pertuzumab (T-DXd + P) vs. the traditional THP regimen. Its data have revolutionized the first-line treatment landscape for HER2-positive breast cancer. Referencing data from the DESTINY Breast-07 study (9), the 12-month PFS rates for the T-DXd monotherapy and T-DXd + P group were 77.3% and 89.4%, respectively. In DESTINY-Breast09, the T-DXd + P group achieved a median PFS of 40.7 months, significantly reducing the risk of disease progression by 44% compared to THP. This data not only shatters the efficacy ceiling of previous targeted therapies, but also for the first time in a large phase III trial confirms that an ADC drug combined with an anti-HER2 monoclonal antibody can exceed the survival benefit of traditional dual-target chemotherapy.

In terms of secondary endpoints, the T-DXd + P group achieved unprecedented highs in median ORR, CR, and DOR. Notably, the 15.1% CR rate showed ongoing potential for improvement with extended follow-up, a trend indicating that this regimen not only significantly prolongs PFS but also holds promise for clinical cure through high responses. This dual breakthrough of long-term survival plus high response rates provides critical evidence-based rationale for individualized treatment strategies. On one hand, the long PFS sets a new benchmark for long-term management of advanced patients. On the other hand, the increasing CR rate offers important reference for cure-oriented therapy in early-stage patients, driving a paradigm shift in HER2-positive breast cancer treatment from disease control to functional cure. This advance also ushers in a chemotherapy-free or low-chemotherapy precision era for HER2-positive breast cancer, holding profound guiding value for the development of similar agents and optimization of treatment pathways.

Despite this, the DESTINY-Breast09 study still faces key challenges in clinical practice. First of all, the proportion of patients previously treated with pertuzumab in the study was less than 10%, which is significantly different from clinical practice in China. The application rate of the trastuzumab-pertuzumab dual-target regimen in Chinese patients with early-stage HER2-positive breast cancer has reached a relatively high level since 2017 (10). This difference has led to uncertainty in the extrapolation of the DESTINY-Breast09 study results to the trastuzumab-pertuzumab pretreated population, and whether its efficacy and safety data are applicable to such patients still needs to be further verified by high-quality clinical studies. Therefore, carrying out prospective studies in the trastuzumab-pertuzumab pretreated population is not only a necessary step to verify the applicability of the DESTINY-Breast09 regimen, but also a key link to promote the localized optimization of treatment strategies for HER2-positive breast cancer, which is of great significance for constructing an evidence-based treatment system in line with the disease characteristics of Chinese patients.

Furthermore, the DESTINY-Breast09 study unveiled the landscape of maintenance therapy after T-DXd discontinuation. Trastuzumab-based maintenance therapy accounted for only 8.7%, and endocrine therapy application rate in hormone receptor-positive patients was 13.5%, significantly lower than 38.3% in the THP group. This data discrepancy profoundly indicates that different maintenance therapy strategies may not only lead to significant divergence in disease recurrence and progression timelines but also interfere with the precise evaluation of core efficacy indicators such as PFS of initial treatment regimens, highlighting the necessity of implementing individualized maintenance therapy in clinical practice. Notably, the DESTINY-Breast09 study deliberately avoided combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy in its study design, and also did not combine PIK3CA inhibitors for PIK3CA-mutated patients (11). This rigorous design strategy effectively stripped the potential interference of combined endocrine therapy on the true efficacy of T-DXd, providing a purer efficacy evaluation environment for the academic community and enabling the study to more accurately anchor the core clinical value of T-DXd monotherapy or combination regimens. This deconfounding design concept not only provides reliable evidence-based medical evidence for optimizing breast cancer treatment regimens but also sets an important methodological benchmark for protocol design in subsequent similar studies, holding landmark significance for promoting the development of precision therapy in breast cancer.

Finally, the treatment discontinuation rate in the T-DXd + P group of the DESTINY-Breast09 study was 20.7%, mainly attributed to adverse events such as pneumonia/ILD and fatigue, among which 2 patients died due to ILD. This has also triggered concerns about safety management in clinical research. In terms of ILD management, grade 1 ILD is usually treated with hormones, and T-DXd therapy can be restarted after the symptoms are completely relieved (12). Although guidelines recommend that no dose adjustment is required if ILD is relieved within 28 days, real-world data show that 33.3% of patients who resume treatment after grade 1 ILD remission will experience grade 1–2 ILD events again. This suggests that clinical management (such as close monitoring and dose adjustment) may reduce the risk of ILD-related deaths.

Conclusions

In conclusion, the T-DXd + P regimen has been demonstrated broad applicability and remarkable efficacy regardless of tumor burden in patients with HER2-positive metastatic breast cancer. It offers a promising treatment option and brings new hope to clinical practice. This innovative approach not only helps improve patient survival but also has the potential to drive breakthroughs in breast cancer therapy. Furthermore, with the maturation of long-term data, the T-DXd + P regimen may provide more opportunities for patients to achieve long-term survival or even cure.

Although long-term OS data are still pending, this study has provided strong evidence for the clinical implementation of the combination regimen. In future applications, factors such as patient age, prior treatment history, and disease characteristics should be comprehensively considered to find the optimal balance among efficacy, toxicity, and accessibility. This research has not only driven the innovation of current treatment paradigms but also paved the way for HER2-positive breast cancer patients to achieve long-term survival and potential cure.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: This work was supported by the National Natural Science Foundation of China (No. 82404074).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-35/coif). Z.J. serves as the Editor-in-Chief of Translational Breast Cancer Research. J.L. serves as the unpaid Managing Editor of Translational Breast Cancer Research. C.H. serves as an unpaid editorial board member of Translational Breast Cancer Research from May 2025 to December 2027. H.W. and Y.P. serve as the unpaid editorial board members of Translational Breast Cancer Research from March 2024 to February 2026. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015;372:724-34. [Crossref] [PubMed]
2. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:519-30. [Crossref] [PubMed]
3. Xu B, Li W, Zhang Q, et al. Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): final analysis of a phase III, randomized, double-blind, placebo-controlled study. Breast Cancer Res Treat 2023;197:503-13. [Crossref] [PubMed]
4. Perez EA, Barrios C, Eiermann W, et al. Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. J Clin Oncol 2017;35:141-8. [Crossref] [PubMed]
5. Cortés J, Kim SB, Chung WP, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med 2022;386:1143-54. [Crossref] [PubMed]
6. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09. J Clin Oncol 2025;43:abstr LBA1008.
7. Ma F, Yan M, Li W, et al. Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial. BMJ 2023;383:e076065. [Crossref] [PubMed]
8. Li J, Jiang Z. Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) Guidelines in 2024: International Contributions from China. Cancer Biol Med 2024;21:838-43. [Crossref] [PubMed]
9. Andre F, Hamilton EP, Loi S, et al. DESTINY-Breast07: Dose-expansion interim analysis of T-DXd monotherapy and T-DXd + pertuzumab in patients with previously untreated HER2+ mBC. J Clin Oncol 2024;42:1009.
10. Li J, Zhou J, Wang H, et al. Trends in Disparities and Transitions of Treatment in Patients With Early Breast Cancer in China and the US, 2011 to 2021. JAMA Netw Open 2023;6:e2321388. [Crossref] [PubMed]
11. Jhaveri KL, Im SA, Saura C, et al. Overall Survival with Inavolisib in PIK3CA-Mutated Advanced Breast Cancer. N Engl J Med 2025;393:151-61. [Crossref] [PubMed]
12. Tarantino P, Modi S, Tolaney SM, et al. Interstitial Lung Disease Induced by Anti-ERBB2 Antibody-Drug Conjugates: A Review. JAMA Oncol 2021;7:1873-81. [Crossref] [PubMed]