Advancing HER2-positive breast cancer treatment: the promise and challenges of trastuzumab deruxtecan over trastuzumab emtansine—DESTINY-Breast03 trial

The DESTINY-Breast03 trial is a phase III, open-label, randomized study comparing trastuzumab deruxtecan (T-DXd) with trastuzumab emtansine (T-DM1) as second-line treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In June 2024, Javier Cortés and colleagues presented an updated efficacy and safety analysis of the DESTINY-Breast03 trial with a median follow-up of 41 months. There had already been two publications that had firmly established T-DXd as the standard second-line treatment before, showing significant improvements in both median progression-free survival (PFS) and overall survival (OS) compared to T-DM1 (1,2).

Indeed, the study, which has 41-month follow-up, continued to demonstrate the superior efficacy of T-DXd, with a median PFS of 29.0 months compared to 7.2 months for T-DM1 [hazard ratio (HR) 0.30, 95% confidence interval (CI): 0.24–0.38]. The median OS was also better with T-DXd at 52.6 months, compared to 42.7 months for T-DM1 (HR 0.73, 95% CI: 0.56–0.94), providing a notable 10-month improvement (3).

However, the results of this trial still need to be interpreted with caution. First, it is important to note that this trial was conducted across 169 sites globally, with approximately 60% of the cohort consisting of Asian patients. The EMILIA trial, which established T-DM1 as a second-line treatment option for HER2-positive metastatic breast cancer, included fewer than 20% of Asian patients (4). Previous studies have indicated that ethnic and pharmacogenomic differences can cause variations in responses to therapies (5). Therefore, this demographic distribution may introduce differences in outcomes.

Another critical factor in interpreting these results is that about 60% of the patients enrolled in this trial had a history of receiving pertuzumab. Given that the current first-line standard treatment for HER2-positive metastatic breast cancer includes trastuzumab, pertuzumab, and a taxane, there is a slight difference between the treatment regimen used in this trial and the one typically administered in clinical practice. Therefore, this difference in pertuzumab treatment history cannot be disregarded as a potential factor influencing long-term OS.

Lastly, the approval status of T-DM1 and T-DXd as second-line treatments varies by country, which could have impacted crossover rates and, consequently, OS outcomes. As a result, long-term OS data may be influenced by treatment variations after T-DXd. In the phase III DESTINY-Breast02 trial, which compared T-DXd with physician’s choice of chemotherapy (TPC) in HER2-positive metastatic breast cancer patients with a history of T-DM1 treatment, the HRs for PFS (HR 0.30, 95% CI: 0.24–0.37) and OS (HR 0.69, 95% CI: 0.55–0.88) were similar to those observed in the DESTINY-Breast03 trial (6). This suggests that T-DXd may achieve similar efficacy as a third-line treatment after T-DM1 as a second-line therapy. However, the effectiveness of therapies following T-DXd, such as T-DM1 or other HER2-targeted treatments, remains unclear. Future evaluations using registry studies and real-world data will be necessary to optimize post-T-DXd treatment strategies.

From a safety perspective, T-DXd was associated with more frequent toxicities compared to T-DM1, consistent with previous analyses and real-world experience. The difference in side effects is likely due to the structural variations between the two drugs. Both T-DXd and T-DM1 are antibody-drug conjugates (ADCs) targeting HER2. T-DXd’s payload, deruxtecan, is a topoisomerase I inhibitor that disrupts DNA replication, while T-DM1’s payload, emtansine, is a microtubule inhibitor that prevents cell division (7). In addition, T-DXd uses a peptide (PEG) linker that can be cleaved within cancer cells, while T-DM1 employs a non-cleavable maytansinoid (MCC) linker (8,9). Since the linker-cleaved DXd possesses membrane permeability, it exerts bystander antitumor effects, demonstrating antitumor activity against the antibody-targeted cancer cells and the surrounding cancer cells in the tumor microenvironment (10). T-DXd also has a higher drug-antibody ratio (DAR), approximately twice that of T-DM1, with a DAR of 8 compared to 3.5, which likely contributes to their varying efficacy and side effect profiles (11).

While the incidence of treatment-emergent adverse events (TEAEs) of any grade, grade 3 or higher, and serious TEAEs were slightly higher with T-DXd, more patients remained on T-DXd despite a higher discontinuation rate due to side effects, suggesting that the safety profile is manageable. However, interstitial lung disease (ILD) was more frequent in patients treated with T-DXd (12). As of November 2023, ILD and/or pneumonia had occurred in 16.7% of T-DXd-treated patients compared to 3.4% in the T-DM1 group, though no grade 4/5 ILD cases were reported. Given the importance of early detection and intervention in ILD, especially for patients with risk factors such as ethnicity, age, and underlying conditions, vigilance is critical (13).

Both the Food and Drug Administration (FDA) and European Society for Medical Oncology (ESMO) recommend using patient-reported outcomes (PROs) to assess treatment toxicity better and to enable early intervention when necessary (14,15). PROs are crucial in breast cancer research because the disease and its treatments can significantly impact patients’ health-related quality of life (HRQoL) (16). In the DESTINY-Breast03 trial, the European Organization for Research and Treatment of Cancer (EORTC) global health status (GHS)/QoL was maintained on both T-DXd and T-DM1 therapies throughout treatment. Time to definitive deterioration (TDD) analyses of Quality of Life Questionnaire Core 30 (QLQ-C30) GHS (primary PRO variable), T-DXd delayed the time to deterioration of GHS and the prespecified PROs deterioration, including pain, compared to T-DM1. As an objective measure, T-DXd extended the median time to the first hospitalization (17). These data suggest long-term HRQoL maintenance with the use of T-DXd. Further analysis of updated PRO data is anticipated and will provide additional insights.

While T-DXd’s superior efficacy makes it an excellent second-line treatment, its toxicity remains a significant concern. In contrast, T-DM1 tends to have lower toxicity than T-DXd. In the results of the DESTINY-Breast03 trial, the incidence of drug-related TEAEs associated with discontinued treatment was 22.6% in the T-DXd group and 7.3% in the T-DM1 group. Drug-related TEAEs associated with dose reduction occurred in 28.0% with T-DXd and 15.3% with T-DM1, and drug-related TEAEs leading to drug interruption occurred in 44.0% and 18.4%, respectively (3). Similarly, the EMILIA trial also demonstrated that the toxicity of T-DM1 is lower, with its manageable adverse event safety profile (4). Overall, T-DM1 tends to have lower toxicity than T-DXd, so T-DM1 is still considered valid as a second-line treatment in certain situations where the toxicity of T-DXd is a concern.

In terms of efficacy, T-DXd is more beneficial than T-DM1. However, additional data are necessary to ascertain the optimal sequence of treatments. For example, it is still unclear whether administering T-DXd followed by T-DM1 yields the same or different outcomes compared to the reverse sequence. In the DESTINY-Breast03 trial, 32.3% of patients in the T-DM1 group received T-DXd as a post-trial anticancer systemic treatment. Sensitivity analysis adjusting for these patients’ OS demonstrated an improvement in OS with T-DXd compared to T-DM1 (3). The timing of T-DXd administration within the treatment setting and the sequence of treatments may affect survival outcomes. Prospective trials that compare these treatment sequences will be essential for refining optimal treatment strategies.

Furthermore, T-DXd continues to be studied in ongoing HER2-positive metastatic breast cancer trials. Notably, the DESTINY-Breast09 trial investigates T-DXd as a first-line treatment (18). Research is also underway to explore combinations of T-DXd with immune checkpoint inhibitors, which could further improve therapeutic outcomes (19,20).

In conclusion, the DESTINY-Breast03 trial demonstrated the superior efficacy of T-DXd, offering significant promise for advancing breast cancer treatment. However, challenges such as the careful management of adverse events like ILD highlight the need for attention to patient safety. The post-treatment with T-DXd and the determination of the optimal treatment sequence, which could affect long-term OS, remain controversial and pose urgent challenges for HER2-positive breast cancer treatment. Thus, further studies will be needed moving forward. Additionally, while T-DXd is currently the standard second-line treatment, in certain situations where concerns about its toxicity arise, the role of T-DM1 as a second-line treatment is still expected to be necessary. Therefore, T-DM1 is likely to continue playing an essential role in breast cancer treatment, with further research anticipated.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-216/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-216/coif). The authors have no 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. Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomized, open-label, phase 3 trial. Lancet 2023;401:105-17. [Crossref] [PubMed]
2. Daiichi Sankyo Co. Ltd. ENHERTU® Enhertu approved in the US for patients with HER2-positive metastatic breast cancer treated with a prior anti-HER2-based regimen. 2022. Available online: https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-approved-in-eu-for-her2-positive-mbc.html#
3. Cortés J, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med 2024;30:2208-15. [Crossref] [PubMed]
4. Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:732-42. [Crossref] [PubMed]
5. Midgley R, Kerr DJ. Capecitabine: have we got the dose right? Nat Clin Pract Oncol 2009;6:17-24. [Crossref] [PubMed]
6. Fehm T, Cottone F, Dunton K, et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2024;25:614-25. [Crossref] [PubMed]
7. Najjar MK, Manore SG, Regua AT, et al. Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer. Genes (Basel) 2022;13:2065. [Crossref] [PubMed]
8. Ali A, Graff SL. Exploring DESTINY: the Past, Present, and Future of Trastuzumab Deruxtecan. Curr Oncol Rep 2024;26:1-9. [Crossref] [PubMed]
9. Hunter FW, Barker HR, Lipert B, et al. Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Br J Cancer 2020;122:603-12. [Crossref] [PubMed]
10. Modi S, Park H, Murthy RK, et al. Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. J Clin Oncol 2020;38:1887-96. [Crossref] [PubMed]
11. Jeon JH, Woo Kim S, Kim YJ, et al. Synthesis and evaluation of antibody-drug conjugates with high drug-to-antibody ratio using dimaleimide-DM1 as a linker- payload. Bioorg Chem 2024;149:107504. [Crossref] [PubMed]
12. Swain SM, Nishino M, Lancaster LH, et al. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management. Cancer Treat Rev 2022;106:102378. [Crossref] [PubMed]
13. Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022;7:100554. [Crossref] [PubMed]
14. Gennari A, André F, Barrios CH, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol 2021;32:1475-95. [Crossref] [PubMed]
15. Di Maio M, Basch E, Denis F, et al. The role of patient-reported outcome measures in the continuum of cancer clinical care: ESMO Clinical Practice Guideline. Ann Oncol 2022;33:878-92. [Crossref] [PubMed]
16. Hong K, Majercak KR, Villalonga-Olives E, et al. Patient-reported outcomes in breast cancer FDA drug labels and review documents. J Patient Rep Outcomes 2021;5:36. [Crossref] [PubMed]
17. Curigliano G, Dunton K, Rosenlund M, et al. Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Ann Oncol 2023;34:569-77. [Crossref] [PubMed]
18. Tolaney SM, Barroso-Sousa R, Jiang Z, et al. 328TiP Phase III study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09. Ann Oncol 2021;32:S507-8. [Crossref]
19. Iwata TN, Ishii C, Ishida S, et al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther 2018;17:1494-503. [Crossref] [PubMed]
20. Hamilton EP, Shapiro CL, Boni V, et al. Primary analysis from DS8201-A-U105: A 2-part, open-label, phase 1b trial assessing trastuzumab deruxtecan with nivolumab in patients with HER2-expressing advanced breast cancer. Ann Oncol 2022;33:S196. [Crossref]