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With Longer Follow-Up, Trastuzumab Deruxtecan Continues to Demonstrate Superior Efficacy Over Trastuzumab Emtansine in Patients with HER2-Positive MBC

Findings from a long-term survival analysis of the DESTINY-Breast03 study
27 Jun 2024
Breast Cancer

In this updated analysis of the phase III DESTINY-Breast03 study conducted in patients with previously treated HER2-positive metastatic breast cancer (MBC), trastuzumab deruxtecan continued to demonstrate clinically meaningful improvement in efficacy compared with trastuzumab emtansine and a manageable safety profile that was consistent with previous results. The median progression-free survival (PFS) and objective response rate (ORR) reinforced the clinical benefit of trastuzumab deruxtecan over trastuzumab emtansine and were consistent with the analysis at the previous data cut-off.

Median overall survival (OS) was reached in both treatment groups in this updated analysis, with an approximate 10-month improvement observed with trastuzumab deruxtecan over trastuzumab emtansine and a reduction in the risk of death by approximately 27%, which has not been previously observed in this setting. The findings are reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Javier Cortés of the Quironsalud Group, Pangaea Oncology, International Breast Cancer Center; IOB Madrid, Hospital Beata Maria Ana; Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid in Madrid, Spain, and colleagues on 2 June 2024 in the Nature Medicine.

Trastuzumab deruxtecan is approved in several regions across the globe for patients with HER2-positive MBC after disease progression on taxane and trastuzumab or in patients who have developed disease recurrence during or within 6 months of completing neoadjuvant and/or adjuvant therapy. The approval of trastuzumab deruxtecan in this setting was based on the results of DESTINY-Breast03, a multicentre phase III study that investigated the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.

The primary endpoint of DESTINY-Breast03 was PFS, as determined by blinded independent central review (BICR), and the key secondary endpoint was OS. In the primary (first interim) analysis with data cut-off on 21 May 2021, the primary endpoint was met with median PFS not reached for trastuzumab deruxtecan compared with 6.8 months for trastuzumab emtansine (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.22–0.37; p < 0.001).

In the second OS interim analysis with data cut-off on 25 July 2022, trastuzumab deruxtecan demonstrated a statistically significant and clinically meaningful OS improvement versus trastuzumab emtansine, with a reduction in the risk for death of approximately 36% (HR 0.64, 95% CI 0.47–0.87; p = 0.0037). However, median OS was not reached in either treatment group at the primary analysis or the second OS interim analysis.

After the demonstrated statistically significant improvement of PFS with trastuzumab deruxtecan versus trastuzumab emtansine in the first interim analysis and updated analysis of PFS at the time of the second OS interim analysis, further assessment of tumour response by BICR was discontinued. In the latest article published in the Nature Medicine, the study investigators report on an exploratory analysis of DESTINY-Breast03 with data cut-off on 20 November 2023, an updated efficacy, including median OS, and safety data with longer follow-up.

Patients with advanced HER2-positive MBC previously treated with taxane and trastuzumab were randomised to trastuzumab deruxtecan 5.4 mg per kg (261 patients) or trastuzumab emtansine 3.6 mg per kg (263 patients). The primary endpoint was PFS by BICR and was previously reported. The key secondary endpoint was OS. Other secondary endpoints included ORR, duration of response and PFS, all assessed by investigator and safety.

At data cut-off on 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (HR 0.30, 95% CI 0.24–0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR 0.73, 95% CI 0.56–0.94) with trastuzumab deruxtecan versus trastuzumab emtansine.

The safety profile of trastuzumab deruxtecan continues to be manageable with no cumulative toxicities observed with longer follow-up. Overall, drug-related treatment-emergent adverse events associated with drug discontinuation, dose reduction and drug interruption continued to be higher with trastuzumab deruxtecan than with trastuzumab emtansine, as observed in previous analyses. With the additional follow-up since the previous analysis, four new interstitial lung disease and/or pneumonitis events occurred in the trastuzumab deruxtecan group, all grade 2. Most new events resolved or resolved with sequalae and occurred during the third year of treatment.

The median OS with trastuzumab deruxtecan in DESTINY-Breast03 is the longest reported OS in this disease setting with more than two-thirds (67.6%) of patients still alive at 3 years. Analyses on the impact of trastuzumab deruxtecan on long-term responders across studies and exploring the efficacy of trastuzumab deruxtecan in the earlier MBC setting (DESTINY-Breast09) are ongoing.

This study was funded by Daiichi Sankyo and AstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialisation collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan.


Cortés J, Hurvitz SA, Im S-A, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nature Medicine; Published online 2 June 2024. DOI: https://doi.org/10.1038/s41591-024-03021-7

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