Nature medicine 2024 Jun 02
Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial.
Abstract
Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (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 T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 .
Related Questions
What are your top takeaways in Breast Cancer from ASCO 2024?
1. DESTINY-Breast06 This phase 3 trial randomized patients to either Trastuzumab deruxtecan (T-DXd) vs. physician’s choice chemotherapy (capecitabine, nab-paclitaxel, paclitaxel) in hormone receptor positive HER2 low or HER2 ultralow (any membrane staining) metastatic breast cancer after prior endoc...
Would you still offer trastuzumab deruxtecan in a patient with progressive HR+/HER2+ breast cancer who has prior history of cell cycle inhibitor related pneumonitis?
In DESTINY-Breast04, about 70% of patients were CDK4/6i treated but were excluded if they had a history of ILD/pneumonitis. So, we don't know if this patient is at higher risk of pneumonitis with trastuzumab deruxtecan. I would consider it if her previous pneumonitis was mild and fully resolved with...
For a patient with well differentiated de novo triple positive metastatic breast cancer who did not respond to THP, do you sequence all available HER2 targeted options before endocrine therapy?
Endocrine combinations for triple positive breast cancer are honestly a bit understudied. We are starting to get more data in this space, SUMMIT, for example, neratinib + fulvestrant + trastuzumab. I think endocrine based combinations are very interesting and there are likely some tumors that are mo...
Are there strategies to mitigate the risk of developing ILD/pneumonitis while using trastuzumab deruxtecan?
The most important strategy is global awareness of ILD as a potentially serious complication that may initially present with subtle signs. Patients and all care team members must not only be aware but remind others in the patient/family care circle. This needs to be reinforced regularly. The recogni...
When, if ever, will you utilize T-DM1 in metastatic HER2+ breast cancer given trastuzumab deruxtecan's significantly improved efficacy vs T-DM1?
We now have very compelling data that trastuzumab deruxtecan (T-DXd) is highly effective in the second line setting and superior to T-DM1. The announcement of results came with the statement that "this study will lead to a paradigm shift in the treatment of Her2-positive metastatic breast cancer". S...
Would you use T-DXd or capecitabine/trastuzumab/tucatinib for HER2+ metastatic breast cancer with predominantly CNS progression after THP?
We now have long-term overall survival data from the DESTINY-Breast03 (DB03) trial, which further supports the efficacy of trastuzumab deruxtecan (T-DXd) in patients with HER2+ metastatic breast cancer, including those with CNS metastases. However, my preference remains unchanged, favoring the HER2C...
What is the best second line treatment for a HER2+ metastatic breast cancer treated with frontline paclitaxel and anti-HER2 therapy?
I would use T-DM1 (ado trastuzumab emtansine) in this situation as a second line therapy. T-DM1 has a very favorable side effect profile. Pertuzumab added a survival benefit when combined docetaxel and trastuzumab (median of 15.7 months) though this was a first-line treatment (Swain et al. NEJM 2015...