Effectiveness of post-trastuzumab deruxtecan treatments and incidence of interstitial lung disease in HER2-positive metastatic breast cancer: a real-world, observational cohort study

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is recommended in the second-line or later setting for patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer (mBC). However, clinical evidence for optimal post-T-DXd treatment is lacking. The EN-SEMBLE study examined the distribution of post-T-DXd treatment regimens, their effectiveness, and the incidence of interstitial lung disease (ILD) in the real-world setting. PATIENTS AND METHODS: EN-SEMBLE was a real-world, observational, cohort study conducted nationwide in Japan. Patients with HER2-positive mBC who received T-DXd between 25 May 2020 and 30 November 2021 and started another treatment regimen after T-DXd discontinuation were eligible for inclusion. Study outcomes included the distribution of the first post-T-DXd treatments; effectiveness outcomes including real-world progression-free survival (rwPFS) and overall survival (OS); incidence of ILD; and outcomes by patient and treatment characteristics. RESULTS: The analysis included 664 patients. The first post-T-DXd treatment was another anti-HER2 therapy in 486/664 patients. This included anti-HER2 antibodies in 361/664 patients, and HER2-tyrosine kinase inhibitors (TKIs) in 113/664 patients. The median first post-T-DXd rwPFS was 4.1 months [95% confidence interval (CI) 3.9-4.5 months], and the median OS was 16.2 months (95% CI 13.8-17.2 months). Outcomes were similar with anti-HER2 antibodies and HER2-TKIs. The rwPFS and OS were numerically longer in patients who discontinued T-DXd due to adverse events (AEs), including ILD, and in patients who had a complete or partial response to T-DXd. The ILD recurrence/exacerbation rate was 3.2% during the first post-T-DXd treatment. CONCLUSIONS: Sequential HER2-targeted therapy as the first post-T-DXd treatment in HER2-positive mBC was feasible and demonstrated clinical benefit, particularly in patients who discontinued T-DXd treatment due to AEs and those who achieved a response to T-DXd. Patients who developed ILD during T-DXd treatment had a low risk of recurrence/exacerbation in subsequent therapy.