Sequential HER2-Targeted Therapy Following Trastuzumab Deruxtecan Discontinuation Among Patients With HER2-Positive Metastatic Breast Cancer

According to results from the real-world EN-SEMBLE study, sequential human epidermal growth factor receptor 2 (HER2)-targeted therapy following trastuzumab deruxtecan (T-DXd) demonstrated clinical promise among patients with HER2-positive metastatic breast cancer who responded to T-DXd however discontinued treatment due to adverse events. 

“[T-DXd] is recommended in the second-line or later setting for patients with [HER2]-positive recurrent or metastatic breast cancer… [however] in real-world clinical practice… [approximately] 5%-15% of patients discontinue because of adverse events, including interstitial lung disease,” stated Kazuki Nozawa, MD, Nagoya Medical Center, Nagoya, Japan, and coauthors. “The EN-SEMBLE study was designed to fill this data gap by focusing on treatment after T-DXd discontinuation.”

In this observational cohort study, researchers enrolled 664 patients who received T-DXd and initiated treatment with another regimen following T-DXd discontinuation across 222 institutions. End points included median T-DXd duration, time to treatment failure, time to next treatment, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). 

At analysis, the median duration of T-DXd was 8.1 months and T-DXd was most frequently followed by anti-HER2 therapy (73%) with either an anti-HER2 antibody (54%) or an anti-HER2-tyrosine kinase inhibitor (17%). Time to treatment failure was 3.8 months and the time to next treatment was 5 months. Treatment discontinuation was mainly due to disease progression (67.5%), interstitial lung disease (22%), and other adverse events (5.1%). 

The median first post–T-DXd PFS was 4.1 months, the median first post–T-DXd OS was 16.2 months, and the median ORR was 14.5%. In the subgroup of patients who received an anti-HER2 antibody, median PFS was 4.1 months, and median OS was 17.2 months. In the subgroup of patients who received an anti-HER2 tyrosine kinase inhibitor, median PFS was 4.3 months, and median OS was 16.3 months. Median PFS was 3.5 months in patients who discontinued T-DXd due to disease progression compared to 7.3 months in patients who discontinued T-DXd due to adverse events. The interstitial lung disease recurrence or exacerbation rate was 3.2%. 

“Sequential HER2-targeted therapy post-T-DXd in HER2-positive [metastatic breast cancer] is feasible, with observed clinical benefits, particularly in patients who discontinue T-DXd treatment due to [adverse events],” concluded Dr Nozawa et al. “ Given that post-T-DXd treatment is one of the biggest unmet needs for the disease, we anticipate that our data will act as a guide to design future studies.”

Source: 

Nozawa K, Iwata H, Mukohara T, et al. Effectiveness of post-trastuzumab deruxtecan treatments and incidence of interstitial lung disease in HER2-positive metastatic breast cancer: A real-world, observational cohort study. ESMO Open. Published online: July 25, 2025. doi: 10.1016/j.esmoop.2025.105511