Survival benefits of trastuzumab deruxtecan in patients with previously treated HER2-low mBC

The therapeutic landscape of HER2-low metastatic breast cancer (mBC) has been transformed by the availability of trastuzumab deruxtecan (T-DXd; Enhertu^®, Daiichi Sankyo & AstraZeneca), an antibody-drug conjugate (ADC). At a recent Hong Kong Breast Cancer Foundation (HKBCF) Academic Meeting, Dr Shanu Modi of Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, US, discussed the efficacy and safety of T-DXd in the phase III DESTINY-Breast04 trial. Local experiences with T-DXd were shared by Dr Roland Leung of the Department of Medicine, the University of Hong Kong.

Clinical landscape of HER2-low mBC
Low level of HER2 expression is defined as an immunohistochemistry (IHC) score of 1+, or 2+ with nega­tive in situ hybridization (ISH). [Breast Cancer Res 2021;23:112] To date, most HER2-targeted therapies have demonstrated limited benefit for pa­tients with HER2-low mBC. [Can­cers 2022;14:3774; J Clin Oncol 2010;28:1131-1137; J Clin Oncol 2020;38:444-453] HER2-low mBC has thus been treated as HER2-negative disease stratified by hormone receptor (HR) status, with limited treatment op­tions following tumour progression. [N Engl J Med 2022;387:9-20]

T-DXd, an ADC with a drug-to-antibody ratio of 8:1, comprises a HER2-directed antibody (trastuzum­ab) linked via a tetrapeptide-based cleavable linker to a topoisomerase I inhibitor payload. Upon internaliza­tion, T-DXd is selectively cleaved by lysosomal protease, leading to intra­cellular release of membrane-perme­able exatecan derivative (DXd), which triggers tumour cell death. Subse­quently, DXd diffuses and exerts its cytotoxic effect on nearby cancer cells via the bystander effect. [Curr Oncol 2023;30:6447-6461; Chem Pharm Bull (Tokyo) 2019;67:173-185]

“When released from T-DXd, DXd retains membrane permeability and enters the tumour microenvironment, targeting neighbouring tumour cells with heterogeneous levels of HER2 ex­pression, including HER2-low tumour cells,” noted Modi.

T-DXd’s durable efficacy in HER2-low mBC 
Phase Ib and II studies of T-DXd showed promising antitumour activity in pretreated patients with HER2-low mBC, with confirmed objective re­sponse rates (ORRs) of 37–37.5 per­cent. Median progression-free survival (PFS) was 6.8–11.1 months, and medi­an overall survival (OS) was 19.3–29.4 months. [J Clin Oncol 2020;38:1887-1896; ESMO Open 2024;9:103016]

The phase III DESTINY-Breast04 trial investigated the efficacy and safety of T-DXd 5.4 mg/kg Q3W vs treatment of physician’s choice (TPC) in 557 patients with HER2-low mBC who had received 1–2 lines of che­motherapy, including those with HR-positive (n=494) and HR-nega­tive (n=63) disease. At a median fol­low-up of 18.4 months, confirmed ORR in the T-DXd group was three times higher than the TPC group across the HR-positive cohort (52.6 vs 16.3 percent) and HR-negative co­hort (50.0 vs 16.7 percent). (Table) [N Engl J Med 2022;387:9-20]

For patients in the HR-positive co­hort, T-DXd demonstrated an approx­imately two-fold increase in median PFS vs TPC (10.1 vs 5.4 months; haz­ard ratio, 0.51; 95 percent confidence interval [CI] 0.40–0.64; p<0.001). Me­dian OS was also significantly pro­longed with T-DXd vs TPC (23.9 vs 17.5 months; hazard ratio, 0.64; 95 percent CI 0.48–0.86; p=0.003). T-DXd also showed similar survival improvements vs TPC in exploratory analyses of the HR-negative cohort (median PFS: 8.5 vs 2.9 months; hazard ratio, 0.46; 95 percent CI, 0.24–0.89) (median OS: 18.2 vs 8.3 months; hazard ratio, 0.48; 95 percent CI, 0.24–0.95).

Updated findings of DESTI­NY-Breast04 further demonstrated T-DXd’s durable efficacy. At a median follow-up of 32.0 months, survival im­provements with T-DXd vs TPC were sustained in the HR-positive cohort (median PFS: 9.6 vs 4.2 months; hazard ratio, 0.37; 95 percent CI, 0.30–0.46) (median OS: 23.9 vs 17.6 months; hazard ratio, 0.69; 95 percent CI, 0.55–0.87). In exploratory analyses of the HR-negative cohort, median PFS was 6.3 vs 2.9 months with T-DXd vs TPC (hazard ratio, 0.29; 95 percent CI, 0.15–0.57), and median OS was 17.1 vs 8.3 months (hazard ratio, 0.58; 95 percent CI, 0.31–1.08). (Table) [Ann Oncol 2023;34:S334-S335]

Safety assessment in DES­TINY-Breast04 showed that pro­longed exposure to T-DXd did not increase toxicity. For any-grade treatment-emergent adverse events (TEAEs), exposure-adjusted incidence rates were 1.2 vs 2.6 per patient-year for the T-DXd vs TPC group. In the T-DXd group, the rate of any-grade interstitial lung disease/pneumonitis, an AE of special interest, was 12.1 percent, with no new cases reported since primary analysis.

“Compared with TPC, T-DXd is as­sociated with significant survival ben­efit for previously treated patients with HER2-low mBC,” commented Modi.

NCCN recommendations
Based on results of DESTI­NY-Breast04, the National Compre­hensive Cancer Network (NCCN) recommends T-DXd as a Category 1 preferred second-line regimen for pa­tients with HR-positive, HER2-low (IHC 1+ or 2+/ISH negative), recurrent un­resectable (local or regional) or stage IV BC who are endocrine-refractory or in visceral crisis, and for patients with HR-negative, HER2-low disease with no germline BRCA1/2 mutation. In both scenarios, T-DXd may be used in a later line if not used in the second line. [NCCN Clinical Practice Guide­lines in Oncology, Breast Cancer, ver­sion 3, 2025]

Summary
“HER2-low mBC represents a new therapeutically targetable population,” concluded Modi. “For patients with HER2-low mBC, T-DXd is the pre­ferred treatment after one line of che­motherapy.”

Discussion
In the overall study cohort (n=557) of DESTINY-Breast04, T-DXd showed greater clinical benefit, defined as a composite of complete response, par­tial response, and >6 months of stable disease, than TPC (70.2 vs 33.7 per­cent). [N Engl J Med 2022;387:9-20] This practice-changing clinical trial es­tablished the pivotal role of T-DXd as a second- or later-line treatment op­tion for patients with HER2-low mBC. [NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, version 3, 2025]

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