Close-up of a healthcare professional holding a HER2-targeted therapy medication, emphasizing advancements in HER2-directed treatment.
Breast Cancer / Articles 07/23/2026

Trastuzumab Deruxtecan and the Evolution of HER2-Directed Therapy

Professional woman with dark hair and a navy blazer smiling at the camera, suitable for medical or healthcare-related content. Jasmin Hundal, MD

Key Points

  • HER2 is best viewed as a continuum rather than a binary variable: Trastuzumab deruxtecan (T-DXd) is active across HER2-positive, HER2-low, and HER2-ultralow breast cancer, broadening the population eligible for HER2-directed therapy.
  • T-DXd’s role now spans metastatic disease (first and later line), early-stage curative-intent disease, HER2-mutant non–small cell lung cancer (NSCLC), and a tumor-agnostic HER2 immunohistochemistry (IHC) 3+ indication.
  • Interstitial lung disease is the defining toxicity across settings and requires proactive monitoring and prompt management.

Historically, HER2 status was treated as a dichotomous variable: Tumors were classified as HER2-positive or -negative, which determined eligibility for HER2-directed therapy. The clinical activity of T-DXd has prompted a revision of this framework. The agent’s activity spans a continuum of HER2 expression and multiple tumor types, and it has demonstrated efficacy in early-stage disease, with implications for testing, selecting treatment, and classifying the disease itself (Table).

Molecular Basis

T-DXd is an antibody-drug conjugate (ADC) comprising a humanized anti-HER2 monoclonal antibody, a cleavable tetrapeptide linker, and a topoisomerase I inhibitor payload (DXd), with a drug-to-antibody ratio of approximately 8:1, compared with approximately 3.5:1 for trastuzumab emtansine (T-DM1).1 

Two characteristics contribute to T-DXd’s clinical activity. First, the linker is stable in circulation, with limited systemic release of the payload, thereby favoring intratumoral delivery and contributing to the therapeutic index.1 Second, the released DXd is membrane-permeable and can diffuse into adjacent cells irrespective of their HER2 expression, a phenomenon called the bystander effect.1 This mechanism reduces the dependence of efficacy on uniformly high HER2 expression and provides a rationale for activity in tumors with low or heterogeneous HER2.

Breast Cancer

T-DXd has demonstrated efficacy across a range of clinical settings in breast cancer, spanning first- and later-line metastatic disease; HER2-low and HER2-ultralow tumors; and, more recently, early-stage curative-intent disease. 

In the second-line setting, DESTINY-Breast03 compared T-DXd with T-DM1 in patients previously treated with trastuzumab and a taxane. Median progression-free survival (PFS) was 29 months by blinded independent central review with T-DXd versus 6.8 months with T-DM1, and a statistically significant overall survival (OS) benefit was observed (hazard ratio [HR], approximately 0.64).2,3 Based on these data, T-DXd is approved in second-line therapy in HER2-positive metastatic breast cancer. 

In the first-line setting, DESTINY-Breast09 evaluated T-DXd, alone or combined with pertuzumab, against a taxane plus trastuzumab plus pertuzumab (THP) in patients who had received no prior chemotherapy or HER2-directed therapy for metastatic disease. At a prespecified interim analysis, median PFS by blinded independent central review was 40.7 months with T-DXd plus pertuzumab versus 26.9 months with THP (HR, 0.56; 95% CI, 0.44-0.71; P < .00001); the confirmed response rate was 85.1% versus 78.6% (complete responses in 15.1% and 8.5%, respectively), and the median duration of response was 39.2 versus 26.4 months.4 Grade 3 or greater adverse events were of similar overall frequency (63.5% vs 62.3%), and adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving T-DXd plus pertuzumab, including 2 grade 5 events, versus 1.0% with THP.4 Data for the T-DXd plus placebo group remain blinded pending the final PFS analysis.

T-DXd has also demonstrated activity in tumors previously categorized as HER2-negative. DESTINY-Breast04 evaluated HER2-low disease (IHC 1+, or IHC 2+ with negative in situ hybridization) after prior chemotherapy; median PFS was approximately 9.9 versus 5.1 months (HR, 0.50; P < .001), and median OS was approximately 23.4 versus 16.8 months (HR, 0.64; P < .001), with benefit observed irrespective of hormone-receptor status.5 DESTINY-Breast06 extended these findings to HER2-ultralow disease, defined as IHC 0 with faint, incomplete membrane staining in 10% or fewer tumor cells, with efficacy consistent with the HER2-low population.6

T-DXd has also been evaluated in early-stage, curative-intent disease across both the neoadjuvant and postneoadjuvant settings. In the neoadjuvant DESTINY-Breast11 trial, the first phase 3 study of T-DXd in high-risk HER2-positive early breast cancer, T-DXd followed by paclitaxel, trastuzumab, and pertuzumab produced a higher pathological complete response rate than dose-dense doxorubicin and cyclophosphamide followed by THP (67.3% vs 56.3%; absolute difference, 11.2%; 95% CI, 4.0-18.3; P = .003), with benefit in both hormone receptor–positive and –negative subgroups and with lower rates of grade 3 or greater and serious adverse events and left-ventricular dysfunction, while interstitial lung disease was low and similar across arms (4.4% vs 5.1%).7 In the postneoadjuvant DESTINY-Breast05 trial, in which 1635 patients with residual invasive disease after neoadjuvant therapy were randomized to adjuvant T-DXd or T-DM1, invasive disease–free survival (iDFS) favored T-DXd (HR, 0.47; 95% CI, 0.34-0.66; P < .001; 3-year iDFS, 92.4% vs 83.7%), although adjudicated drug-related interstitial lung disease was more frequent than with T-DM1 (9.6% vs 1.6%, including 2 deaths).8 Together, these trials extend the role of T-DXd into the curative-intent treatment of high-risk, early-stage HER2-positive disease.

Non–Small Cell Lung Cancer and Tumor-Agnostic Use

The biology of HER2 in lung cancer differs from that of breast cancer, and the clinical development of T-DXd reflects this distinction. DESTINY-Lung02 established the activity of T-DXd in previously treated, HER2-mutant NSCLC, with a confirmed objective response rate of approximately 58%, and supported the first approval of a HER2-directed therapy in this disease.9 In 2024, T-DXd received the first tumor-agnostic approval of a HER2-directed agent, for HER2 IHC 3+ solid tumors after prior systemic therapy, based on the IHC 3+ cohorts of DESTINY-PanTumor02 and related trials.10,11

Differences in HER2 Biology and Testing

In breast cancer, HER2 dysregulation predominantly reflects amplification-driven protein overexpression distributed along a continuum from strongly positive to low and ultralow, so the relevant biomarker is the quantity of HER2 protein, assessed by IHC and in situ hybridization.12 In NSCLC, by contrast, HER2 alterations are predominantly activating mutations, most commonly exon 20 insertions, frequently the serving as the oncogenic driver and associated with younger age, never-smoking status, and a high incidence of brain metastases. Thus, the relevant biomarker is the mutation itself, detected by next-generation sequencing of tissue or plasma, and comprehensive molecular profiling at diagnosis is required to identify these patients.13 

Safety and Clinical Implications

Interstitial lung disease is the most significant toxicity and the subject of a boxed warning. Most events are low grade, but fatal cases have been reported.14 Rates vary by setting and regimen; for example, approximately 12% with T-DXd plus pertuzumab in the first-line metastatic setting and approximately 10% in the postneoadjuvant setting, compared with approximately 4% to 5% across arms in the neoadjuvant DESTINY-Breast11 trial.4,7,8 Baseline and serial imaging, early evaluation of new respiratory symptoms, prompt interruption of treatment, and corticosteroid therapy are standard components of management.15 More broadly, the evidence supports characterizing HER2 as a continuous, mechanistically heterogeneous target rather than a binary one, an approach that informs both the choice of diagnostic assay and the selection of therapy across breast and lung cancers and now extends to the neoadjuvant and postneoadjuvant treatment of early-stage disease.

Table: Current FDA-Approved Indications for Trastuzumab Deruxtecan

Disease settingPatient populationHER2 requirementPrior therapy requirement
Early breast cancer (neoadjuvant)Stage II-III breast cancerHER2-positive(IHC 3+ or ISH+)None
Early breast cancer (adjuvant)Residual invasive disease after neoadjuvant therapyHER2-positive (IHC 3+ or ISH+)Prior neoadjuvant trastuzumab (± pertuzumab) and taxane
Metastatic breast cancer (first line)Unresectable or metastatic breast cancerHER2-positive (IHC 3+ or ISH+)First-line treatment
Metastatic breast cancer (later line)Unresectable or metastatic breast cancerHER2-positive (IHC 3+ or ISH+)Prior anti-HER2 therapy in metastatic setting OR recurrence during/within 6 months of completing neoadjuvant/adjuvant therapy
HR+/HER2-low or HER2-ultralow metastatic breast cancerUnresectable or metastatic diseaseHER2-low (IHC 1+ or IHC 2+/ISH−) OR HER2-ultralow (IHC 0 with membrane staining)Progression on ≥1 endocrine therapy in the metastatic setting
HER2-low metastatic breast cancerUnresectable or metastatic diseaseHER2-low (IHC 1+ or IHC 2+/ISH−)Prior chemotherapy in the metastatic setting or recurrence during/within 6 months after adjuvant chemotherapy
NSCLCUnresectable or metastatic NSCLCActivating HER2 (ERBB2) mutationPrior systemic therapy
Gastric/GEJ adenocarcinomaLocally advanced or metastatic gastric or GEJ adenocarcinomaHER2-positive (IHC 3+ or IHC 2+/ISH+)Prior trastuzumab-based regimen
Tumor-agnostic solid tumorsUnresectable or metastatic solid tumorsHER2-positive (IHC 3+)Prior systemic therapy and no satisfactory alternative treatment options

Abbreviations: GEJ, gastroesophageal junction; IHC, immunohistochemistry; ISH, in situ hybridization; NSCLC, non–small cell lung cancer.

References

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