DESTINY-Breast04: Trastuzumab Deruxtecan in HER2-Low Metastatic Breast Cancer

Primary endpoint (PFS, HR-positive cohort): 10.1 vs 5.4 months — HR 0.51 (95% CI 0.40–0.64; P<0.001) Key secondary (OS, all patients): 23.4 vs 16.8 months — HR 0.64 (95% CI 0.49–0.84; P=0.001) Safety signal: Drug-related interstitial lung disease/pneumonitis in 12.1% of trastuzumab deruxtecan–treated patients, including 3 fatal cases (0.8%)

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Clinical Bottom Line

DESTINY-Breast04 established trastuzumab deruxtecan as the first HER2-directed therapy to demonstrate a survival benefit in patients with HER2-low metastatic breast cancer — a population that was previously considered HER2-negative and ineligible for anti-HER2 treatment. The trial showed that trastuzumab deruxtecan nearly doubled progression-free survival and meaningfully extended overall survival compared with physician's choice chemotherapy in heavily pretreated patients, regardless of hormone receptor status.

This trial redefined how oncologists classify and treat breast cancer. Before DESTINY-Breast04, HER2-low (IHC 1+ or IHC 2+/ISH-negative) was not a therapeutically actionable category — these patients were grouped with HER2-negative disease and treated with standard chemotherapy. The results opened a new treatment option for roughly half of all patients with metastatic breast cancer who express low levels of HER2, fundamentally expanding the population eligible for HER2-directed therapy. Trastuzumab deruxtecan received FDA approval for HER2-low metastatic breast cancer in August 2022 based on these data and is now firmly embedded in treatment guidelines as a preferred option after prior chemotherapy.

The key safety concern is interstitial lung disease and pneumonitis, an identified risk with trastuzumab deruxtecan that occurred in approximately one in eight treated patients, including fatal cases. This mandates proactive monitoring with imaging, patient education on respiratory symptoms, and prompt dose holds and corticosteroid initiation at the earliest sign of pulmonary toxicity.

Trial Overview

Study Design

• Trial name and registration: DESTINY-Breast04, NCT03734029
• Design: Phase 3, randomized, two-group, open-label trial; prespecified interim analysis for overall survival
• Randomization: 2:1 (trastuzumab deruxtecan : physician's choice), stratified by HER2-low status (IHC 1+ vs IHC 2+ and ISH-negative), number of previous lines of chemotherapy for metastatic disease (one vs two), and hormone-receptor status (positive [with vs without previous CDK4/6 inhibitor therapy] vs negative)
• Setting: Unresectable or metastatic HER2-low breast cancer; one or two previous lines of chemotherapy for metastatic disease
• Enrollment period and sites: December 27, 2018, through December 31, 2021. Multinational trial across sites in Europe, Israel, Asia, and North America.

Mechanism of Action

Trastuzumab deruxtecan (T-DXd, Enhertu) is an antibody-drug conjugate consisting of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload (deruxtecan, a camptothecin derivative) via a cleavable tetrapeptide-based linker. T-DXd binds to HER2 on the tumor cell surface, is internalized, and the linker is cleaved by lysosomal enzymes, releasing the cytotoxic payload intracellularly. The released payload has membrane-permeable properties, enabling a bystander killing effect on neighboring tumor cells — a property hypothesized to be particularly relevant in HER2-low tumors where HER2 expression is heterogeneous [2].

Patient Population

• Key eligibility: Patients with HER2-low metastatic breast cancer (IHC 1+ or IHC 2+/ISH-negative by central testing) who had received one or two previous lines of chemotherapy for metastatic disease, or who had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with hormone receptor–positive disease must have received at least one line of endocrine therapy. Treated, stable brain metastases were permitted. Patients with a history of noninfectious interstitial lung disease treated with glucocorticoids or suspected interstitial lung disease on screening imaging were excluded.
• Biomarker selection: HER2-low status determined by central testing using VENTANA HER2/neu (4B5) IUO Assay system
• Sample size flow: 713 screened → 557 randomized (373 trastuzumab deruxtecan, 184 physician's choice) → 543 treated (371 trastuzumab deruxtecan, 172 physician's choice) → 557 analyzed (intention-to-treat population)

Baseline Characteristics

Baseline characteristics were well balanced between the two groups. The majority of patients had hormone receptor–positive disease (approximately 89%), reflecting the planned enrollment of 480 hormone receptor–positive and 60 hormone receptor–negative patients. Both arms were heavily pretreated, with a median of 3 prior lines of therapy for metastatic disease and approximately two-thirds of patients with prior CDK4/6 inhibitor exposure.

Treatment Protocol

Experimental Arm: Trastuzumab Deruxtecan (n=373 randomized; safety population n=371)

Trastuzumab deruxtecan - Dose and schedule: 5.4 mg per kilogram of body weight administered intravenously every 3 weeks - Treatment duration: Not reported in this publication (treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria) - Median treatment duration: 8.2 months (range, 0.2 to 33.3) - Median relative dose intensity: Not reported in this publication

Control Arm: Physician's Choice (n=184 randomized; safety population n=172)

Physician's choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel - Dose and schedule: Administered in accordance with the local label or the National Comprehensive Cancer Network guidelines - Treatment duration: Not reported in this publication - Median treatment duration: 3.5 months (range, 0.3 to 17.6)

The chemotherapy choices in the physician's choice arm were eribulin (51.1%), capecitabine (20.1%), nab-paclitaxel (10.3%), gemcitabine (10.3%), and paclitaxel (8.2%).

Efficacy Outcomes

Primary Endpoint: Progression-Free Survival in the Hormone Receptor–Positive Cohort

Definition: Progression-free survival assessed by means of blinded independent central review in the hormone receptor–positive cohort Analysis population: Intention-to-treat, hormone receptor–positive cohort (n=494; 331 trastuzumab deruxtecan, 163 physician's choice) Statistical method: Stratified log-rank test; hazard ratio estimated with stratified Cox regression Median follow-up: 18.4 months (95% CI, 17.7 to 18.9)

Trastuzumab deruxtecan: 10.1 months (95% CI, 9.5 to 11.5) Physician's choice: 5.4 months (95% CI, 4.4 to 7.1) Comparison: HR 0.51 (95% CI, 0.40 to 0.64; P<0.001)

Trastuzumab deruxtecan approximately doubled progression-free survival compared with physician's choice chemotherapy in the hormone receptor–positive cohort, with a 49% reduction in the risk of disease progression or death.

Key Secondary Endpoints

Progression-Free Survival Among All Patients

Definition: Progression-free survival assessed by blinded independent central review among all randomized patients Analysis population: Intention-to-treat, all patients (n=557; 373 trastuzumab deruxtecan, 184 physician's choice) Formally tested: Yes (within the statistical hierarchy)

Trastuzumab deruxtecan: 9.9 months (95% CI, 9.0 to 11.3) Physician's choice: 5.1 months (95% CI, 4.2 to 6.8) Comparison: HR 0.50 (95% CI, 0.40 to 0.63; P<0.001)

The PFS benefit in the overall population was consistent with the primary analysis in the hormone receptor–positive cohort.

Overall Survival in the Hormone Receptor–Positive Cohort

Definition: Overall survival in the hormone receptor–positive cohort Analysis population: Intention-to-treat, hormone receptor–positive cohort Formally tested: Yes (interim analysis with a stopping boundary of 0.0075)

Trastuzumab deruxtecan: 23.9 months (95% CI, 20.8 to 24.8) Physician's choice: 17.5 months (95% CI, 15.2 to 22.4) Comparison: HR 0.64 (95% CI, 0.48 to 0.86; P=0.003)

The P value of 0.003 crossed the prespecified interim stopping boundary of 0.0075, establishing statistical significance for the overall survival benefit in the hormone receptor–positive cohort.

Overall Survival Among All Patients

Definition: Overall survival among all randomized patients Analysis population: Intention-to-treat, all patients Formally tested: Yes (interim analysis with a stopping boundary of 0.0075)

Trastuzumab deruxtecan: 23.4 months (95% CI, 20.0 to 24.8) Physician's choice: 16.8 months (95% CI, 14.5 to 20.0) Comparison: HR 0.64 (95% CI, 0.49 to 0.84; P=0.001)

The P value of 0.001 also crossed the interim stopping boundary. Trastuzumab deruxtecan demonstrated a 36% reduction in the risk of death compared with physician's choice chemotherapy across the full intention-to-treat population.

Confirmed Objective Response Rate — Hormone Receptor–Positive Cohort

Analysis population: Hormone receptor–positive cohort (response evaluable)

Trastuzumab deruxtecan: 52.6% (95% CI, 47.0 to 58.0; 175 responders) Physician's choice: 16.3% (95% CI, 11.0 to 22.8; 27 responders)

In the trastuzumab deruxtecan group, 12 patients (3.6%) had a complete response compared with 1 patient (0.6%) in the physician's choice group. Progressive disease as best overall response was observed in 26 patients (7.8%) versus 35 patients (21.1%) in the respective groups.

Confirmed Objective Response Rate — All Patients

Analysis population: All patients

Trastuzumab deruxtecan: 52.3% (95% CI, 47.1 to 57.4; 195 responders) Physician's choice: 16.3% (95% CI, 11.3 to 22.5; 30 responders)

Duration of Response — Hormone Receptor–Positive Cohort

Analysis population: Hormone receptor–positive cohort responders

Trastuzumab deruxtecan: 10.7 months (median) Physician's choice: 6.8 months (median)

Exploratory Endpoints

Efficacy in the Hormone Receptor–Negative Cohort

Although the hormone receptor–negative cohort was small (63 patients by randomization), results were consistent with the overall population.

Progression-free survival:

• Trastuzumab deruxtecan: 8.5 months (95% CI, 4.3 to 11.7)
• Physician's choice: 2.9 months (95% CI, 1.4 to 5.1)
• HR 0.46 (95% CI, 0.24 to 0.89)

Overall survival:

• Trastuzumab deruxtecan: 18.2 months (95% CI, 13.6 to not evaluable)
• Physician's choice: 8.3 months (95% CI, 5.6 to 20.6)
• HR 0.48 (95% CI, 0.24 to 0.95)

Confirmed objective response rate:

• Trastuzumab deruxtecan: 50.0% (95% CI, 33.8 to 66.2)
• Physician's choice: 16.7% (95% CI, 3.6 to 41.4)

These exploratory analyses were not formally tested in the statistical hierarchy and should be interpreted with caution given the small sample size; however, the consistent magnitude and direction of benefit across both HR-positive and HR-negative subsets reinforces that the activity of trastuzumab deruxtecan in HER2-low disease is not limited to hormone receptor–positive patients.

Safety

Safety Population

Trastuzumab deruxtecan: n=371; Physician's choice: n=172

Safety Summary

Several features of this safety profile merit attention. Despite the higher efficacy of trastuzumab deruxtecan, the rate of grade ≥3 adverse events was actually lower with trastuzumab deruxtecan (52.6%) than with physician's choice chemotherapy (67.4%). The exposure-adjusted incidence rates supported this difference: 1.30 per patient-year for trastuzumab deruxtecan versus 2.66 per patient-year for physician's choice. Dose reductions were less frequent with trastuzumab deruxtecan (22.6% vs 38.4%), although discontinuation due to adverse events was higher (16.2% vs 8.1%), driven largely by interstitial lung disease.

Grade ≥3 Adverse Events of Clinical Significance

Neutropenia and leukopenia were substantially more common with physician's choice chemotherapy. In contrast, trastuzumab deruxtecan was associated with higher rates of nausea (any grade: 73.0% vs 23.8%), vomiting (any grade: 34.0% vs 9.9%), and thrombocytopenia (any grade: 23.7% vs 9.3%), though these were predominantly low grade.

Adverse Events of Special Interest

⚠️ Interstitial Lung Disease / Pneumonitis: Critical Safety Signal

Drug-related interstitial lung disease or pneumonitis, as adjudicated by an independent committee, occurred in 45 patients (12.1%) who received trastuzumab deruxtecan, compared with 1 patient (0.6%) in the physician's choice group. The grade distribution in the trastuzumab deruxtecan group was:

• Grade 1: 13 (3.5%)
• Grade 2: 24 (6.5%)
• Grade 3: 5 (1.3%)
• Grade 5 (fatal): 3 (0.8%)

No grade 4 events were reported. The median time to onset of ILD/pneumonitis in the trastuzumab deruxtecan group was 129 days (range, 26 to 710).

Clinical implication: The 12.1% incidence of ILD/pneumonitis with 3 fatal cases underscores the need for vigilant pulmonary monitoring. Clinicians should perform baseline CT imaging, educate patients on respiratory symptoms (cough, dyspnea, fever), and maintain a low threshold for repeat imaging. At first signs of ILD, trastuzumab deruxtecan should be held immediately, and corticosteroid therapy should be initiated promptly per management guidelines [2].

Left Ventricular Dysfunction

In the trastuzumab deruxtecan group, left ventricular dysfunction was reported in 17 patients (4.6%). By laboratory assessment, LVEF grade 2 events (10 to 19% decrease from baseline) occurred in 44 of 371 patients (11.9%) in the trastuzumab deruxtecan group and 10 of 172 patients (5.8%) in the physician's choice group. LVEF grade 3 events (>20% decrease from baseline) were observed in 5 patients (1.5%) in the trastuzumab deruxtecan group and no patients in the physician's choice group.

Deaths

Fatal adverse events occurred in 14 patients (3.8%) in the trastuzumab deruxtecan group and 5 patients (2.9%) in the physician's choice group. Drug-related deaths in the trastuzumab deruxtecan group included pneumonitis (in 2 patients [0.5%]), ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, and sepsis (1 patient [0.3%] each). There were no drug-related deaths in the physician's choice group.

Subgroup Analyses

Subgroup analyses of the primary endpoint (PFS in the hormone receptor–positive cohort) showed consistent benefit across prespecified subgroups:

By HER2-low status (trastuzumab deruxtecan arm):

• HER2 IHC 1+: median PFS 10.3 months

• HER2 IHC 2+ and ISH-negative: median PFS 10.1 months

By prior CDK4/6 inhibitor use (trastuzumab deruxtecan arm):

• With previous CDK4/6 inhibitor treatment: median PFS 10.0 months

• Without previous CDK4/6 inhibitor treatment: median PFS 11.7 months

The consistent benefit across both HER2 IHC 1+ and IHC 2+/ISH-negative subsets is clinically important: it indicates that the activity of trastuzumab deruxtecan is not limited to the higher end of HER2-low expression and supports use regardless of whether a patient's HER2 score is 1+ or 2+/ISH-negative. The efficacy in patients with prior CDK4/6 inhibitor exposure — which represented approximately two-thirds of the hormone receptor–positive population — confirms the activity of this agent in the contemporary treatment landscape.

Hazard ratios by subgroup and interaction P values were presented in the supplementary materials (Fig. S2) but were not available for this extraction.

These subgroup analyses were prespecified and were not powered for formal statistical comparisons. Results should be interpreted as hypothesis-generating.

Key Comparator Trials

Cross-trial comparisons are limited by differences in patient populations, trial designs, and endpoints. These data are presented for context, not for direct statistical comparison.

Contextual Notes

DESTINY-Breast04 was the first trial to establish trastuzumab deruxtecan in HER2-low breast cancer and led to the creation of "HER2-low" as a clinically actionable category. The subsequent DESTINY-Breast06 trial [4] moved trastuzumab deruxtecan earlier in the treatment sequence, testing it after progression on endocrine therapy (before or in lieu of chemotherapy) in HR-positive, HER2-low and HER2-ultralow metastatic breast cancer. That trial also introduced the concept of "HER2-ultralow" (IHC >0 to <1+), further expanding the potential eligible population.

TROPiCS-02 [5] evaluated sacituzumab govitecan, another antibody-drug conjugate (targeting Trop-2 rather than HER2), in HR-positive/HER2-negative metastatic breast cancer after 2–4 prior chemotherapy lines. While there is significant population overlap between these trials, the mechanism and target are distinct, and the two agents represent complementary rather than directly competing options. The sequencing of trastuzumab deruxtecan and sacituzumab govitecan remains an active area of clinical investigation.

A key consideration is that DESTINY-Breast04 enrolled patients after one or two prior chemotherapy lines, whereas many patients in current practice may be candidates for trastuzumab deruxtecan earlier in the treatment sequence based on DESTINY-Breast06 data. The optimal positioning of trastuzumab deruxtecan relative to other available agents (sacituzumab govitecan, standard chemotherapies, and investigational agents) continues to evolve.

Grey Zones and Unanswered Questions

• HER2-zero patients were excluded. DESTINY-Breast04 required HER2 IHC 1+ or IHC 2+/ISH-negative. Patients with IHC 0 (truly HER2-negative) were not eligible. Subsequent data from DESTINY-Breast06 have explored the HER2-ultralow category, but the boundary of HER2 expression below which trastuzumab deruxtecan loses efficacy remains undefined. The reproducibility and reliability of IHC 0 versus IHC 1+ scoring across pathology laboratories adds further uncertainty.

• Optimal sequencing with other ADCs is unknown. With both trastuzumab deruxtecan and sacituzumab govitecan approved in overlapping populations, the optimal sequence — which ADC first, and whether one retains activity after the other — lacks prospective randomized data. Cross-resistance between these mechanistically distinct agents is not well characterized.

• Brain metastases were underrepresented. Only 6.4% and 4.3% of patients in the two arms had brain metastases at baseline, and only treated, stable brain metastases were permitted. CNS activity of trastuzumab deruxtecan in HER2-low disease is therefore not well established from this trial, although intracranial responses have been reported in HER2-positive disease.

• The trial was open-label. Knowledge of treatment assignment may influence progression assessment and reporting of subjective adverse events (nausea, fatigue, decreased appetite). Although the primary endpoint used blinded independent central review for progression determination, patient-reported outcomes and symptom-based toxicity data are susceptible to bias.

• Long-term ILD risk remains uncertain. With a median follow-up of 18.4 months and a median time to ILD onset of 129 days (range up to 710 days), late-onset ILD events may not be fully captured. The cumulative risk with prolonged therapy — particularly in patients who achieve durable responses — warrants continued surveillance.

Clinical Implications

Where This Fits in the Treatment Sequence

For patients with HER2-low metastatic breast cancer (IHC 1+ or IHC 2+/ISH-negative) who have received one or two prior lines of chemotherapy for metastatic disease, trastuzumab deruxtecan is now a preferred treatment option. NCCN guidelines [3] recommend trastuzumab deruxtecan as a preferred option for HER2-low metastatic breast cancer after prior chemotherapy for both HR-positive and HR-negative disease. Since the publication of DESTINY-Breast04, the DESTINY-Breast06 data have further expanded the potential treatment window earlier in the algorithm for HR-positive patients. Clinicians should reassess HER2 status at the time of treatment decision-making, ideally on the most recent biopsy specimen, given that HER2 expression can change over the course of disease and treatment.

Practical Considerations

• Dosing: 5.4 mg/kg IV every 3 weeks. No loading dose required.
• Pulmonary monitoring: Baseline CT scan. Advise patients to report any new or worsening respiratory symptoms immediately. Repeat imaging at any suspicion of ILD. Per prescribing information [2], permanently discontinue for grade ≥2 ILD/pneumonitis.
• Cardiac monitoring: Assess LVEF by echocardiogram or MUGA scan at baseline and at regular intervals during treatment, given the LVEF changes observed (grade 2 events in 11.9%, grade 3 in 1.5% of treated patients).
• Antiemetic prophylaxis: The high incidence of nausea (73.0% any grade, 4.6% grade ≥3) warrants proactive antiemetic regimens. Most institutions employ a three-drug antiemetic regimen (5-HT3 antagonist, dexamethasone, NK1 receptor antagonist) or adapted moderate-emetogenic regimens.
• HER2 testing: Ensure HER2 IHC testing is performed with validated assays. The distinction between IHC 0 and IHC 1+ is clinically meaningful and may be challenging to reproduce across laboratories. When in doubt, re-testing or pathology consultation should be considered.

Post-Progression Options

Crossover rates and subsequent therapy information were not reported in this publication. After progression on trastuzumab deruxtecan, treatment options include sacituzumab govitecan (for Trop-2–expressing disease), standard single-agent chemotherapies, clinical trials, or best supportive care, depending on performance status and prior therapy exposure. The optimal sequencing strategy after trastuzumab deruxtecan failure is an area of active investigation.

Regulatory and Guideline Status

Regulatory

• FDA: Trastuzumab deruxtecan received accelerated approval in August 2022 for adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Subsequently, the indication has been broadened to include HER2-ultralow breast cancer based on DESTINY-Breast06 data. Regulatory status should be verified with current FDA/EMA labeling [2].
• EMA: Approved for similar indications in the European Union.

⚠️ Regulatory status verified as of March 2026. Confirm current approval status and labeled indications before clinical use at FDA.gov or EMA.europa.eu.

Guidelines

• NCCN: Trastuzumab deruxtecan is listed as a preferred regimen for HER2-low metastatic breast cancer after prior chemotherapy (Category 1) [3]. It is also recommended in earlier treatment lines based on subsequent trial data.

Companion Diagnostics

HER2-low status must be determined by a validated immunohistochemistry assay. The VENTANA HER2/neu (4B5) IUO Assay system was used for central testing in this trial. Standard HER2 IHC testing performed in clinical practice (using FDA-approved assays) is used for patient selection; no separate companion diagnostic is required beyond standard HER2 testing.

About the Author

Andrew Stevenson is the founder and systems architect of kill-cancer.com, a clinical intelligence platform delivering structured, source-traced oncology trial analysis to practicing clinicians. He holds 17 Google technical certifications in data systems, automation, and applied AI — the engineering foundation behind the extraction and verification pipeline that produces every article on this platform. Every number traces directly to its source publication. Zero calculation. Zero editorializing. Zero hallucination.

Five siblings lost to cancer built the urgency. The engineering builds the trust.

📧 andrew@kill-cancer.com 🌐 kill-cancer.com 💬 kill-cancer.com/forum

Disclaimer

This article is intended for healthcare professionals only. It is not medical advice and should not be used as a substitute for professional clinical judgment. Treatment decisions should be made in consultation with qualified healthcare providers based on individual patient circumstances.

All trial data presented in this article are sourced directly from the published clinical trial report and its supplementary materials. Numbers are reproduced exactly as reported; no calculations, derivations, or estimates have been performed.

Trial results are presented as reported in the source publication. Updated data, label changes, or guideline revisions published after the source article may alter clinical applicability.

Comparator trial data presented in Section 8 are sourced from their respective published reports and are provided for contextual purposes only. Cross-trial comparisons have inherent limitations and should not be interpreted as direct statistical comparisons.

References

1. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387:9-20. doi:10.1056/NEJMoa2203690
2. Enhertu (trastuzumab deruxtecan) prescribing information. U.S. Food and Drug Administration. Accessed March 2026.
3. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 1.2026. Accessed March 2026.
4. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan vs physician's choice treatment in patients with HER2-low or HER2-ultralow hormone receptor–positive metastatic breast cancer: DESTINY-Breast06. JAMA. 2024. doi:10.1001/jama.2024.18268
5. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer (TROPiCS-02): final overall survival results. J Clin Oncol. 2023;41(21):3709-3720. doi:10.1200/JCO.22.01966