FDA Approval of Trastuzumab Deruxtecan: Advancing Treatment for HR-Positive HER2-Low and Ultralow Metastatic Breast Cancer

Highlight

– The FDA approved trastuzumab deruxtecan (T-DXd) for adult patients with unresectable or metastatic HR-positive breast cancer exhibiting HER2-low or HER2-ultralow expression after progression on endocrine therapy.
– This approval was based on DESTINY-Breast06, a pivotal multicenter randomized controlled trial demonstrating significant progression-free survival (PFS) improvement compared with chemotherapy.
– The indication includes a newly defined HER2-ultralow category (IHC 0 with membrane staining), supported by an approved diagnostic assay.
– T-DXd provides a novel treatment alternative in the metastatic setting without prior chemotherapy exposure, expanding options beyond standard endocrine and chemotherapy regimens.

Study Background and Disease Burden

Breast cancer remains the most common malignancy among women worldwide, with metastatic breast cancer (MBC) associated with poor prognosis and limited curative options. Approximately 70% of breast cancers are hormone receptor-positive (HR-positive), for which endocrine therapy (ET) is a foundational treatment. However, progression on ET necessitates alternative therapies.

The human epidermal growth factor receptor 2 (HER2) status critically informs breast cancer management. Historically, HER2-positive cancers (IHC 3+ or IHC 2+ with ISH amplification) benefit from HER2-targeted agents. Yet, the vast majority of HR-positive breast cancers are classified as HER2-negative or HER2-low (IHC 1+ or IHC 2+/ISH-negative), a heterogeneous group lacking approved HER2-targeted therapies.

Recent advances have shown that antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), can target and eradicate HER2-low expressing tumors by delivering potent cytotoxic payloads. The inclusion of the HER2-ultralow category, defined as IHC 0 with incomplete or faint membrane staining, addresses an unmet need for patients whose tumors express minimal HER2 yet may respond to such targeted therapies.

Study Design

The approval derived from the DESTINY-Breast06 trial, a randomized, open-label, multicenter study enrolling 866 adult patients with unresectable or metastatic HR-positive breast cancer, who had disease progression on prior endocrine therapy but had not received chemotherapy in the metastatic setting.

Patients were stratified based on prior CDK4/6 inhibitor use, prior taxane in (neo)adjuvant settings, and HER2 status categorized into HER2-low (IHC 1+ or IHC 2+/ISH-) and HER2-ultralow (IHC 0 with membrane staining). Within the population, 713 patients had HER2-low and 153 had HER2-ultralow tumors.

They were randomized 1:1 to receive either trastuzumab deruxtecan (T-DXd) or investigator’s choice of chemotherapy, consisting of paclitaxel, nab-paclitaxel, or capecitabine. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR), with key secondary endpoints including overall survival and safety parameters.

Key Findings

In the HER2-low cohort, T-DXd demonstrated a median PFS of 13.2 months (95% CI, 11.4 to 15.2), compared to 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy arm, yielding a hazard ratio (HR) for progression or death of 0.62 (95% CI, 0.52 to 0.75, P < .0001). This represents a 38% risk reduction in disease progression or death.

Importantly, the trial also met its key secondary endpoint in the overall population, including both HER2-low and HER2-ultralow subgroups, where T-DXd conferred a PFS benefit with an HR of 0.64 (95% CI, 0.54 to 0.76, P < .0001).

These findings establish the efficacy of T-DXd in patients with minimal HER2 expression and expand the understanding of HER2 as a continuous rather than binary therapeutic target.

Safety outcomes were consistent with prior T-DXd studies. Common adverse events included nausea, fatigue, and neutropenia. Notably, interstitial lung disease (ILD) or pneumonitis occurred at rates consistent with the established safety profile, underscoring the need for vigilant monitoring during therapy.

Expert Commentary

The FDA approval of trastuzumab deruxtecan for HR-positive, HER2-low and ultralow breast cancers represents a paradigm shift in metastatic breast cancer management. By extending targeted therapy to a previously unaddressed subset of HER2-low and ultralow tumors, this approval offers a precision medicine approach grounded in robust clinical evidence.

Dr. L. Amiri-Kordestani and colleagues highlight that this is the first regulatory recognition of HER2-ultralow expression as a clinically actionable category. The contemporaneous approval of a companion diagnostic assay facilitates precise patient selection, optimizing therapeutic benefit and minimizing unnecessary exposure.

Nonetheless, questions remain regarding long-term outcomes, optimal sequencing relative to other systemic therapies, and management of toxicities such as ILD. Future studies will elucidate T-DXd’s role across varied breast cancer subtypes and earlier disease stages.

Conclusion

Trastuzumab deruxtecan offers a significant advancement for adults with hormone receptor-positive, unresectable or metastatic breast cancer with HER2-low or ultralow expression who have progressed after endocrine therapy. The DESTINY-Breast06 data confirm clinically meaningful progression-free survival improvements compared to chemotherapy without prior metastatic chemotherapy exposure.

This indication broadens the therapeutic horizon by defining and targeting the HER2-ultralow subgroup, accompanied by an approved diagnostic test. Integration of T-DXd into clinical practice may reduce reliance on chemotherapy, improve patient outcomes, and exemplify the evolving paradigm of personalized oncology.

Ongoing real-world evidence and further trials will be critical to determine durability of benefit, overall survival impact, and management strategies for adverse events. In summary, T-DXd is a transformative option for a previously underserved metastatic breast cancer population, filling an important unmet medical need.

References

Dilawari A, Zhang H, Shah M, Gao X, Fiero M, Bhatnagar V, Pierce W, Mixter B, Pazdur R, Amiri-Kordestani L. US Food and Drug Administration Approval Summary: Trastuzumab Deruxtecan for the Treatment of Adult Patients With Hormone Receptor-Positive, Unresectable or Metastatic Human Epidermal Growth Factor Receptor 2-Low or Human Epidermal Growth Factor Receptor 2-Ultralow Breast Cancer. J Clin Oncol. 2025 Sep 10;43(26):2942-2951. doi: 10.1200/JCO-25-00812. Epub 2025 Aug 5. PMID: 40763319.

Curigliano G, et al. HER2-low breast cancer: a new subtype of breast cancer. Nat Rev Clin Oncol. 2021 Jan;18(1):59-60. doi:10.1038/s41571-020-00466-2.

Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jan 6;386(3):193-204. doi:10.1056/NEJMoa2102430.

Schwartzberg LS, et al. Biomarker Analysis of Trastuzumab Deruxtecan’s Activity in HER2-Low Metastatic Breast Cancer. J Clin Oncol. 2023;41(9):1828-1838.