HER3-DXd

Overview

HER3-DXd (patritumab deruxtecan; U3-1402/MK-1022) is an investigational antibody–drug conjugate being studied in HER3-expressing solid tumors, particularly EGFR-mutated non-small-cell lung cancer (NSCLC) and breast cancer. It remains investigational: a US application for accelerated approval in previously treated EGFR-mutated NSCLC was withdrawn in May 2025 after the confirmatory phase 3 trial did not significantly improve overall survival. (merck.com)

Mechanism of action

HER3-DXd combines:

• Patritumab, a fully human IgG1 antibody targeting HER3/ERBB3;
• A tumor-selective, cleavable tetrapeptide linker; and
• DXd, an exatecan-derived topoisomerase-I inhibitor payload.

After binding HER3, the conjugate is internalized and releases DXd, causing DNA damage and cell death. Preclinical evidence also suggests that the payload can induce features of immunogenic cell death. Clinical responses have occurred across different levels of HER3 expression, so HER3 immunohistochemistry has not yet been established as a definitive predictive biomarker. (pmc.ncbi.nlm.nih.gov)

Efficacy

EGFR-mutated NSCLC: In the single-arm phase 2 HERTHENA-Lung01 trial, 225 evaluable patients previously treated with an EGFR inhibitor and platinum chemotherapy had a confirmed objective response rate (ORR) of 29.8%, median response duration of 6.4 months, median progression-free survival (PFS) of 5.5 months, and median overall survival of 11.9 months. (pmc.ncbi.nlm.nih.gov)

In the randomized phase 3 HERTHENA-Lung02 trial after third-generation EGFR-inhibitor therapy, HER3-DXd improved median PFS modestly versus platinum-based chemotherapy—5.8 versus 5.4 months; hazard ratio 0.77. ORR was 35.2% versus 25.3%, respectively. However, overall survival was not significantly improved, which contributed to withdrawal of the US regulatory application. (ascopubs.org)

Breast cancer: A phase 1/2 study in heavily pretreated metastatic disease reported ORRs of 30.1% in HR-positive/HER2-negative breast cancer, 22.6% in triple-negative disease, and 42.9% in HER2-positive disease, although the HER2-positive cohort contained only 14 patients. (pmc.ncbi.nlm.nih.gov)

In the subsequent single-arm phase 2 ICARUS-BREAST01 trial of 99 patients with HR-positive/HER2-negative advanced breast cancer, ORR was 53.5% by investigator assessment and 55.6% by retrospective independent review. Median PFS was 9.2 months and median response duration was 9.3 months; randomized confirmation is still needed. (nature.com)

Safety

The main toxicities are gastrointestinal and hematologic, including nausea, fatigue, diarrhea, thrombocytopenia, neutropenia and anemia. Interstitial lung disease/pneumonitis is an important identified risk and has included rare fatal cases.

In HERTHENA-Lung02, grade 3 or higher treatment-emergent adverse events occurred in 73% with HER3-DXd versus 57% with chemotherapy, driven partly by grade 3 or higher thrombocytopenia (30% versus 7.9%). (ascopubs.org)

In ICARUS-BREAST01, grade 3 or higher treatment-related events occurred in 50.1% of patients. The most frequent treatment-related events were fatigue (83%), nausea (75%), diarrhea (53%) and alopecia (40%). Eight patients had independently adjudicated drug-related interstitial lung disease, predominantly grade 1 or 2. (nature.com)

Further reading

• HERTHENA-Lung01 phase 2 NSCLC trial
• HERTHENA-Lung02 phase 3 conference abstract
• Phase 1/2 metastatic breast-cancer study
• ICARUS-BREAST01 phase 2 study
• US regulatory-application withdrawal

Last updated: Sep 2026