HER3-DXd

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Cancer types include:

bladder cancer breast cancer cervical cancer esophageal cancer head and neck cancer

HealthScout AI Analysis

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Overview

HER3-DXd (patritumab deruxtecan; U3‑1402; MK‑1022) is an investigational HER3‑directed antibody–drug conjugate (ADC) being developed primarily for EGFR‑mutated non–small cell lung cancer (NSCLC) after EGFR‑TKI and chemotherapy. A pivotal, single‑arm phase 2 trial (HERTHENA‑Lung01) reported an objective response rate (ORR) of 29.8% in 225 heavily pretreated patients; median duration of response (DOR) was 6.4 months, median progression‑free survival (PFS) 5.5 months, and median overall survival (OS) 11.9 months. A phase 3 trial (HERTHENA‑Lung02) met its primary endpoint, demonstrating superior PFS versus platinum/pemetrexed; OS data were immature at the time of the topline release. In May 2025, the sponsors withdrew a U.S. BLA after phase 3 OS results did not show a benefit; an earlier 2024 FDA complete response letter cited manufacturing inspection findings. (ascopubs.org)

Mechanism of action

HER3-DXd consists of a fully human anti‑HER3 IgG1 (patritumab) linked via a tetrapeptide‑cleavable linker to a membrane‑permeable topoisomerase I inhibitor payload (DXd, an exatecan derivative); the drug‑to‑antibody ratio is approximately 8. After HER3 binding and internalization, lysosomal cleavage releases DXd, causing DNA damage; payload permeability enables a bystander effect. (accp1.onlinelibrary.wiley.com)

Efficacy

EGFR‑mutated NSCLC, post EGFR‑TKI and platinum (phase 2, HERTHENA‑Lung01, n=225; 5.6 mg/kg Q3W):
ORR 29.8% (95% CI, 23.9–36.2); DOR 6.4 months (95% CI, 4.9–7.8); PFS 5.5 months (95% CI, 5.1–5.9); OS 11.9 months (95% CI, 11.2–13.1). Activity was seen across HER3 expression levels and resistance mechanisms. (ascopubs.org)
EGFR‑mutated NSCLC (phase 1 U102 expansion, 5.6 mg/kg Q3W, n=57):
ORR 39% and median PFS 8.2 months in EGFR‑TKI–resistant disease. (pmc.ncbi.nlm.nih.gov)
EGFR‑mutated NSCLC after third‑generation EGFR‑TKI and platinum (phase 1 U102 translational update, n=78 efficacy‑evaluable):
ORR 41.0% (95% CI, 30.0–52.7), median PFS 6.4 months, median OS 16.2 months; exploratory genomics suggested potential acquired resistance in ERBB3 and TOP1. (pubmed.ncbi.nlm.nih.gov)
Phase 3 (HERTHENA‑Lung02, randomized vs platinum/pemetrexed):
Met primary endpoint (statistically significant PFS improvement vs chemotherapy; topline). OS was immature at topline announcement. (daiichisankyo.us)
HER3‑expressing metastatic breast cancer (phase 1/2, first‑in‑human, pooled cohorts):
ORR ~30% in HR+/HER2–; 22.6% in TNBC; 42.9% in HER2+ cohorts; median DOR 5.9–8.3 months depending on subtype/dose. (ascopubs.org)

Safety

Across NSCLC studies, the most common grade ≥3 treatment‑emergent adverse events (TEAEs) include thrombocytopenia, neutropenia, anemia, and leukopenia; gastrointestinal AEs (nausea, vomiting) and fatigue are frequent. In HERTHENA‑Lung01 (n=225), grade ≥3 TEAEs occurred in 64.9%; dose interruptions 40.4%, reductions 21.3%, and discontinuations 7.1%. Adjudicated drug‑related interstitial lung disease (ILD) occurred in 5.3% (1 grade 5); median time to onset was 53 days (range 9–230). (ascopubs.org)

Active trials using HER3-DXd

Found 4 active trials using this drug:

KEYMAKER-U01 Substudy 01G: A Phase 2, Umbrella Study With Rolling Arms of Investigational Agents in Combination With Pembrolizumab With or Without Platinum-based Chemotherapy in Treatment-Naïve Participants With Stage IV Non-small Cell Lung Cancer (NSCLC)

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 2 Start date: March 30, 2025

HealthScout AI summary: This trial enrolls adults with treatment-naïve stage IV squamous or non-squamous NSCLC (ECOG 0-1, no actionable EGFR/ALK/ROS1 mutations for squamous histology) and compares standard pembrolizumab plus platinum-based chemotherapy to pembrolizumab combined with HER3-DXd, an antibody-drug conjugate targeting HER3 (ERBB3) with a topoisomerase I inhibitor payload.

ClinicalTrials.gov ID: NCT06731907

HERTHENA-PanTumor01 (U31402-277): A Phase 2, Multicenter, Multicohort, Open-Label, Proof of Concept Study of Patritumab Deruxtecan (HER3-DXd; U3-1402) in Subjects With Locally Advanced or Metastatic Solid Tumors

Sponsor: Daiichi Sankyo (industry) Phase: 2 Start date: Feb. 26, 2024

HealthScout AI summary: Adults with measurable, unresectable locally advanced or metastatic solid tumors that have progressed after standard therapies, enrolled in tumor-specific refractory cohorts (e.g., melanoma post–PD-(L)1, SCCHN post platinum/PD-(L)1, HER2-negative gastric/GEJ, HGS ovarian, cervical, endometrial, urothelial, ESCC, pancreatic, mCRPC, nonsquamous NSCLC without drivers, and HR+/HER2– breast cancer after CDK4/6 and chemo). Single-arm therapy is patritumab deruxtecan (HER3-DXd) 5.6 mg/kg IV q3w, an HER3-targeted antibody–drug conjugate delivering a topoisomerase I inhibitor (DXd).

ClinicalTrials.gov ID: NCT06172478

KEYMAKER-U01 Substudy 01A: A Phase 1/2, Umbrella Study With Rolling Arms of Investigational Agents With Pembrolizumab With or Without Chemotherapy in Treatment-Naive Participants With Stage IV Non-small Cell Lung Cancer (NSCLC)

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 1/2 Start date: Dec. 19, 2019

HealthScout AI summary: This trial enrolls adults with previously untreated stage IV squamous or non-squamous NSCLC (without targetable driver mutations) to receive pembrolizumab plus chemotherapy combined with an investigational immunotherapy or antibody-drug conjugate targeting TIGIT (vibostolimab), CD27 (boserolimab), ILT4 (MK-4830), ILT3 (MK-0482), B7-H3 (I-DXd), or HER3 (HER3-DXd). Patients must have available tumor tissue and good organ function; those with active CNS disease, significant comorbidities, or prior systemic therapy for metastatic NSCLC are excluded.

ClinicalTrials.gov ID: NCT04165070

A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects With Metastatic or Unresectable Non-small Cell Lung Cancer

Sponsor: Daiichi Sankyo (industry) Phase: 1 Start date: Oct. 30, 2017

HealthScout AI summary: This trial enrolls adults with locally advanced or metastatic non-small cell lung cancer—including EGFR-mutant disease post-EGFR TKI, KRAS-G12C-mutant after KRAS-G12C inhibitor, and EGFR-wildtype post-systemic therapy—to receive HER3-DXd (patritumab deruxtecan), an antibody-drug conjugate targeting HER3 and delivering a topoisomerase I inhibitor payload. Treatment is given intravenously every three weeks, with safety, dosing, and activity being evaluated across molecular subtypes.

ClinicalTrials.gov ID: NCT03260491