Patritumab deruxtecan

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Also known as:

U3-1402

Cancer types include:

breast cancer non-small cell lung cancer small cell lung cancer

TrialFetch AI Analysis

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Overview

Patritumab deruxtecan (HER3-DXd; U3-1402) is an investigational HER3‑directed antibody–drug conjugate (ADC) being studied across solid tumors. The most advanced program is in EGFR‑mutated non–small cell lung cancer (NSCLC) after EGFR TKI therapy. A pivotal phase 2 trial (HERTHENA‑Lung01) reported objective responses and disease control in a heavily pretreated population and was published in the Journal of Clinical Oncology. A subsequent randomized phase 3 trial (HERTHENA‑Lung02) met its primary endpoint of improved progression‑free survival versus platinum–pemetrexed, but later topline analyses reported no overall‑survival benefit; the U.S. BLA seeking accelerated approval was then voluntarily withdrawn in May 2025. (ascopubs.org)

Mechanism of action

Composition: a fully human anti‑HER3 IgG1 (patritumab) linked via a cleavable tetrapeptide linker to a membrane‑permeable topoisomerase I inhibitor payload (DXd; an exatecan derivative) with an average drug‑to‑antibody ratio ≈8. After HER3‑mediated internalization and lysosomal cleavage, DXd induces DNA damage; its permeability supports a bystander effect. (accp1.onlinelibrary.wiley.com)
Rationale: HER3 is broadly expressed across tumors and implicated in resistance to EGFR‑targeted therapy; preclinical studies showed activity against EGFR‑TKI–resistant NSCLC. (aacrjournals.org)

Efficacy

NSCLC, EGFR‑mutated (post‑EGFR TKI and platinum chemotherapy)
- Phase 2, HERTHENA‑Lung01 (n=225 at 5.6 mg/kg Q3W): confirmed ORR 29.8% (95% CI 23.9–36.2); median duration of response (DOR) 6.4 months; median PFS 5.5 months; median OS 11.9 months. Intracranial activity among patients with baseline brain metastases included a CNS ORR 33.3% (10/30). (ascopubs.org)
- Phase 3, HERTHENA‑Lung02: reported a statistically significant PFS improvement versus platinum–pemetrexed; later topline results indicated OS did not reach statistical significance, and the U.S. BLA was withdrawn (May 2025). Detailed results were slated for ASCO 2025. (daiichisankyo.us)

Breast cancer (HER3‑expressing, previously treated)
- Phase 1/2, multicenter: HR+/HER2– cohort (n=113) ORR 30.1%, median PFS 7.4 months; TNBC HER3‑high (n=53) ORR 22.6%, median PFS 5.5 months; HER2+ (n=14) ORR 42.9%, median PFS 11.0 months. Responses occurred across HER3‑high and HER3‑low expression. (pubmed.ncbi.nlm.nih.gov)

Other tumor types
- A phase 2 colorectal cancer study (design) is ongoing/reported as a trial‑in‑progress; efficacy data not yet established. (ascopubs.org)

Safety

Safety is characterized by hematologic and gastrointestinal adverse events and a class‑associated risk of interstitial lung disease (ILD)/pneumonitis.
- NSCLC phase 2 (HERTHENA‑Lung01): grade ≥3 TEAEs in 64.9%; most common were thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%). Treatment‑related ILD adjudicated in 5.3% (one grade 5 event); treatment discontinuation due to TEAEs 7.1%. (daiichisankyo.us)
- Breast cancer phase 1/2: grade ≥3 TEAEs in 71.4%; common hematologic toxicities included decreased neutrophils and platelets; treatment‑related ILD in 6.6% (three grade 3 and one grade 5 event). (ascopubs.org)

Regulatory status (United States; as of October 7, 2025)

A BLA for accelerated approval (based on HERTHENA‑Lung01) received a Complete Response Letter in June 2024 due to third‑party manufacturing inspection findings; in May 2025 the sponsors voluntarily withdrew the BLA after phase 3 OS did not reach statistical significance. (daiichisankyo.us)

Active trials using Patritumab deruxtecan

Found 3 active trials using this drug:

KEYMAKER-U01 Substudy 01F: A Phase 1b/2 Umbrella Study With Rolling Arms of Investigational Agents for Previously Treated Participants With Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With KRAS G12C Mutations

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 1/2 Start date: Dec. 16, 2025

TrialFetch AI summary: Enrolling adults with advanced/metastatic nonsquamous NSCLC harboring KRAS G12C who have progressed after 1–2 prior lines including both PD-1/PD-L1 therapy and platinum chemotherapy, with no prior KRAS-targeted therapy and without active CNS disease or significant ILD/pneumonitis history. Patients are randomized to the investigational selective KRAS G12C-GDP covalent inhibitor MK-1084 combined with either patritumab deruxtecan (HER3-targeted topoisomerase I ADC), sacituzumab tirumotecan (TROP2-targeted topoisomerase I ADC), or cetuximab (EGFR monoclonal antibody).

ClinicalTrials.gov ID: NCT07286149

An Open-label, Randomized, Phase 3 Study to Evaluate Patritumab Deruxtecan Monotherapy Versus Treatment of Physician's Choice in Hormone Receptor-positive, HER2-negative Unresectable Locally Advanced or Metastatic Breast Cancer (HERTHENA-Breast04)

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 3 Start date: July 21, 2025

TrialFetch AI summary: Adults with HR+/HER2- unresectable locally advanced or metastatic breast cancer with measurable disease and progression after prior CDK4/6 inhibitor plus endocrine therapy are randomized to patritumab deruxtecan (HER3-targeted topoisomerase I antibody-drug conjugate) versus physician’s choice chemotherapy (paclitaxel, nab-paclitaxel, capecitabine, liposomal doxorubicin) or trastuzumab deruxtecan. Key exclusions include candidates for further endocrine therapy or PARP inhibitor (gBRCA+), visceral crisis, prior chemo for advanced disease, prior anti-HER3 or topo I ADCs, and active ILD/pneumonitis.

ClinicalTrials.gov ID: NCT07060807

HERTHENA-Breast-01: A Phase 1b/2, Multicenter, Open-label, Dose-Finding Study to Evaluate the Safety and Antitumor Activity of Patritumab Deruxtecan in Participants With HER2 Positive Unresectable Locally Advanced Breast Cancer or Metastatic Breast Cancer

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 1/2 Start date: Feb. 26, 2025

TrialFetch AI summary: This study enrolls adults with HER2-positive unresectable locally advanced or metastatic breast cancer who have received at least two prior lines of anti-HER2 therapy, and evaluates patritumab deruxtecan (a HER3-directed antibody-drug conjugate) in combination with standard anti-HER2 therapies (trastuzumab with or without pertuzumab or tucatinib). Eligibility excludes those with active CNS metastases and certain comorbidities.

ClinicalTrials.gov ID: NCT06686394