HER3-DXd in Breast Cancer and NSCLC Brain Metastases and Solid Tumor Leptomeningeal Disease

NCT05865990 | Completed Phase 2 DMC

• 2 other identifiers: MEDOPP5752023-503251-10-00
• Study Type: interventional
• Target: 63
• Locations: 2 countries
• Sites: 8

Brief Summary

The goal of this phase II clinical trial\] is to analyze the efficacy of patritumab deruxtecan (HER3-DXd) in patients with metastatic breast cancer (MBC) or advanced non-small cell lung cancer (aNSCLC) with active brain metastases (BM) who have received at least one line of systemic therapy in the advanced setting, or patients with active leptomeningeal carcinomatosis/disease (LMD) after radiotherapy from an advanced solid tumor who do not need immediate local treatment, and have not received prior treatment with an anti-HER3 targeted drug\]. The main questions it aims to answer are:

• The intracranial objective response rate (ORR-IC) per local investigator as judged by best central nervous system (CNS) response according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria of HER3-DXd in patients with active BM from MBC (Cohort 1) and aNSCLC (Cohort 2).
• The overall survival (OS) rate at 3 months of HER3-DXd in patients with advanced solid tumors with untreated LMD (Cohort 3). Participants will receive HER3-DXd on day (D1) of each 21-day cycle until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. Researchers will compare historical groups to see if HER3-DXd positively impacts patient outcomes.

Conditions

Metastatic Breast Cancer; Advanced Non-Small Cell Squamous Lung Cancer; Solid Tumor, Adult

Keywords

Brain Metastasis; Leptomeningeal Disease

Outcome Measures

Primary Outcomes (2)

• Efficacy: Local determination of intracranial objective response rate (ORR-IC) in cohort 1 and cohort 2.

  Rate of patients with complete response (CR) or partial response (PR) determined locally by investigator, using Response Assessment in Neuro-Oncology Brain Metastases (RANO)-BM criteria in cohort 1 and cohort 2.

  From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months

• Efficacy: Overall survival (OS) rate at 3 months in cohort 3.

  3-month OS, defined as the rate of patients alive at 3 months after treatment initiation in cohort 3.

  From baseline up to 3 months

Secondary Outcomes (13)

• Efficacy: Central determination of ORR in cohort 1, cohort 2, and cohort 3.

  From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months

• Efficacy: progression-free survival (PFS) in cohort 1, cohort 2, and cohort 3.

  From baseline up to 12 months

• Efficacy: bicompartmental clinical benefit rate (CBR) in cohort 1, cohort 2, and cohort 3.

  From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months

• Efficacy: disease control rate (DCR) in cohort 1, cohort 2, and cohort 3.

  From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months

• Efficacy: time to response (TTR) in cohort 1, cohort 2, and cohort 3.

  From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months

Other Outcomes (8)

• Efficacy endpoints according to HER3 expression level and tumor type in cohort 1, cohort 2, and cohort 3.

  From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months

• Efficacy endpoints according to the prior administration of treatment with or without an antibody drug conjugate (ADC)-based therapy in cohort 1, cohort 2, and cohort 3.

  From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months

• Predictive or prognostic biomarkers in MRI and/or CT scan images according to disease activity status or response to treatment in cohort 1, cohort 2, and cohort 3.

  From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months

Study Arms (1)

Patritumab deruxtecan (HER3-DXd)

EXPERIMENTAL

HER3-DXd will be dosed at 5.6 mg/kg body weight as an intravenous (IV) infusion administered on day 1 (D1) of each 21-day cycle for patients from all cohorts until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. * Cohort 1: MBC with untreated or progressing BM after local treatment. * Cohort 2: aNSCLC with untreated or progressing BM after local treatment. * Cohort 3: advanced solid tumor with treatment-naive LMD or LMD progressing after radiotherapy.

Drug: Patritumab deruxtecan

Interventions

Patritumab deruxtecan DRUG

HER3 directed antibody drug conjugate (ADC) that is comprised of a fully human anti-HER3 immunoglobulin gamma-1 (IgG1) monoclonal antibody attached to a topoisomerase I inhibitor payload (an exatecan derivative, DXd) via a stable tetrapeptide-based cleavable linker.

Also known as: HER3-DXd

Patritumab deruxtecan (HER3-DXd)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.
• Age ≥ 18 years at the time of signing ICF.
• Life expectancy ≥ 6 weeks.
• Karnofsky Performance Status (KPS) ≥70%, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
• Patient must be able to tolerate therapy.
• No indication for immediate local therapy (neurosurgery, brain radiotherapy).
• Patient has adequate bone marrow, liver, and renal function:
• Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 14 days prior to hematological assessments during the screening period): White blood cell (WBC) count \> 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
• Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or known history of Gilbert's disease); both alkaline phosphatase (ALP) and Gamma Glutamyl Transferase (GGT) ≤ 2.5 times ULN (ALP ≤ 5 times ULN in patients with liver and/or bone metastases, and GGT increased in patients with liver metastases); aspartate transaminase (AST); alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 times ULN in patients with liver metastases); international normalized ratio (INR) \< 1.5. Prothrombin time (PT) or Prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) ≤ 1.5 × ULN, except for subjects receiving coumarin-derivative anticoagulants, factor Xa inhibitors, or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator from product safety requirements (PSR).
• Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 based on Cockcroft-Gault glomerular filtration rate estimation for patients with creatinine levels above institutional normal.
• Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0).
• Note: Except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion.
• For women of childbearing potential: agreement to remain abstinent (must refrain from heterosexual intercourse) or use highly effective contraceptive methods, or two effective contraceptive methods, as defined in the CSP, during the treatment period and for at least 7 months after the last dose of study treatment, whichever is longer. Women of childbearing potential must have a negative serum pregnancy test within 14 days before study treatment initiation (with result available prior to dosing) and must agree to refrain from donating eggs during the entire study treatment period and for 7 months after the last administration of the study drug.
• For male subjects: being surgically sterile or having agreed to true abstinence (must refrain from heterosexual intercourse) or having female partners willing to agree with true abstinence or use barrier contraceptive measures mentioned above during the entire study treatment period and for 4 months after the last administration of the study drug. Male patients must agree to refrain from donating sperm during the entire study treatment period and for 4 months after the last administration of the study drug.
• Patient must be accessible for treatment and follow-up.

You may not qualify if:

• Patients will be excluded from the study if they meet any of the following criteria:
• Current participation in another therapeutic clinical trial.
• Treatment with approved or investigational cancer therapy within 14 days prior to initiation of study drug.
• Patients have a concurrent malignancy or malignancy within five years of study enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required.
• Previous systemic therapy with any anti-HER3 directed drug.
• Known allergy or hypersensitivity to HER3-DXd or any of the drug components.
• Radiotherapy or limited-field palliative radiotherapy within seven days prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously irradiated.
• Patients with an active cardiac disease or a history of cardiac dysfunction or conduction abnormalities including any of the following:
• Unstable angina pectoris or documented myocardial infarction within 6 months prior to study entry.
• Symptomatic pericarditis.
• Documented congestive heart failure (CHF) (New York Heart Association \[NYHA\] Class III-IV).
• Left ventricular ejection fraction (LVEF) \< 50% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO).
• Ventricular arrhythmias except for benign premature ventricular contractions.
• Other cardiac arrhythmias requiring a pacemaker or not controlled with medication.
• Long QT syndrome (corrected QT interval by Fredericia \[QTcF\] \> 450 ms, average of triplicate determinations at screening), or diagnosed or suspected long QT syndrome or known family history of long QT syndrome.

Sponsors & Collaborators

• MedSIR: lead
• Daiichi Sankyo: collaborator

Study Sites (8)

Salzburg Cancer research Institute-Center for Clinical Cancer and Immunology Trials

Salzburg, Austria

Location

Medical University of Vienna

Vienna, Austria

Location

Hospital Universitari Dexeus

Barcelona, Spain

Location

Hospital Universitari Vall D'Hebron

Barcelona, Spain

Location

Hospital Beata María Ana

Madrid, Spain

Location

Hospital Quirónsalud Sagrado Corazón

Seville, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, Spain

Location

Hospital Arnau de Vilanova de Valencia

Valencia, Spain

Location

Related Publications (3)

• Bartsch R, Marhold M, Garde-Noguera J, Gion M, Ruiz-Borrego M, Greil R, Valero M, Llombart-Cussac A, Garcia-Mosquera JJ, Arumi M, Cortes J, Campolier M, Guerrero JA, Slebe F, Martinez-Garcia E, Jimenez-Cortegana C, Vaz-Batista M, Oberndorfer F, Furtner J, Fuereder T, Berghoff AS, Preusser M. Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of breast cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2025 Nov;26(11):1467-1478. doi: 10.1016/S1470-2045(25)00470-X.

  PMID: 41167215 DERIVED

• Fuereder T, Garde-Noguera J, Garcia-Mosquera JJ, Ruiz-Borrego M, Valero M, Llombart-Cussac A, Gion M, Greil R, Arumi M, Campolier M, Guerrero JA, Raimondi G, Mancino M, Jimenez-Cortegana C, Vaz-Batista M, Oberndorfer F, Marhold M, Berghoff AS, Furtner J, Bartsch R, Preusser M. Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of non-small-cell lung cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2025 Nov;26(11):1454-1466. doi: 10.1016/S1470-2045(25)00465-6.

  PMID: 41167214 DERIVED

• Preusser M, Garde-Noguera J, Garcia-Mosquera JJ, Gion M, Greil R, Arumi M, Ruiz-Borrego M, Llombart-Cussac A, Valero M, Cortes J, Campolier M, Guerrero JA, Gonzalez-Alonso P, Jimenez-Cortegana C, Rodriguez-Morato J, Vaz-Batista M, Oberndorfer F, Marhold M, Berghoff AS, Furtner J, Fuereder T, Bartsch R. Patritumab deruxtecan in leptomeningeal metastatic disease of solid tumors: the phase 2 TUXEDO-3 trial. Nat Med. 2025 Aug;31(8):2797-2805. doi: 10.1038/s41591-025-03744-1. Epub 2025 May 30.

  PMID: 40447851 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Brain Neoplasms; Meningeal Neoplasms

Interventions

patritumab deruxtecan

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Matthias Preusser, MD

  Medical Oncologist. Head of Clinical Division of Oncology, Medical University of Vienna

  PRINCIPAL INVESTIGATOR

• Rupert Bartsch, MD, PhD

  Consultant Hematology and Medical Oncology, Medical University of Vienna

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: An international, multicenter, single-arm, three-cohort, two-stage optimal Simon's design, phase II clinical trial.

Study Record Dates

• First Submitted: April 10, 2023
• First Posted: May 19, 2023
• Study Start: November 24, 2023
• Primary Completion: November 29, 2024
• Study Completion: April 3, 2026
• Last Updated: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

AU (2); ES (6)