Datopotamab Deruxtecan (Dato-DXd) for Non-Small Cell Lung Cancer (NSCLC) Patients With Active Brain Metastases

NCT06676917 | Withdrawn Phase 2

• 2 other identifiers: MEDOPP7502024-512369-14-00
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This trial will study a type of advanced lung cancer that is defined as non-squamous non-small cell lung cancer (NSCLC) with active brain metastases (BMs). This type of cancer originates in peripheral lung tissue, which is composed of cancer cells that look different from normal lung cells when viewed under a microscope and is characterized by the presence of BMs, which indicates the spreading of such cancer cells into the brain. NSCLC tumors often have specific genetic alterations or mutations that drive their growth and are known as actionable genomic alterations (AGA). This trial will include patients with NSCLC tumors characterized by the presence or absence of such AGA. Patients will be treated with datopotamab deruxtecan (Dato-DXd), a Tumor-associated calcium signal transducer 2 (TROP2)-directed antibody drug conjugate (ADC) that works by targeting TROP2 protein that is differentially expressed in cancer cells. The main purpose of the study is to analyze the efficacy (to find out how effective a treatment is) of Dato-DXd in patients who have NSCLC with active BMs. Dato-DXd efficacy will be determined by assessing the proportion of patients who experience a significant reduction in tumor size or whose cancer disappears completely, as determined at any timepoint during the study period by the investigators conducting the trial.

Conditions

Non-small Cell Lung Cancer

Keywords

Brain; Metastases; NSCLC; Datopotamab; Deruxtecan; Dato-DXd; DS-1062a

Outcome Measures

Primary Outcomes (1)

• Intracranial Objective Response Rate (ORR-IC)

  To assess the efficacy in terms of ORR-IC, defined as the rate of patients with complete response (CR) or partial response (PR) for intracranial (IC) lesions, determined locally by investigator, according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.

  From date of inclusion until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed through study completion, an average of 8 months.

Secondary Outcomes (12)

• Extracranial Objective Response Rate (ORR-EC) and overall lesions (bicompartmental ORR)

  From date of inclusion until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed through study completion, an average of 8 months.

• Progression-Free survival (PFS) for IC lesions

  From date of inclusion until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed through study completion, an average of 8 months.

• Clinical Benefit Rate (CBR) for IC lesions

  From date of inclusion until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed through study completion, an average of 8 months.

• Disease Control Rate (DCR) for IC lesions

  From date of inclusion until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed through study completion, an average of 8 months.

• Time To Response (TTR) for IC lesions

  From date of inclusion until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed through study completion, an average of 8 months.

Study Arms (1)

Datopotamab deruxtecan (Dato-DXd)

EXPERIMENTAL

Dato-DXd, administered as 6 mg/kg intravenous (IV) infusion on day 1 (D1) of each 21-day cycle until unacceptable toxicity, disease progression, patient's consensus withdrawal, death, or discontinuation from the study treatment for any other reason, whichever occurs first. Concomitant prophylactic dexamethasone mouthwash will be recommended to prevent stomatitis, anti-emetic agents will be highly recommended for preventing nausea/vomiting, antihistamines and antipyretics will be required for preventing infusion-related reactions (IRR) and the use of artificial tears will be advised for the prevention of ocular surface events.

Drug: Datopotamab deruxtecan

Interventions

Datopotamab deruxtecan DRUG

Trophoblast cell surface antigen 2 (TROP2)-directed antibody drug conjugate (ADC) consisting of a humanized anti-TROP2 monoclonal antibody (MAAP-9001a), a GGFG tetra-peptide linker, and a Topo I inhibitor (MAAA-1181a, derived from exatecan). Upon binding to TROP2 on the cell surface, Dato-DXd internalizes into the cells and releases MAAA-1181a in the cytoplasm which inhibits cell replication and promotes cell apoptosis.

Also known as: Dato-DXd, DS-1062a

Datopotamab deruxtecan (Dato-DXd)

Eligibility Criteria

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

You may qualify if:

• To be eligible to participate in this trial, an individual must meet ALL the following criteria:
• Participant must be capable to understand the purpose of the study and have signed a written informed consent form (ICF) prior to beginning specific protocol procedures.
• Female or male adults ≥ 18 years old at the time of signing ICF.
• Histologically documented non-squamous NSCLC.
• Patients may have symptoms attributed to BM.
• No indication for immediate local therapy (neurosurgery, brain radiotherapy) for BM as per local investigator.
• Note: in the case immediate local therapy is needed, the study's medical monitor should be consulted.
• Type II leptomeningeal disease (LMD) per ESMO-EANO guidelines are allowed (Le Rhun et al., 2023).
• Patients must have known AGA status determined on the most recent analyzed biopsy prior to study entry, and meets following criteria for NSCLC:
• a. Participants without AGA:
• i. Must have documented negative test results for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK).
• ii. Must have no known genomic alterations in ROS proto-oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF) V600, human epidermal growth factor receptor 2 (HER2), mesenchymal-epithelial transition (MET) exon 14 skipping or rearranged during transfection (RET).
• b. Participants with AGA must have one or more documented actionable genomic alteration(s): EGFR, ALK, ROS1, NTRK, BRAF V600, HER2, MET exon 14 skipping, or RET.
• Measurable disease according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, with at least one measurable brain lesion of ≥ 10 mm on T1-weighted, gadolinium-enhanced MRI.
• Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2.

You may not qualify if:

• An individual who meets ANY of the following criteria will be excluded from participation in this trial:
• Current participation in another therapeutic clinical trial, except other translational studies.
• Treatment with approved or investigational cancer therapy within 14 days prior to initiation of study drug.
• Mixed small-cell lung cancer (SCLC) and NSCLC histology.
• Histologically documented squamous-cell carcinoma (SCC).
• Had prior therapy with:
• Tumor-associated calcium signal transducer 2 (TROP2)-targeted therapy.
• Any agent including an antibody drug conjugate (ADC) containing a chemotherapeutic agent targeting topoisomerase I.
• Type I LMD per ESMO-EANO guidelines (Le Rhun et al., 2023).
• Patients with symptomatic brain metastasis requiring increasing dose of steroids.
• Known history of invasive malignancy within 5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor's Medical Monitor is required.
• Has a history of severe hypersensitivity reactions to either the drug or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or its analogs.
• Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
• Patients who received prior radiotherapy to the brain within 4 weeks of start of study intervention or received radiotherapy to the chest within 4 weeks of start of study intervention or have ongoing radiation-related toxicities requiring corticosteroids.
• Note: Target lesions will be selected according to RANO-BM criteria. Lesions with prior local treatment (i.e. stereotactic radiosurgery or surgical resection) can be considered measurable if progression has occurred since the time of local treatment. However, careful consideration should be given to lesions previously treated with stereotactic radiosurgery, in view of the possibility of treatment effect.

Sponsors & Collaborators

• MedSIR: lead
• Daiichi Sankyo: collaborator

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Matthias Preusser, MD

  Medical University of Vienna, Vienna General Hospital (Austria)

  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: A multicenter, open-label, non-comparative, single-arm, phase II trial

Study Record Dates

• First Submitted: November 5, 2024
• First Posted: November 6, 2024
• Study Start: June 1, 2025
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: August 8, 2025

Record last verified: 2025-08