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

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.

In this international, multicenter, open-label, single-arm, single-group, two-stage optimal Simon's design, phase II clinical trial patients will be treated 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. Male or female patients ≥ 18 years of age with non-squamous NSCLC, symptomatic or asymptomatic untreated or progressing brain metastases (BMs) after local treatment, and with or without actionable genomic alterations (AGA). Note I: Patients without AGA must meet 1 of the following prior therapy requirements for advanced or metastatic NSCLC: * Platinum-based chemotherapy in combination with α-PD-1/α-PD-L1 antibody as the only prior line of therapy. * Platinum-based chemotherapy and α-PD-1/α-PD-L1 antibody (in either order) sequentially as the only 2 prior lines of therapy. Note II: Patients with AGA must meet the following for advanced or metastatic NSCLC: * Treatment with 1 or 2 prior lines of targeted therapy that is locally approved for the participant's genomic alteration. * Platinum-based chemotherapy as the only prior line of cytotoxic therapy. * May have received up to one α-PD-1/α-PD-L1 antibody alone or in combination with a cytotoxic agent. Evidence of at least one measurable brain lesion of ≥10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging (MRI). Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, life expectancy ≥ 6 weeks, and adequate bone marrow and organ function are mandatory. A total of 20 patients will be enrolled as follows: I. 10 patients in the stage I of the study. II. 10 patients in the stage II of the study. After signing the ICF and confirmed eligibility, patients will receive 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. Patients discontinuing the study treatment period prematurely, will enter a post-treatment follow-up period during which survival and new anti-cancer therapy information will be collected every 3 months (± 7 days), until death, lost to follow-up, elective withdrawal from the study, or the end of study (EoS), whichever occurs first. This information may be collected by telephone call.