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

Inclusion Criteria

• •To be eligible to participate in this trial, an individual must meet ALL the following criteria:
• •1. 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.
• •2. Female or male adults ≥ 18 years old at the time of signing ICF.
• •3. Histologically documented non-squamous NSCLC.
• •4. Patients may have symptoms attributed to BM.
• •5. 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.
• •6. Type II leptomeningeal disease (LMD) per ESMO-EANO guidelines are allowed (Le Rhun et al., 2023).
• •7. 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.
• •8. 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.
• •9. Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2.
• •10. Minimum life expectancy of ≥ 6 weeks at screening.
• •11. Patients without AGA must meet 1 of the following prior therapy requirements for advanced or metastatic NSCLC:
• •a. Received platinum-based chemotherapy in combination with α-PD-1/α-PD-L1 monoclonal antibody (mAb) as the only prior line of therapy.
• •i. Includes participants who received prior platinum-based/chemotherapy with or without radiotherapy with maintenance α-PD-1/α-PD-L1 mAb for stage III disease and relapsed/progressed within 6 months from the last dose of platinum-based chemotherapy.
• •ii. Includes participants who received prior platinum-based/chemotherapy with or without radiotherapy (with or without maintenance α-PD-1/α-PD-L1 mAb) for stage III disease and subsequently received α-PD-1/α-PD-L1 mAb therapy (with or without platinum-based chemotherapy) for recurrent disease.
• •iii. Includes patients with stage II/III diseases who received prior platinum-based/chemotherapy with or without α-PD-1/α-PD-L1 mAb administered in the neoadjuvant/perioperative or adjuvant setting and relapsed/progressed within 6 months from the last dose of platinum-based chemotherapy.
• •iv. Includes patients with stage II/III diseases who received prior platinum-based/chemotherapy with or without α-PD-1/α-PD-L1 mAb administered in the neoadjuvant/perioperative or adjuvant setting and subsequently received α-PD-1/α-PD-L1 mAb therapy (with or without platinum-based chemotherapy) for recurrent disease.
• •b. Received platinum-based chemotherapy and α-PD-1/α-PD-L1 mAb (in either order) sequentially as the only 2 prior lines of therapy.
• •12. Patients with AGA must meet the following for advanced or metastatic NSCLC:
• •a. Participants who have been treated with 1 or 2 prior lines of applicable targeted therapy that is locally approved for the participant's genomic alteration at the time of screening; i. Participants who received a targeted agent as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of targeted therapy for the same genomic alteration (which may or may not be same agent used in the adjuvant setting) for relapsed/progressive disease.
• •ii. Participants who have been treated with a prior TKI must receive additional approved targeted therapy, if locally available and clinically appropriate, for the applicable genomic alteration, or the participant will not be allowed in the study.
• •b. Participants who have received platinum-based chemotherapy as the only prior line of cytotoxic therapy: i. One platinum-containing regimen for advanced disease ii. Those who received a platinum-containing regimen as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of platinum-containing therapy (which may or may not be same as in the adjuvant setting) for relapsed/progressive disease.
• •c. May have received up to one α-PD-1/α-PD-L1 mAb alone or in combination with a cytotoxic agent.
• •13. Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks of primary tissue and/or any metastatic site at the time of inclusion. If archival tissue is not available, a newly obtained baseline biopsy of an accessible tumor lesion is required prior to start of study treatment.
• •14. Left ventricular ejection fraction (LVEF) of ≥ 50% or ≥ institution lower limit of normal (LLN) as assessed by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
• •15. Patient has adequate bone marrow, liver, and renal function within 7 days before first study treatment dose:
• •16. Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support): 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 ≥ 9.0 g/dL (≥ 5.6 mmol/L).
• •17. Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or know history of Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) \< 1.5.
• •18. Adequate treatment washout period before randomization.
• •19. Resolution of all acute toxic effects of prior anticancer 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.
• •20. Females of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 7 months after the last dose of study treatments. Female patients must refrain from egg cell donation and breastfeeding during this same period of time.
• •21. Male participants who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening until 4 months after the last administration of the study drug. Male participants must not donate or bank sperm during this same period of time.
• •22. Patient must be accessible for treatment and follow-up.