DATOPOTAMAB DERUXTECAN for Non-small cell lung cancer | Non-squamous non-small cell lung cancer | Brain metastases

Inclusion criteria

• {"criterion_text":"- 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.\n- Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2.\n- Minimum life expectancy of ≥ 6 weeks at screening.\n- Patients without AGA must meet 1 of the following prior therapy requirements for advanced or metastatic NSCLC: a.\tReceived 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.\tIncludes 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.\tReceived platinum-based chemotherapy and α-PD-1/α-PD-L1 mAb (in either order) sequentially as the only 2 prior lines of therapy.\n- 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.\tParticipants 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 (which may or may not be same agent used in the adjuvant setting) for relapsed/progressive disease. b.\tParticipants who have been treated with 1 prior line of platinum-based chemotherapy alone or in combination with one α-PD-1/α-PD-L1 antibody: i.\tOne platinum-containing regimen alone or in combination with one α-PD-1/α-PD-L1 antibody for advanced disease. ii.\tThose 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.\tMay have received up to one α-PD-1/α-PD-L1 mAb alone or in combination with a cytotoxic agent.\n- 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.\n- 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.\n- Patient has adequate bone marrow and liver function within 7 days before first study treatment dose:\n- Hematological (without platelet, red blood cell transfusion/plasma transfusion within 1 week prior to screening assessment, 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).\n- 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 (≤ 5 in patients with liver metastases); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) < 1.5.\n- Adequate treatment washout period before randomization.\n- Female or male adults ≥ 18 years old at the time of signing ICF.\n- 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.\n- 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 treatment. Female patients must refrain from egg cell donation and breastfeeding during this same period of time.\n- 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.\n- Patient must be accessible for treatment and follow-up.\n- Histologically documented non-squamous NSCLC.\n- Patients may have symptoms attributed to BM.\n- 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.\n- Type II leptomeningeal disease (LMD) per ESMO-EANO guidelines are allowed.\n- Patients must have known AGA status prior to study entry as per local investigator practice, 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.\tMust 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.\n- 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.\n- Patients with no, stable or decreasing dose of corticosteroids for 7 days."}

Exclusion criteria

• {"criterion_text":"- Current participation in another therapeutic clinical trial, except other translational studies.\n- Has a history of severe hypersensitivity reactions to other monoclonal antibodies.\n- 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.\n- Major surgical procedure or significant traumatic injury within 14 days before the first dose of study treatment or anticipation of need for major surgery within the course of the study treatment.\n- Has an active cardiac disease or a history of cardiac dysfunction or conduction abnormalities including, but not confined, to any of the following: a.\tUnstable angina pectoris, documented myocardial infarction, or symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) within 6 months prior to study entry. b.\tSymptomatic pericarditis. c.\tHistory of CHF NYHA Class III or IV. d.\tHistory of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia), which is symptomatic or requires treatment (NCI-CTCAE grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers will be permitted to enroll. e.\tQT Interval Corrected by Fridericia’s formula (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG). f.\tHistory of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes. g.\tCongenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.\n- Has clinically significant corneal disease.\n- Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.\n- Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of the study enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.\n- Significant third-space fluid retention (for example ascites or pleural effusion) and is not amenable for required repeated drainage.\n- Pregnant or lactating females or patients not willing to apply highly effective contraception as defined in the protocol.\n- Receipt of live or attenuated vaccine within 30 days prior to the first dose of study treatment.\n- Treatment with approved or investigational cancer therapy within 14 days prior to initiation of study drug.\n- Has active or uncontrolled infection with hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.\n- Has known human immunodeficiency virus (HIV) infection that is not well controlled.\n- Other active uncontrolled infection at the time of enrollment.\n- Is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.\n- A history of uncontrolled seizures, central nervous system (CNS) disorders, or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs or interfering with subject safety.\n- Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate patient participation.\n- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study.\n- Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator.\n- Mixed small-cell lung cancer (SCLC) and NSCLC histology, or large cell neuroendocrine carcinoma (LCNEC) histology.\n- Histologically documented squamous-cell carcinoma (SCC).\n- Had prior therapy with: a.\tTumor-associated calcium signal transducer 2 (TROP2)-targeted therapy. b.\tAny agent including an antibody drug conjugate (ADC) containing a chemotherapeutic agent targeting topoisomerase I.\n- Type I LMD per ESMO-EANO guidelines.\n- Patients with symptomatic brain metastasis requiring increasing dose of steroids.\n- 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.\n- Has a history of severe hypersensitivity reactions to either the drug or inactive ingredients (included but not limited to polysorbate 80) of Dato-DXd or its analogs."}

Primary endpoints

• {"endpoint_text":"- ORR-IC, defined as the rate of patients with complete response (CR) or partial response (PR) for IC lesions determined locally by investigator, using RANO-BM criteria.","definition_or_measurement_approach":"Rate of patients with complete response (CR) or partial response (PR) for intracranial (IC) lesions determined locally by investigator using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria."}

Secondary endpoints

• {"endpoint_text":"- ORR, defined as the rate of patients with CR or PR determined locally by investigator as per RECIST v.1.1 for EC lesions (ORR-EC) and overall lesions.\n- PFS, defined as the period from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. It will be determined locally by investigator as per RANO-BM for IC lesions and RECIST v.1.1 for EC and overall lesions.\n- CBR, defined as the rate of patients with objective response (CR or PR), or stable disease for at least 24 weeks, as per RANO-BM for IC lesions and RECIST v.1.1 for EC and overall lesions.\n- DCR, defined as the rate of patients with objective response (CR or PR), or stable disease (SD), as per RANO-BM for IC and RECIST v.1.1 for EC and overall lesions.\n- TTR, defined as the period from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, as per RANO-BM for IC lesions and RECIST v.1.1 for EC and overall lesions.\n- DoR, defined as the period from the first occurrence of a documented objective response to disease progression or death from any cause, observed for patients who achieved a CR or PR, as per RANO-BM for IC and RECIST v.1.1 for EC and overall lesions.\n- OS, defined as the period from treatment initiation to death from any cause or last available follow-up.\n- Best percentage of change in tumor burden as per RANO-BM for IC lesions and RECIST v.1.1 for EC and overall measurable lesions.\n- Neurologic function as per NANO scale.\n- Safety endpoints: Safety and tolerability as per NCI-CTCAE v.5.0 and Corneal Toxicity Severity Grading Scale.\n- Safety endpoints: Assessment of QoL and neurocognitive function with EORTC QLQ-C30 and the brain specific tool (EORTC QLQ-BN20).","definition_or_measurement_approach":"ORR-EC/overall: Rate of patients with CR or PR by investigator per RECIST v1.1. PFS: time from treatment start to progression or death per RANO-BM for IC and RECIST v1.1 for EC/overall. CBR: CR/PR or stable disease ≥24 weeks per RANO-BM for IC and RECIST v1.1 for EC/overall. DCR: CR/PR or SD per RANO-BM and RECIST v1.1. TTR: time from treatment start to first objective response (≥30% tumor shrinkage) per RANO-BM/RECIST v1.1. DoR: time from first documented response to progression or death per RANO-BM/RECIST v1.1. OS: time from treatment start to death or last follow-up. Best percentage change in tumor burden: per RANO-BM (IC) and RECIST v1.1 (EC/overall). Neurologic function: assessed by NANO scale. Safety: assessed by NCI-CTCAE v5.0 and Corneal Toxicity Severity Grading Scale. QoL/neurocognitive: EORTC QLQ-C30 and QLQ-BN20."}

Other endpoints

• {"endpoint_text":"- Exploratory endpoints: Exploratory endpoints are still to be defined but can include (but are not limited to): Association of clinical outcomes, safety and/or tolerability profile with mutation profiling, copy number variability, gene expression, multiplex assays, proteomic analyses, digital pathology, immunohistochemistry, taxonomic or functional analyses performed on tissue and/or liquid biopsy samples.\n- Exploratory endpoints: Exploratory endpoints are still to be defined but can include (but are not limited to): Association of treatment efficacy and/or safety outcomes with radiological imaging biomarkers in all patients.","definition_or_measurement_approach":"Exploratory endpoints: analyses of biomarkers (mutation profiling, copy number, gene expression, multiplex assays, proteomics, digital pathology, IHC, taxonomic/functional analyses) on tissue and/or liquid biopsy samples; and association of treatment efficacy/safety with radiological imaging biomarkers. Specific analyses and methods to be defined in protocol."}

Austria

Earliest CTIS Part Ii Submission Date

24-06-2025

Latest Decision Or Authorization Date

14-07-2025

Processing Time Days

20

Number Of Sites

2

Number Of Participants

4

Spain

Earliest CTIS Part Ii Submission Date

27-06-2025

Latest Decision Or Authorization Date

14-07-2025

Processing Time Days

17

Number Of Sites

8

Number Of Participants

16

Primary sponsor

Full Name

Medica Scientia Innovation Research S.L.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Spain

Third parties

• {"country":"","full_name":"Daiichi Sankyo","duties_or_roles":"Source of monetary support","organisation_type":""}