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.
Exclusion Criteria:
An individual who meets ANY of the following criteria will be excluded from participation
in this trial:
1. Current participation in another therapeutic clinical trial, except other
translational studies.
2. Treatment with approved or investigational cancer therapy within 14 days prior to
initiation of study drug.
3. Mixed small-cell lung cancer (SCLC) and NSCLC histology.
4. Histologically documented squamous-cell carcinoma (SCC).
5. Had prior therapy with:
1. Tumor-associated calcium signal transducer 2 (TROP2)-targeted therapy.
2. Any agent including an antibody drug conjugate (ADC) containing a
chemotherapeutic agent targeting topoisomerase
Type I LMD per ESMO-EANO guidelines (Le Rhun et al., 2023).
7. Patients with symptomatic brain metastasis requiring increasing dose of steroids.
8. 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.
9. 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.
10. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
11. 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.
12. 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.
13. Has an active cardiac disease or a history of cardiac dysfunction or conduction
abnormalities including, but not confined, to any of the following:
1. Unstable 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.
2. Symptomatic pericarditis.
3. History of CHF NYHA Class III or
History 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.
5. QT 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 ECG.
6. History 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.
7. Congenital long QT syndrome, family history of long QT syndrome, or unexplained
sudden death under 40 years of age in first-degree relatives.
14. Has clinically significant corneal disease.
15. Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis that
required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis
that cannot be ruled out by imaging at screening.
16. 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.
17. Significant third-space fluid retention (for example ascites or pleural effusion)
and is not amenable for required repeated drainage.
18. Pregnant or lactating females or patients not willing to apply highly effective
contraception as defined in the protocol.
19. Receipt of live or attenuated vaccine within 30 days prior to the first dose of
study treatment.
20. Has active or uncontrolled known 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 antibody [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.
21. Has known human immunodeficiency virus (HIV) infection that is not well controlled.
22. Other active uncontrolled infection at the time of enrollment.
23. Has an active autoimmune disease that has required systemic treatment in past 2
years, or any diagnosis of immunodeficiency, or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of study treatment.
24. 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.
25. Known substance abuse or any other concurrent severe and/or uncontrolled medical
condition that would, in the investigator's judgment, contraindicate patient
participation.
26. 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.
27. Inability or unwillingness to comply with the requirements of the protocol in the
opinion of the investigator.
