Inclusion Criteria:
- - Male/female participants who are at least 18 years of age on the day of signing
informed consent with a histologically confirmed diagnosis of NSCLC will be enrolled
in this study.
Histologically confirmed metastatic non-squamous NSCLC with PD-L1 tumor proportion score
<50% determined by local or central laboratory using antibodies 22C3'
- - Documented negative test results for EGFR and ALK actionable genomic alterations by
local test;
- No known actionable genomic alterations in ROS1, NTRK, RET, HER2, or MET.
- - No prior systemic therapy for advanced or metastatic NSCLC.
Patients who received
chemotherapy or immunotherapy for localized or locally advanced NSCLC are eligible
if progression occurred at least 6 months after the last dose of systemic treatment.
- - Participants who have AEs due to previous anticancer therapies must have recovered
to ≤Grade 1 or baseline.
Participants with endocrine-related AEs who are adequately
treated with hormone replacement or participants who have ≤Grade 2 neuropathy are
eligible.
- - The participant (or legally acceptable representative if applicable) provides
written informed consent for the trial.
- - Have measurable disease based on RECIST 1.1, including the following:
Presence of 1 or more measurable central nervous system (CNS) metastases that have not
received prior radiation therapy, or presence of 1 or more measurable central nervous
system (CNS) metastases that has received prior radiation therapy but has unequivocally
progressed within the radiation therapy field; Measurable brain metastasis is defined as
any lesion that can be accurately measured in at least one dimension as ≥ 10mm.
Patients
with brain metastases lesions ≥ 5 mm and < 10 mm are considered to have measurable
disease and are allowed to be enrolled if MRI slice thickness is 1.5 mm or less.
Presence of 1 or more measurable extracranial lesion; Lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in such
lesions.
- - No neurological symptoms that require immediate and significant intervention, in the
opinion of the treating physician.
Patients with neurologic symptoms that do not
require significant medical intervention are allowed. Patients may also be enrolled
after control of neurological symptoms that require immediate and significant
intervention.
Patients with neurologic symptoms that are controlled with anticonvulsants are allowed.
Patients with neurologic symptoms that are controlled with stable (for at least 1 week),
low dose dexamethasone (≤4 mg daily) are allowed.
- - No leptomeningeal carcinomatosis.
- - Archival tumor tissue sample or newly obtained [core, incisional or excisional]
biopsy of a tumor lesion has been provided.
Formalin-fixed, paraffin embedded (FFPE)
tissue blocks are preferred to slide (preferably a minimum of 20 slides).
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
intervention.
Life expectancy of > 12 weeks.
Has had an adequate treatment washout period before Cycle 1 Day 1, defined as:
Major surgery: ≥ 3 weeks. Chloroquine/hydroxychloroquine: > 14 days.
- - Participants who are HBsAg positive are eligible if they have received HBV
anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior
to inclusion.
Note: Participants should remain on anti-viral therapy throughout study intervention and
follow local guidelines for HBV anti-viral therapy post completion of study intervention.
- - Hepatitis B screening tests are not required unless: Known history of HBV infection.
As mandated by local health authority. Participants with a history of HCV infection
are eligible if HCV viral load is undetectable at screening.
- - Note: Participants must have completed curative anti-viral therapy at least 4 weeks
prior to inclusion.
Hepatitis C screening tests are not required unless:
Known history of HCV infection As mandated by local health authority.
- - HIV-infected participants must have well-controlled HIV on ART, defined as:
Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of
screening Participants on ART must have achieved and maintained virologic
suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit
of detection) using the locally available assay at the time of screening and for at
least 12 weeks before screening.
- - It is advised that participants must not have had any AIDS-defining opportunistic
infections within the past 12 months.
Participants on ART must have been on a stable regimen, without changes in drugs or dose
modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART
throughout the study The combination ART regimen must not contain any antiretroviral
medications that interact with CYP3A4 inhibitors/inducers/substrates
(https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interacti
ons-table-substrates-inhibitors-and-inducers)
- - Negative pregnancy test (serum) for women of childbearing potential.
- - Have adequate organ function.
Specimens must be collected within 10 days prior to
the start of study intervention.
- - Hematological: Absolute neutrophil count (ANC) ≥1500/µL; Platelets ≥100 000/µL;
Hemoglobin.
≥9.0 g/dL or ≥5.6 mmol/La;
- - Renal: Creatinine OR Measured or calculatedb creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with
creatinine levels >1.5 × institutional ULN.
- - Hepatic: Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with
total bilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for
participants with liver metastases)
- Coagulation: International normalized ratio (INR) OR prothrombin time (PT) Activated
partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving
anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended
use of anticoagulants;
- ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST
(SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);
GFR=glomerular filtration rate; ULN=upper limit of normal.
1. Criteria must be met without erythropoietin dependency and without packed red
blood cell (pRBC) transfusion within the last 2 weeks.
2. Creatinine clearance (CrCl) should be calculated per institutional standard.
Exclusion Criteria:
- - Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to inclusion.
- - Has received prior radiotherapy to the brain within 2 weeks of the start of therapy,
or received radiotherapy to the chest within 4 weeks of start of therapy, or that
have ongoing radiation-related toxicities requiring corticosteroid.
- - Has received a live vaccine or live-attenuated vaccine within 30 days before the
first dose of study intervention.
Administration of killed vaccines is allowed.
- - Has received an investigational agent or has used an investigational device within 4
weeks prior to study intervention administration.
- - Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
Use
of dexamethasone ≤ 4 mg/day (or another steroid at equivalent doses) is allowed for
treatment of neurological symptoms.
- - Has spinal cord compression.
- - Uncontrolled or significant cardiovascular disease, including: Mean QT interval
corrected for heart rate using Fridericia's formula (QTcF) interval >470 msec
regardless of sex; Myocardial infarction within 6 months prior to inclusion;
Uncontrolled angina pectoris within 6 months prior to inclusion; Known LVEF <50% by
ECHO or MUGA scan within 28 days before inclusion; New York Heart Association Class
2 to 4 congestive heart failure (CHF) at screening; Uncontrolled hypertension within
7 days before inclusion.
- - Known additional malignancy that is progressing or has required active treatment
within the past 5 years.
Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in
situ of the bladder, which have undergone potentially curative therapy are not
excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason
score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in
active surveillance with stable disease are not excluded.
- - Has severe hypersensitivity (≥Grade 3) to either pembrolizumab and/or any of its
excipients and/or Dato-DXd including its excipients (e.g. polysorbate 80).
- - Has a history of non-infectious 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.
- - Clinically severe pulmonary compromise resulting from intercurrent pulmonary
illnesses (including pulmonary embolism within 3 months of enrollment, severe
asthma, severe oxygen-dependent chronic obstructive pulmonary disease, restrictive
lung disease, pleural effusion) or autoimmune disease with lung involvement (i.e.
rheumatoid arthritis, Sjogren disease, sarcoidosis, etc) with pulmonary involvement
documented or suspected at screening.
- - Clinically significant known corneal disease.
- - Known active tuberculosis infection (clinical evaluation that may include clinical
history, physical examination and radiographic findings, or tuberculosis testing in
line with local practice).
- - Severe infection within 4 weeks prior to the first dose of study treatment (Cycle 1,
Day 1), including but not limited to hospitalization for complications of infection,
bacteraemia, or severe pneumonia.
- - Treatment with oral or IV antibiotics within 2 weeks prior to initiation of study
treatment (Cycle 1, Day 1).
- - Has not adequately recovered from major surgery or has ongoing surgical
complications.
- - Has a history or current evidence of any condition, therapy, or laboratory
abnormality or other circumstance that might confound the results of the study,
interfere with the participant's participation for the full duration of the study,
such that it is not in the best interest of the participant to participate, in the
opinion of the treating investigator.
- - Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- - Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting 3 months before Cycle 1 Day 1 and
continuing for at least 6 months for male subjects and 7 months for female subjects
after the last dose.
- - Female participants must be at least 1 year post-menopausal, surgically sterile, or
using at least 1 highly effective form of birth control (a highly effective method
of contraception is defined as one that can achieve a failure rate of less than 1%
per year when used consistently and correctly.
) Women of childbearing potential who
are sexually active with a non-sterilized male partner must agree to use at least 1
highly effective method of birth control. They should have been stable on their
chosen method of birth control for a minimum of 3 months before Cycle 1 Day 1 and
continue for at least 7 months after the last dose. Female participants must refrain
from egg cell donation or retrieval for their own use, and breastfeeding from first
dose throughout the study and for at least 7 months after the last dose of study
drug. Any non-sterilized male partner of a woman of childbearing potential must use
a male condom plus spermicide (condom alone in countries where spermicides are not
approved) throughout this period.
- - Male participants who intend to be sexually active with a female partner of
childbearing potential must be surgically sterile or use an acceptable method of
contraception from the time of screening throughout the total duration of the study
and the drug washout period (at least 6 months after the last dose of study
intervention), in addition to the female partner using a highly effective
contraceptive method, to prevent pregnancy in a partner.
Male participants must not
donate or bank sperm during this same time period. Preservation of sperm should be
considered prior to inclusion. Not engaging in heterosexual activity (sexual
abstinence) for the duration of the study and drug washout period is an acceptable
practice, if this is the preferred usual lifestyle of the participant. Periodic or
occasional abstinence, the rhythm method, and the withdrawal method are not
acceptable methods of contraception.
- - Has had an allogenic tissue/solid organ transplant.
