| Eligibility |
Inclusion Criteria:
- COHORT A Patients with histologically or cytologically confirmed stage IV NSCLC who
did not receive any prior systemic therapy for advanced disease and have synchronous
untreated brain metastases which does not cause neurologic symptoms and does not
require systemic corticosteroid treatment within 10 days before initiating study
treatment (controlled seizures with antiepileptic drugs should be allowed).
- COHORT B Patients with histologically or cytologically confirmed stage IV NSCLC who
did not receive any prior systemic therapy for advanced disease and have synchronous
brain metastasis causing neurologic signs and symptoms controlled with medium-low
doses of corticosteroids (= 25mg/d of prednisone or = 4mg/d of dexamethasone) but have
good performance status (ECOG PS0-1). At least one untreated brain lesion in patients
who already received focal radiotherapy (stereotactic focal radiotherapy) of prior
brain lesions are eligible if novel brain lesions appear which are measurable and not
suitable for focal radiotherapy.3. Patients with early or locally advanced NSCLC who
have recurred after 6 months of completing adjuvant or neoadjuvant chemotherapy and
have brain metastases are also eligible
- ECOG performance status 0-1
- Patients aged = 18 years
- Systemic measurable disease by computed tomography (CT) per response evaluation
criteria in solid tumors version (RECIST) 1.1 criteria and brain measurable disease by
magnetic resonance imaging (MRI) per RANO-BM criteria.
- Availability of a formalin-fixed paraffin-embedded block containing tumor tissue or 10
unstained slides. Archival tumor tissue can be sent if it was obtained less than 12
months ago.
- Correct hematological, hepatic and renal function. i. Neutrophils = 1500×109/L ii.
Platelets = 100 ×109/L iii. Hemoglobin = 9.0 g/dL iv. Serum creatinine = 1.5 x ULN or
creatinine clearance (CrCl) = 45 mL/min (if using the Cockcroft-Gault formula below):
a. Female CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum creatinine in
mg/dL b. Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine
in mg/dL v. AST/ALT = 3 x ULN. Patients with documented liver metastases: AST and/or
ALT = 5 × ULN vi. Total Bilirubin = 1.5 x ULN (except subjects with Gilbert Syndrome,
who can have total bilirubin < 3.0 x ULN) vii. PT/APTT = 1.5 × upper limit of normal
(ULN). This applies only to patients who are not receiving therapeutic
anticoagulation; patients receiving therapeutic anticoagulation should be on a stable
dose
- Patient consent must be obtained in the appropriate manner as established in the
applicable local and regulatory requirements
- Patients must be accessible for treatment and follow-up
- Women of childbearing potential, including women who had their last menstrual period
in the last 2 years, must have a negative serum or urine pregnancy test within 3 days
before randomization.
- All sexually active men and women of childbearing potential must use a highly
effective contraceptive method (<1% failure rate) during the study treatment and for a
period of at least 5 months for females and 7 months for males following the last
administration of trial drugs.
Exclusion Criteria:
- Patients with a history of other malignant diseases within the past 3 years, with the
exception of the following:
- properly treated non-melanotic skin cancer
- cancer in situ treated with curative intent
- nonmuscular propria invasive carcinoma of the bladder
- or other malignancies treated with curative intent and without signs of disease
for a period of > 3 years after the end of the treatment and which, in the
opinion of the physician in charge of their treatment, do not present a
substantial risk of relapse of the previous malignant disease.
- Patients harboring epidermal growth factor receptor (EGFR) mutations or anaplastic
lymphoma kinase (ALK) and ROS Proto-Oncogene 1 (ROS1) rearrangements sensitive to
available targeted inhibitor therapy
- Patients with a combination of small cell lung cancer and non-small cell lung cancer,
a carcinoid lung tumor or large cell neuroendocrine carcinoma
- Patients that received live attenuated vaccines within 30 days prior to randomization
- Leptomeningeal carcinomatosis or metastases in the brain stem, mid-brain, pons,
medulla or causing obstructive hydrocephalus
- Single exclusive brain metastasis amenable to surgical treatment or radiosurgery
- Prior surgical resection of brain or spinal lesions in the prior 28 days
- Patients who have received prior neoadjuvant, adjuvant chemotherapy, radiotherapy, or
chemo-radiotherapy with curative intent for non-metastatic disease less than 6 months
before enrollment since the last chemotherapy, radiotherapy, or chemo-radiotherapy
- History of a primary immunodeficiency, history of organ allogeneic transplantation,
use of immunosuppressive drugs within 28 days before randomization or previous history
of toxicity of severe immune mechanism (grade 3 or 4) with other immunological
treatments
- Patients with an active, known or suspected autoimmune disease. Participants with type
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to be enrolled
- Patients with active or uncontrolled infections or with serious medical conditions or
disorders that may not allow patient management as established in the protocol
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of
radiation pneumonitis put of the radiation field on screening chest CT scan. History
of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Significant comorbidities that preclude the administration of chemotherapy according
to the investigator's criteria
- Any positive test result for hepatitis B virus or hepatitis C virus indicating
presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen)
positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative)
- Previous treatment with immune checkpoint inhibitors
- Patients who have suffered untreated and / or uncontrolled cardiovascular disorders
and / or who have symptomatic cardiac dysfunction (unstable angina, congestive heart
failure, myocardial infarction in the previous year or ventricular cardiac arrhythmias
that require medication, history of atrioventricular conduction of second or third
degree)
- Pregnant or breastfeeding women
- History of allergy or hypersensitivity to any of the study drug components
- Patients with a condition other than brain metastases requiring systemic treatment
with either corticosteroids (> 10 mg daily prednisone equivalent) or other
immunosuppressive medications within 14 days of randomization. Inhaled or topical
steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent,
are permitted in the absence of active autoimmune disease.
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