RANDOMIZED, OPEN LABEL, MULTICENTER, PHASE III STUDY OF ENTRECTINIB VERSUS CRIZOTINIB IN PATIENTS WITH LOCALLYADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER HARBORING ROS1 GENE REARRANGEMENTS WITH AND WITHOUT CENTRAL NERVOUS SYSTEM METASTASES

•Age >= 18 years
•Histologically- or cytologically-confirmed diagnosis of advanced or recurrent
(Stage IIIB/C, not amenable for radical treatment) or metastatic (Stage IV)
NSCLC that harbors a documented ROS1 gene rearrangement
•No prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or
other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for
radical treatment) or metastatic (Stage IV) NSCLC
•Prior radiotherapy is allowed if more than 14 days have elapsed between the
end of treatment and randomization. Patients who received brain irradiation
must have completed whole brain radiotherapy at least 14 days prior and/or
stereotactic radiosurgery at least 7 days prior to the start of entrectinib
treatment
•Measurable systemic disease according to RECIST v1.1
•Patients with measurable and non-measurable CNS lesions per RECIST v1.1,
including leptomeningeal carcinomatosis, are eligible, provided that the
patient is neurologically stable for at least 1 week prior to the first dose of
study treatment
•Life expectancy of at least 12 weeks
•Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
•Adequate hematologic, renal, liver function
• Recovery from effects of any major surgery or significant traumatic injury at
least 28 days before the first dose of study treatment
• Ability to comply with the study protocol, in the investigator*s judgment
• Ability to swallow entrectinib and crizotinib intact without chewing,
crushing, or opening the capsules
• For women of childbearing potential: agreement to remain abstinent (refrain
from heterosexual intercourse) or use contraception, and agreement to refrain
from donating eggs, as defined in the protocol

•For men: agreement to remain abstinent or use contraceptive measures, and
agreement to refrain from donating sperm

•Current participation in another therapeutic clinical trial
•Prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other
systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for
radical treatment) or metastatic (Stage IV) NSCLC
•NCI-CTCAE v5.0 Grade 3 or higher toxicities due to any prior therapy
(excluding alopecia, fatigue, nausea and lack of appetite), which have not
shown improvement and are strictly considered to interfere with current study
medication
•History of recent (within the past 3 months) symptomatic congestive heart
failure or ejection fraction <= 50% observed during screening for the study
•History of prolonged QTc interval
•History of additional risk factors for torsades de pointes
•Peripheral sensory neuropathy >= Grade 2
•Known interstitial lung disease, interstitial fibrosis, or history of tyrosine
kinase inhibitor-induced pneumonitis
•Previous malignancy within the past 3 years (other than curatively treated
basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by
endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that
is considered to have no impact on PFS and OS for the current NSCLC)
•Incomplete recovery from any surgery prior to the start of study treatment
that would interfere with the determination of safety or efficacy
•Active GI disease or other malabsorption syndrome that would reasonably impact
drug absorption
•History of prior therapy-induced pneumonitis
•Any condition (in the past 3 months) that would interfere with the
determination of safety or efficacy of study treatments
•Known active infections that would interfere with the assessment of safety or
efficacy of study treatments (bacterial, fungal or viral, including human
immunodeficiency virus positive)
•History of hypersensitivity to any of the additives in the entrectinib and/or
crizotinib drug formulations
• Pregnant or breastfeeding, or intending to become pregnant during the study
or within 3 months after the final dose of entrectinib or crizotinib
• HIV-positive patients may be enrolled, unless these patients meet any of the
riteria stated in the protocol

•Any clinically significant concomitant disease or condition that could
interfere with, or for which the treatment might interfere with, the conduct of
the study or the absorption of oral medications or that would, in the opinion
of the Principal Investigator, pose an unacceptable risk to the patient in this
study
•Any psychological, familial, sociological, or geographical condition
potentially hampering compliance with the study protocol requirements and/or
follow-up procedures; those conditions should be discussed with the patient
before trial entry