Activity of Lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with 2nd generation ALK inhibitor

• Age >=18 years old
• Histologically or cytologically confirmed diagnosis of NSCLC with ALK
rearrangement, assessed by FISH assay (Abbott Molecular Inc) or by
Immunohistochemistry (IHC) (Ventana Inc) approved by FDA. Liquid biopsy is an
acceptable method for the diagnosis of ALK rearrangement in case there is no
leftover biopsy/cytological specimen.
• Stage III (not eligible for local therapy) or stage IV (according to UICC TNM
staging v8.0)
• WHO performance status (WHO PS) of 0-2
• Previous treatment with at least one 2nd-generation ALK inhibitor. The
2nd-generation ALK TKI (including but not limited ceritinib, alectinib,
brigatinib) should be the latest therapy.
• Progressive disease during treatment with 2nd-generation ALK inhibitor prior
to the administration of lorlatinib
• Measurable disease according to RECIST version 1.1 by computed tomography
(CT) or magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain MRI
performed within 28 days prior to study enrolment
• Collection of blood sample for cohort allocation.
Note: if blood sample cannot be collected (patient's refusal or any other
reason), patient will not be eligible for this study
• Treated and/or untreated brain or leptomeningeal metastases will be allowed
if asymptomatic and/or controlled (stable dose of steroids 7 days before the
beginning of lorlatinib treatment)
• Adequate bone marrow and organ function
• Women of child bearing potential (WOCBP) must have a negative serum pregnancy
test within 3 days prior to the first dose of lorlatinib
• Women of childbearing potential must use a highly effective non-hormonal
method of contraception during the study treatment period and for at least 35
days after the last dose of lorlatinib. If a hormonal method of contraception
is unavoidable, then a condom must be used in combination with the hormonal
method.
• Male patients with female partners of childbearing potential must use
effective contraception, including a condom, and male patients with pregnant
partners must use condoms, during the study treatment period and for at least
14 weeks after the last dose of lorlatinib.
• Female subjects who are breast feeding should discontinue nursing prior to
the first dose of study treatment and until 7 days after the last dose of
lorlatinib
• Patient is willing and able to comply with the protocol for the duration of
the study including undergoing treatment and scheduled visits and examinations
including follow up
• Before patient registration, written informed consent must be given according
to ICH/GCP, and national/local regulations

Enrolment in optional prospective sub-study:
• The patient has received at least 6 months of second generation ALK-TKI
therapy (if crizotinib-pretreated)
OR
• The patient has received at least 12 months of second generation ALK-TKI
therapy (if crizotinib-naïve)
• Patient is willing and able to comply with the sub-study requirements
including scheduled visits and examinations including follow up
• Before patient registration, written informed consent must be given according
to ICH/GCP, and national/local regulations

• Spinal cord compression. Patients who received adequate treatment (surgery or
radiotherapy) and has adequate control of the pain and stabilization and/or
recovery of neurological symptoms/function for the 3 weeks prior to study entry
are allowed
• Major surgery within 4 weeks prior to study enrolment. Complete wound healing
from major surgery must have occurred 3 weeks before the first dose of study
treatment.
• Minor surgical procedures (including port insertion, uncomplicated tooth
extractions) without complete wound healing at the latest 1 week before the
first dose of study treatment.
• Radiation therapy within 2 weeks of study entry
• Any systemic anti-cancer therapy or an investigational drug treatment
completed within 7 days prior to start lorlatinib (in case of clinically
meaningful risk of tumour flare according to investigator's assessment,
discussion with EORTC is required before enrolment)
• Any unresolved toxicities from prior systemic therapy
• Active infection requiring therapy
• Known active hepatitis B (HBV) or hepatitis C (HCV).
• Known human immunodeficiency virus (HIV), or acquired immunodeficiency
syndrome (AIDS)-related illness
• Any of the following cardiac criteria:
• Clinically significant cardiovascular disease (that is active or occurred <3
months prior to enrolment): cerebral vascular accident/stroke, myocardial
infarction, unstable angina, congestive heart failure (New York Heart
Association Classification Class >= II), second-degree or third-degree AV block
(unless paced) or any AV block with PR >220 msec
• Ongoing cardiac dysrhythmias of NCI CTCAE Grade >=2, uncontrolled atrial
fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is
otherwise healthy such as long-distance runners, etc.)
• Abnormal Left Ventricular Ejection Fraction (LVEF): LVEF <50% (assessed by
MUGA or ECHO)
• History of interstitial lung disease (ILD) or history of (non-infectious)
pneumonitis that required oral or IV steroids (other than COPD exacerbation) or
current pneumonitis or current evidence of interstitial lung disease. Patients
with history of prior radiation pneumonitis are not excluded
• Any serious or uncontrolled acute or chronic medical or psychiatric
condition, including recent (within the past year) or active suicidal ideation
or behaviour, chronic alcoholism, drug addiction, or laboratory abnormality
that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation
of study results and, in the judgment of the investigator, would make the
patient not eligible for this study
• Hereditary problems of galactose intolerance, total lactase deficiency, or
glucose-galactose malabsorption
• Inability to swallow and/or retain oral tablets or impaired gastrointestinal
function or disease that may significantly alter the absorption of lorlatinib
(e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome,
small bowel resection with decreased intestinal absorption)
• Evidence of active hematologic or primary solid tumour malignancy (other than
completely resected non-melanoma skin cancer, successfully treated in situ
carcinoma for example in situ cervical cancer, completely resected and
successfully treated papillary thyroid cancer, or localized and presumed cured
prostate cancer) within the last 3 years
• History of hypersensitivity to excipients of Lorlatinib
• Patients currently receiving (or unable to stop use at least 3 plasma
half-lives of the strong CYP3A4/5 inducer before lorlatinib treatment is
started) medications or herbal supplements known to be strong inducers of
cytochrome P450 (CYP) 3A4/5
• Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule; those conditions should be discussed with the patient before
registration in the trial