Lorlatinib After Failure of First-line TKI in Patients with Advanced ROS1-positive NSCLC (ALBATROS)

Inclusion Criteria:

• Signed Written Informed Consent: Subjects must have signed and dated an IRB/IECapproved written informed consent form in accordance with regulatory andinstitutional guidelines. This must be obtained before the performance of anyprotocol related procedures that are not part of normal subject care. Subjects mustbe willing and able to comply with scheduled visits, treatment schedule, andlaboratory testing

• Patients with histologically or cytologically confirmed diagnosis of locallyadvanced not eligible to a local treatment or metastatic NSCLC (Stage IIIB, IIIC orIV accordingly to 8th classification TNM, UICC 2015) that carries an ROS1rearrangement, as determined by the molecular biology platform of the investigatorby FISH assay or by Immunohistochemistry (IHC), or Next Generation Sequencing (NGS)or RNA sequencing approach.

• Disease Status Requirements: Disease progression meeting RECISTv1.1 after one priorline of treatment with crizotinib or entrectinib (+ one line of chemotherapy with orwithout immunotherapy before TKI treatment).

Note: patient with disease progression after treatment with another ROS1-TKI may still be eligible upon discussion with IFCT.

• Tumor Requirements: All Patients must have at least one measurable target lesionaccording to RECIST v1.1. The radiological assessment has to be done within thetimelines indicated. In addition, patients with asymptomatic and neurologicallystable CNS metastases (including patients controlled with stable or decreasingsteroid use within the last week prior to study entry) will be eligible. The brainmetastases may be newly diagnosed after disease progression with crizotinib orentrectinib or be present as progressive disease after surgery, whole brainradiotherapy or stereotactic radiosurgery (see Exclusion Criterion for the lapsedtime period required between the end of radiotherapy and study entry). Patients whohave leptomeningeal disease (LM) or carcinomatous meningitis (CM) will be eligibleif the LM/CM is visualized on MRI or if documented baseline cerebral spinal fluid (CSF) positive cytology is available and asymptomatic and neurologically stable (including patients controlled with stable or decreasing steroid use within the lastweek prior to study entry).

• Tumor Sample Requirement: Tumour biopsy sampling on fresh tissue (FFPE blocksrequired) obtained after progression on crizotinib or entrectinib. Tumour biopsyshould be exploitable for molecular analysis. If the tumour biopsy is notexploitable, the inclusion will be allowed if two blood samples are provided fortumoral cfDNA analysis. The Sponsor will monitor a posteriori the exploitability ofprovided tumour biopsies and will investigate the impossibility to perform or repeattissue tumor sampling.

• Age ≥18 years.

• Life expectancy of at least 12 weeks, in the opinion of the Investigator.

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2

• Adequate Bone Marrow Function, including: Absolute Neutrophil Count (ANC) ≥1.5 x 109/L; Platelets ≥100 x 109/L; Hemoglobin ≥9 g/dL.

• Adequate Pancreatic Function, including: Serum lipase ≤1.5 x ULN.

• Adequate Renal Function, including: Serum creatinine ≤1.5 x ULN or estimatedcreatinine clearance ≥45 mL/min as calculated using the method standard for theinstitution.

• Adequate Liver Function, including: Total serum bilirubin ≤1.5 x ULN; AspartateAminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN; ≤5.0 x ULN ifthere is liver metastases involvement.

• Participants must have recovered from treatment toxicities to CTCAE Grade ≤ 1 (forparticipants who have developed interstitial lung disease [ILD], they must havefully recovered) except for AEs that in the investigator' judgment do not constitutea safety risk for the patient.

• Participants must have recovered from effects of any major surgery, or significanttraumatic injury, at least 35 days before the first dose of lorlatinib

• For all females of childbearing potential, a negative pregnancy test must beobtained within the screening period. A patient is of childbearing potential if, inthe opinion of the investigator, she is biologically capable of having children andis sexually active. Additionally, all females of childbearing potential must providean agreement to remain abstinent or use two adequate methods of contraception,including at least one method with a failure rate of < 1% per year, during thetreatment period and for at least 90 days after the last dose of study drug.

• For men: agreement to remain abstinent or use an effective method of contraception (e.g., condom) during the treatment period and for at least 14 weeks after the lastdose of study drug and agreement to refrain from donating sperm during this sameperiod.

• Evidence of a personally signed and dated informed consent document indicating thatthe patient has been informed of all pertinent aspects of the study.

• Willingness and ability to comply with the study scheduled visits, treatment plans,laboratory tests and other procedure.

• Participant has national health insurance coverage.

• Washout period: if previous progression on ROS1-TKI: 7 days from last dose of thedrug. The washout period may be shortened to 2 days at investigator discretion.

Exclusion Criteria:

• Participants with disease progression on front-line treatment with TKI i.e.crizotinib or entrectinib limited to CNS or one non-CNS site (oligo-metastasis) andeligible to a local ablative treatment (surgery or stereotaxic radiotherapy).

• Histological transformation with neuro-endocrine differentiation.

• Spinal cord compression is excluded unless the patient demonstrates good paincontrol attained through therapy and there is stabilization or recovery ofneurological function for the 4 weeks prior to study entry.

• Patients with symptomatic and neurologically instable CNS metastases orleptomeningeal metastasis (including patients that require increasing doses ofsteroids within one week prior to Day 0 of screening phase and during the screeningphase to manage CNS symptoms).

• Major surgery within 35 days of study entry. Minor surgical procedures (eg, portinsertion, mediastinoscopy, surgical procedure for re-sampling) are not excluded,but sufficient time at investigator discretion should have passed for wound healing.

• Radiation therapy within 2 weeks of study entry (except palliative to relieve bonepain). Palliative radiation (≤15 fractions) must have been completed at least 48hours prior to study entry. Stereotactic or small field brain irradiation must havecompleted at least 2 weeks prior to study entry. Whole brain radiation must havecompleted at least 4 weeks prior to study entry.

• Prior therapy with an antibody or drug specifically targeting T-cell co-stimulationor immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1,anti-PD-L2, anti-CD137, or anti-CTLA-4.

• Active and clinically significant bacterial, fungal, or viral infection includinghepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), oracquired immunodeficiency syndrome (AIDS)-related illness.

• Clinically significant cardiovascular disease (that is, active or <3 months prior toenrollment): cerebral vascular accident/stroke, myocardial infarction, unstableangina, 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 fibrillationof any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthysuch as long-distance runners, athletic patients etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.

• Patients with predisposing characteristics for acute pancreatitis according toinvestigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease,alcoholism [more than 4 drinks on any day or 14 drinks per week where 1 drink isdefined as the alcoholic beverage containing approximately 14 grams of pure alcohol,eg, 12 fl oz/360 mL regular beer or 5 fl oz/150 mL of wine] in the last month.

• History of bilateral or Grade 3 or 4 interstitial fibrosis or diffuse interstitiallung disease. Patients with history of prior radiation pneumonitis are not excluded.

• Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and, in the judgment of the investigator, would make the patientinappropriate for entry into this study.

• Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer,in situ cervical cancer, papillary thyroid cancer, DCIS of the breast or localizedand presumed cured prostate cancer) within the last 3 years.

• Active inflammatory gastrointestinal disease, chronic diarrhea, symptomaticdiverticular disease or previous gastric resection or lap band.

• Current use or anticipated need for food or drugs prohibited (see chapter 7.9 fordetails).

• Patients presenting with abnormal Left Ventricular Ejection Fraction (LVEF) byechocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutionallower limits.

• Breastfeeding female patients (including patients who intend to interruptbreastfeeding).

• Liver disease characterized by: ALT or AST level > 3 the upper normal limit (UNL) (≥ 5 x UNL for patients with liver metastases) confirmed on 2 consecutive measures ORimpaired excretory function (e.g.. hyperbilirubinemia) or synthetic function orother conditions of decompensated liver disease e.g.: coagulopathy, Hepaticencephalopathy, hypoalbuminemia, ascites and bleeding from esophageal varices ORAcute viral or autoimmune or other types of hepatitis.