Inclusion Criteria:
1. Signed Written Informed Consent:
- Subjects must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be
obtained before the performance of any protocol related procedures that are not
part of normal subject care.
- Subjects must be willing and able to comply with scheduled visits, treatment
schedule, and laboratory testing
2. Patients with histologically or cytologically confirmed locally advanced not eligible
to a local treatment or metastatic NSCLC (Stage IIIB or IV accordingly to 8th
classification TNM, UICC 2015) that carries an ALK rearrangement, as determined by the
molecular biology platform of the investigator by FISH assay or by
Immunohistochemistry (IHC), or Next Generation Sequencing (NGS) or RNA sequencing
approach .
3. Disease Status Requirements: Disease progression meeting RECISTv1.1 after first-line
alectinib or brigatinib only. No prior chemotherapy is allowed in the metastatic
disease setting.
4. Tumor Requirements: All Patients must have at least one measurable target lesion
according to RECIST v1.1. In addition, patients with asymptomatic and neurologically
stable CNS metastases (including patients controlled with stable or decreasing steroid
use within the last week prior to study entry) will be eligible. The brain metastases
may be newly diagnosed after disease progression with alectinib or brigatinib or be
present as progressive disease after surgery, whole brain radiotherapy or stereotactic
radiosurgery (see Exclusion Criterion for the lapsed time period required between the
end of radiotherapy and study entry). Patients who have leptomeningeal disease (LM) or
carcinomatous meningitis (CM) will be eligible if 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 last week prior to study entry).
5. Tumor Sample Requirement: Tumour biopsy sampling on fresh tissue (FFPE blocks
required) at time of progression on first-line TKI is mandatory. Tumour biopsy should
be exploitable for molecular analysis. If the tumour biopsy is not exploitable, the
inclusion will be allowed if two blood samples are provided for tumoral cfDNA
analysis. The Sponsor will monitor a posteriori the exploitability of provided tumour
biopsies and will investigate the impossibility to perform or repeat tissue tumor
sampling.
6. Age ≥18 years.
7. Life expectancy of at least 12 weeks, in the opinion of the Investigator.
8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2
9. Adequate Bone Marrow Function, including:
- Absolute Neutrophil Count (ANC) ≥1.5 x 109/L;
- Platelets ≥100 x 109/L;
- Hemoglobin ≥9 g/dL.
10. Adequate Pancreatic Function, including:
- Serum lipase ≤1.5 x ULN.
11. Adequate Renal Function, including:
- Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as
calculated using the method standard for the institution.
12. Adequate Liver Function, including:
- Total serum bilirubin ≤1.5 x ULN;
- Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN;
≤5.0 x ULN if there is liver metastases involvement.
13. Participants must have recovered from treatment toxicities to CTCAE Grade ≤ 1 (for
participants who have developed interstitial lung disease [ILD], they must have fully
recovered) except for AEs that in the investigator' judgment do not constitute a
safety risk for the patient.
14. Participants must have recovered from effects of any major surgery, or significant
traumatic injury, at least 35 days before the first dose of lorlatinib
15. For all females of childbearing potential, a negative pregnancy test must be obtained
within the screening period. A patient is of childbearing potential if, in the opinion
of the investigator, she is biologically capable of having children and is sexually
active. Additionally, all females of childbearing potential must provide an 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 the treatment period and for
at least 90 days after the last dose of study drug.
16. For men: agreement to remain abstinent or use a barrier method of contraception (e.g.,
condom) during the treatment period and for at least 90 days after the last dose of
study drug and agreement to refrain from donating sperm during this same period.
17. Evidence of a personally signed and dated informed consent document indicating that
the patient has been informed of all pertinent aspects of the study.
18. Willingness and ability to comply with the study scheduled visits, treatment plans,
laboratory tests and other procedure.
19. Participant has national health insurance coverage.
20. Washout period: if previous progression on ALK-TKI: 7 days from last dose of the drug.
The washout period may be shortened to 2 days at investigator discretion.
Exclusion Criteria:
1. Patients who experienced a clinical benefit of less than 6 months with front-line
alectinib or brigatinib.
2. Participants with disease progression on front-line treatment with 2G ALK-TKI i.e.
brigatinib or alectinib limited to CNS or one non-CNS site (oligometastasis) and
eligible to a local ablative treatment (surgery or stereotaxic radiotherapy).
3. Transdifferentiation into small cell lung cancer.
4. Spinal cord compression is excluded unless the patient demonstrates good pain control
attained through therapy and there is stabilization or recovery of neurological
function for the 4 weeks prior to study entry.
5. Patients with symptomatic and neurologically instable CNS metastases or leptomeningeal
metastasis (including patients that require increasing doses of steroids within one
week prior to Day 0 of screening phase and during the screening phase to manage CNS
symptoms).
6. Major surgery within 35 days of study entry. Minor surgical procedures (eg, port
insertion, mediastinoscopy, surgical procedure for re-sampling) are not excluded, but
sufficient time at investigator discretion should have passed for wound healing.
7. Radiation therapy within 2 weeks of study entry (except palliative to relieve bone
pain). Palliative radiation (≤15 fractions) must have been completed at least 48 hours
prior to study entry. Stereotactic or small field brain irradiation must have
completed at least 2 weeks prior to study entry. Whole brain radiation must have
completed at least 4 weeks prior to study entry.
8. Prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or
immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1,
anti-PD-L2, anti-CD137, or anti-CTLA-4.
9. Active and clinically significant bacterial, fungal, or viral infection including
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or
acquired immunodeficiency syndrome (AIDS)-related illness.
10. Clinically significant cardiovascular disease (that is, active or <3 months prior to
enrollment): 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.
11. 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, athletic patients etc.), machine-read ECG with QTc >470
msec, or congenital long QT syndrome.
12. Patients with predisposing characteristics for acute pancreatitis according to
investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease,
alcoholism [more than 4 drinks on any day or 14 drinks per week where 1 drink is
defined 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.
13. History of bilateral or Grade 3 or 4 interstitial fibrosis or diffuse interstitial
lung disease. Patients with history of prior radiation pneumonitis are not excluded.
14. Other severe acute or chronic medical or psychiatric condition, including recent
(within the past year) or active suicidal ideation or behavior, 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
inappropriate for entry into this study.
15. Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer, in
situ cervical cancer, papillary thyroid cancer, DCIS of the breast or localized and
presumed cured prostate cancer) within the last 3 years.
16. Active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic
diverticular disease or previous gastric resection or lap band.
17. Current use or anticipated need for food or drugs prohibited (see chapter 8.9.2 for
details).
18. Patients presenting with abnormal Left Ventricular Ejection Fraction (LVEF) by
echocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutional lower
limits.
19. Breastfeeding female patients (including patients who intend to interrupt
breastfeeding).
