A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China

A PHASE 2, MULTI-CENTER, OPEN-LABEL, DUAL-COHORT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LORLATINIB (PF-06463922) MONOTHERAPY IN ALK INHIBITOR-TREATED LOCALLY ADVANCED OR METASTATIC ALK-POSITIVE NON-SMALL CELL LUNG CANCER PATIENTS IN CHINA

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03909971

Enrollment

109

Registered

2019-04-10

Start date

2019-04-28

Completion date

2024-10-21

Last updated

2025-11-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Keywords

ALK positive, ALK inhibitor-treated, NSCLC

Brief summary

A Phase 2, multi center, open label, dual cohort study to evaluate the efficacy and safety of lorlatinib (PF 06463922) monotherapy in ALK inhibitor treated locally advanced or metastatic ALK positive non small cell lung cancer patients in China

Detailed description

This is a Phase 2, China only, multi center, open label, dual cohort study, in ALK positive locally advanced or metastatic NSCLC patients will be enrolled to receive lorlatinib monotherapy. * (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor. * (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib.

Interventions

DRUGLorlatinib

ALK inhibitor-treated ALK-positive NSCL treatment

Study design

Allocation

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK positive NSCLC where ALK status has been previously established by the Ventana ALK (D5F3) CDx Assay (Roche Diagnostics), the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular), or the EML4 ALK Fusion Gene Detection Kit (AmoyDx). 2. Subject should have: 1. (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor; 2. (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib, with or without prior crizotinib. 3. Prior treatment with an ALK inhibitor must have completed 5 half lives prior to study entry. 4. All Subjects must have at least 1 measurable extracranial target lesion according to RECIST v1.1 that has not been previously irradiated. CNS metastases are allowed if: 1. Asymptomatic: either not currently requiring corticosteroid treatment, or on a stable or decreasing dose of 10 mg QD prednisone or equivalent; or 2. Previously diagnosed and treatment has been completed with full recovery from the acute effects of radiation therapy or surgery prior to enrollment, and if corticosteroid treatment for these metastases has been withdrawn for at least 4 weeks with neurological stability. 5. Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2. 6. Age 18 years (or 20 years as required by local regulation). 7. Adequate bone marrow functions: 1. Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L; 2. Platelets 100,000/mm3 or 100 x 109/L; 3. Hemoglobin 9 g/dL. 8. Adequate pancreatic function: 1. Serum total amylase 1.5 x upper limit of normal (ULN);\* 2. Serum lipase 1.5 x ULN. \*if total amylase \>1.5 x ULN, but pancreatic amylase is within the ULN, then subject may be enrolled. 9. Adequate renal function: a. Serum creatinine 1.5 x ULN or estimated creatinine clearance 60 mL/min as calculated using the method standard for the institution. 10. Adequate liver function: 1. Total serum bilirubin 1.5 x ULN; 2. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 2.5 x ULN (5.0 x ULN in case of liver metastases). 11. Acute effects of prior radiotherapy and chemotherapy resolved to baseline severity or to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 except for AEs that in the investigator's judgment do not constitute a safety risk for the subject. 12. Serum or urine pregnancy test (for females of childbearing potential) negative at screening. Female subjects of non childbearing potential must meet at least 1 of the following criteria: 1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause (which may be confirmed with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state if appropriate; 2. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 3. Have medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential. 13. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study. 14. Willing and able to comply with the study scheduled visits, treatment plans, laboratory tests, and other procedures.

Exclusion criteria

Subjects with any of the following characteristics/conditions will not be included in the study: 1. More than 1 prior chemotherapy regimen prior to enrollment in advanced/metastatic setting. If disease recurred/relapsed within the adjuvant chemotherapy treatment or \<=6 months after the completion of the adjuvant chemotherapy, then the adjuvant chemotherapy is considered as the first line systemic chemotherapy to the disease. 2. Systemic anti cancer therapy completed within a minimum of 5 half lives of study enrollment. 3. Prior therapy with an antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways, including, but not limited to, anti programmed cell death protein 1 (anti PD 1), anti programmed cell death protein ligand 1 (anti PD L1), anti PD L2, anti cluster of differentiation 137 (anti CD137), or anti cytotoxic T lymphocyte associated antigen 4 (anti CTLA 4) antibody. 4. Known epidermal growth factor receptor (EGFR) activating mutations; known prior therapy with EGFR TKI(s) (the prior treatment with brigatinib is allowed as an ALK TKI). 5. Major surgery within 4 weeks prior to enrollment. Minor surgical procedures (eg, port insertion) are not excluded, but sufficient time should have passed for adequate wound healing. 6. Radiation therapy within 2 weeks prior to enrollment. Palliative radiation must have been completed at least 48 hours prior to enrollment. Stereotactic or partial brain irradiation must have completed at least 2 weeks prior to enrollment. Whole brain irradiation must have completed at least 4 weeks prior to enrollment. 7. Spinal cord compression unless the subject has good pain control attained through therapy, and there is complete recovery of neurological function for the 4 weeks prior to enrollment. 8. Gastrointestinal abnormalities, including inability to take oral medication; requirement for intravenous alimentation; prior surgical procedures affecting absorption including total gastric resection or lap band; active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease; treatment for active peptic ulcer disease in the past 6 months; malabsorption syndromes. 9. Known prior or suspected severe hypersensitivity to lorlatinib or any component in the formulation; known prior therapy with lorlatinib. 10. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness. 11. Clinically significant cardiovascular disease (both arterial and venous) and non vascular cardiac conditions, (active or within 3 months prior to enrollment, which may include, but not are limited to: * Arterial disease such as cerebral vascular accident/stroke (including transient ischemic attack -TIA), myocardial infarction, unstable angina; * Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary embolism; * Nonvascular cardiac disease such as congestive heart failure (New York Heart Association Classification Class ≥ II), second degree or third degree atrioventricular block (unless paced) or any AV block with PR interval \>220 msec; or * Ongoing cardiac dysrhythmias of CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as \<50 bpm (unless subject is otherwise healthy such as long distance runners, etc.), machine read electrocardiogram (ECG) with QTc \>470 msec, or congenital long QT syndrome. 12. Subject with predisposing characteristics for acute pancreatitis according to investigator judgment, including but not limited to uncontrolled hyperglycemia, current gallstone disease, in the last month prior to enrollment. 13. History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis. 14. Evidence of active malignancy (other than NSCLC, non melanoma skin cancer, or localized and presumed cured prostate cancer or any in situ cancer which does not currently require treatment) within the last 3 years prior to enrollment. 15. Concurrent use of any of the following food or drugs (consult the sponsor if in doubt whether a food or a drug falls into any of the above categories) within 12 days prior to the first dose of administration of lorlatinib: 1. Known strong CYP3A inhibitors (eg, strong CYP3A inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits \[eg, Seville oranges, pomelos\], boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, ritonavir alone and with danoprevir or elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, telaprevir, troleandomycin, and voriconazole). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed; 2. Known CYP3A substrates with narrow therapeutic index, such as astemizole\*, terfenadine\*, cisapride\*, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil, fentanyl (including transdermal patch) or ergot alkaloids (ergotamine, dihydroergotamine) (\*withdrawn from US market); 3. Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's Wort); 4. Known P glycoprotein (P gp) substrates with a narrow therapeutic index (eg, digoxin). 16. 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 and/or the sponsor, would make the subject inappropriate for entry into this study. 17. Subject who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study. 18. Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation. 19. Pregnant female participants; breastfeeding female participants; fertile male participants and female participants of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 97 days if male or 35 days if female, after the last dose of investigational product.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Objective Response (Cohort 1)	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)	Objective response rate (ORR) was defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 relative to the total participants in the analysis population. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR was defined as a greater than equal to (\>=) 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Independent Central Radiology (ICR) was used for disease progression assessment.

Secondary

Measure	Time frame	Description
Percentage of Participants With Objective Response (Cohort 2)	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)	ORR was defined as the percentage of participants with a best overall confirmed response of CR or PR according to RECIST version 1.1 relative to the total participants in the analysis population. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. ICR was used for disease progression assessment.
Progression-Free Survival (PFS) Based on ICR Assessment	From first dose (Cycle 1 Day 1) to documented PD by ICR, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)	PFS was defined as the time from first dose to first documentation of objective disease progression (PD) or to death due to any cause, whichever came first. PD: at least a \>=20 percent (%) increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, PD was defined as unequivocal progression of existing non-target lesions, or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. Analysis was performed using Kaplan Meier method. ICR was used for disease progression assessment.
Progression-Free Survival Based on Investigator Assessment	From first dose (Cycle 1 Day 1) to documented progression of disease by investigator, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)	PFS was defined as the time from first dose to first documentation of objective PD or to death due to any cause, whichever came first. PD: at least a \>=20 % increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, PD was defined as unequivocal progression of existing non-target lesions, or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. Analysis was performed using Kaplan Meier method. Investigator assessment was used for disease progression assessment.
Overall Survival	From first dose (Cycle 1 Day 1) to date of death due to any cause (up to 271 weeks of treatment exposure)	Overall survival was defined as the time from first dose to the date of death due to any cause. Analysis was performed using Kaplan Meier method.
Percentage of Participants With Intracranial Objective Response (IC-OR) Based on ICR Assessment	From first dose (Cycle 1 Day 1) to documented PD by ICR (up to 271 weeks of treatment exposure)	IC-OR: percentage of participants with a best overall confirmed intracranial response of CR or PR according to RECIST version 1.1 relative to total participants in the analysis population but limited to intra cranial lesions only in participants with central nervous system metastases. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>= 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. 95% CI was based on Clopper-Pearson method.
Percentage of Participants With Intracranial Objective Response Based on Investigator Assessment	From first dose (Cycle 1 Day 1) to documented progression of disease by investigator (up to 271 weeks of treatment exposure)	IC-OR: percentage of participants with a best overall confirmed intracranial response of CR or PR according to RECIST version 1.1 relative to total participants in the analysis population but limited to intra cranial lesions only in participants with central nervous system metastases. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>= 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. 95% CI was based on Clopper-Pearson method
Duration of Response (DOR) Based on ICR Assessment	From first documentation of CR or PR to documented progression of disease by ICR, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)	DOR: time from first documentation of CR or PR to first documentation of PD or death due to any cause, whichever occurred first. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10mm. PR:\>=30% decrease in sum of longest dimensions of target lesions taking as a reference baseline sum longest dimensions. PD:\>=20 % increase in sum of longest dimensions of target lesions taking as a reference smallest sum of longest dimensions recorded since treatment started, or the appearance of one or more new lesions. In addition to relative increase of 20% sum must also demonstrate an absolute increase of at least 5 mm and for non-target lesions PD: unequivocal progression of existing non-target lesions or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at time of analysis were censored at date of last tumor assessment. Analysis was performed using Kaplan Meier method.
DOR Based on Investigator Assessment	From first documentation of CR or PR to documented PD by investigator, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure	DOR: time from first documentation of CR or PR to first documentation of PD or death due to any cause, whichever occurred first. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10mm. PR:\>=30% decrease in sum of longest dimensions of target lesions taking as a reference baseline sum longest dimensions. PD:\>=20 % increase in sum of longest dimensions of target lesions taking as a reference smallest sum of longest dimensions recorded since treatment started, or the appearance of one or more new lesions. In addition to relative increase of 20% sum must also demonstrate an absolute increase of at least 5 mm and for non-target lesions PD: unequivocal progression of existing non-target lesions or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at time of analysis were censored at date of last tumor assessment. Analysis was performed using Kaplan Meier method.
Duration of Intracranial Response Based on ICR Assessment	From first documentation of CR or PR to documented progression of disease by ICR, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)	Duration of intracranial response: time from first documentation of CR or PR considering only lesions having disease site=brain to first documentation of PD or death due to any cause, whichever occurred first, participants who had at least 1 intracranial lesion.CR: disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in \<10mm.PR:\>=30% decrease in the sum of the longest dimensions of target lesions taking reference the baseline sum longest dimension. PD:\>=20% increase in sum of longest dimensions of target lesion, or appearance of one or more new lesion. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm and for non-target lesion PD: unequivocal progression of existing non-target lesion, or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. Kaplan Meier method was used.
Duration of Intracranial Response Based on Investigator Assessment	From first documentation of CR or PR to documented progression of disease by investigator, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)	Duration of intracranial response: time from first documentation of CR or PR considering only lesions having disease site=brain to first documentation of PD or death due to any cause, whichever occurred first, participants who had at least 1 intracranial lesion.CR: disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in \<10mm.PR:\>=30% decrease in the sum of the longest dimensions of target lesions taking reference the baseline sum longest dimension. PD:\>=20% increase in sum of longest dimensions of target lesion or appearance of one or more new lesion. In addition to relative increase of 20% sum must also demonstrate an absolute increase of at least 5mm and for non-target lesion PD: unequivocal progression of existing non-target lesion, or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. Kaplan Meier method was used.
Time to Tumor Response Based on ICR Assessment	From first dose (Cycle 1 Day 1) to first documented CR or PR (up to 271 weeks of treatment exposure)	Time to tumor response was defined as the time from first dose to first documentation of objective tumor response CR or PR. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Time to Tumor Response Based on Investigator Assessment	From first dose (Cycle 1 Day 1) to documented first CR or PR (up to 271 weeks of treatment exposure)	Time to tumor response was defined as the time from first dose to first documentation of objective tumor response CR or PR. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Number of Participants With Adverse Events (AEs)	From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks	AE:any untoward medical occurrence in a study participant administered a product or medical device;event did not necessarily have a causal relationship with treatment or usage.Serious AE:any untoward medical occurrence at any dose resulted in death;life-threatening;required inpatient or prolongation of existing hospitalization;persistent or significant disability/incapacity; congenital anomaly/birth defect or that was considered to be an important event.AEs were graded by the National Cancer Institute Common Terminology Criteria AE(NCICTCAE)v4.03 where,Grade(G)1:mild AE;G2:moderate;G3:severe;G4:life-threatening consequences,urgent intervention indicated;G5:death related to AE. Focus of AE summaries was on treatment-emergent AE(TEAE).AE was considered TEAE if the event occurred during the on-treatment period.On-treatment:time from first dose of study treatment through end of study follow-up(i.e.,up to 28 days after last dose of treatment. Participant with G3or4 and5 AEs were reported.
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks	Laboratory tests included hematology, chemistry and lipids. Laboratory test results were graded according to NCI CTCAE version 4.03, where Grade 0: no AE, Grade 1 : mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Shifts from Grade \<=2 at baseline to Grade 3 or 4 post-baseline were considered clinically significant. Only categories with non-zero values were reported in this outcome measure.
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks	Vital signs evaluation included diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse rate and weight. Blood pressure and pulse rate were recorded in sitting position after the participant had been sitting quietly for at least 5 minutes. The pre-specified criteria included: sitting SBP change \>=40 millimeters of mercury (mmHg) increase, \>=40 mmHg decrease; sitting DBP change \>=20 mmHg increase, change \>=20 mmHg decrease, or change \>=60 mmHg increase; sitting pulse rate value \<50 beats per minute (bpm), \>120 bpm, change \>=30 bpm increase, or change \>=30 bpm decrease; weight 10% \<= change \<20% increase, change \>=20% increase or change \>=10% decrease. One participant can have more than one vital sign data meeting pre-specified criteria.
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks	The QT intervals were corrected for heart rate (QTc) using standard correction factors (ie, QTcF \[Fridericia's\], QTcB \[Bazett's\], and possibly a study-specified factor, as appropriate). The pre-specified criteria included: PR interval change \>= 50% and baseline \<200 msec, change \>=25% and baseline \>=200 msec; QRS interval change \>=50% and baseline \<100 msec, change \>=25% and baseline \>=100 msec; QTcB values \<=450 msec, 450 \< Value \<= 480 msec, 480 \< Value \<= 500 msec, value \>500 msec, change \<=30 msec, 30 \< Change \<= 60 msec, change \>60 msec; QTcF value \<=450 msec, 450 \< Value \<= 480 msec, 480 \< Value \<= 500 msec, Value \> 500 msec, change \<=30 msec, 30 \< Change \<=60 msec and change \>60 msec. . One participant can have more than one ECG data meeting pre-specified criteria.
Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria	From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks	Echocardiogram or multigated acquisition scan were performed to monitor LVEF. Pre-specified criteria included shift from baseline normal to post-baseline below lower limit of normal (LLN) \>=20-point decrease from baseline in LVEF% .
Cycle 1 Day 1 Maximum Plasma Concentration (Cmax)	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1	The loratinib Cmax was estimated using non-compartmental analysis.
Cycle 1 Day 1 Time to Cmax (Tmax)	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1	The loratinib Tmax was estimated using non-compartmental analysis.
Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau)	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1	The loratinib AUCtau was estimated using non-compartmental analysis.
Steady-State Cmax	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1	The loratinib Cmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Steady-State Tmax	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1	The loratinib Tmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Steady-State AUCtau	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1	The loratinib AUCtau was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Apparent Clearance (CL/F)	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1	The loratinib CL/F was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Observed Accumulation Ratio (Rac)	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1	The loratinib Rac was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Number of Participants With Central Nervous System-Related Adverse Events	From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks	An AE was any untoward medical occurrence in a study participant administered a product or medical device; the event did not necessarily have a causal relationship with the treatment or usage. The central-nervous system-related AEs included AEs under the cluster terms of mood effects, cognitive effects, psychotic effects, and speech effects.

Other

Measure	Time frame	Description
Percentage of Participants With Objective Response (Cohort 1)-Final Analysis	From first dose (Cycle 1 Day 1) to documented disease progression by ICR (up to 271 weeks of treatment exposure)	ORR was defined as the percentage of participants with a best overall confirmed response of CR or PR according to RECIST version 1.1 relative to the total participants in the analysis population. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. ICR was used for disease progression assessment.

Countries

China

Participant flow

Pre-assignment details

The study enrolled 109 participants, with 67 in Cohort 1 and 42 in Cohort 2.

Participants by arm

Arm	Count
Cohort 1 Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	67
Cohort 2 Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	42
Total	109

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	2
Overall Study	Death	6	6
Overall Study	Global Deterioration of Health Status	2	2
Overall Study	No longer benefit from Lorlatinib	2	0
Overall Study	Participant transition to rollover study	26	9
Overall Study	Participant was unwilling to come to site visit	0	1
Overall Study	Progressive Disease	28	21
Overall Study	Withdrawal by Subject	2	1

Baseline characteristics

Characteristic	Cohort 1	Cohort 2	Total
Age, Continuous	50.4 Years STANDARD_DEVIATION 10.85	52.1 Years STANDARD_DEVIATION 13.36	51.0 Years STANDARD_DEVIATION 11.84
Age, Customized <18 years	0 Participants	0 Participants	0 Participants
Age, Customized >65 years	6 Participants	7 Participants	13 Participants
Age, Customized Between 18 and 65 years	61 Participants	35 Participants	96 Participants
Race/Ethnicity, Customized Asian Chinese	67 Participants	42 Participants	109 Participants
Sex: Female, Male Female	33 Participants	23 Participants	56 Participants
Sex: Female, Male Male	34 Participants	19 Participants	53 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	28 / 67	26 / 42
other Total, other adverse events	67 / 67	42 / 42
serious Total, serious adverse events	23 / 67	16 / 42

Outcome results

Primary

Percentage of Participants With Objective Response (Cohort 1)

Objective response rate (ORR) was defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 relative to the total participants in the analysis population. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR was defined as a greater than equal to (\>=) 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Independent Central Radiology (ICR) was used for disease progression assessment.

Time frame: From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Population: The analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Value (NUMBER)
Cohort 1	Percentage of Participants With Objective Response (Cohort 1)	70.1 Percentage of participants

p-value: <0.0001Fisher Exact

Secondary

Apparent Clearance (CL/F)

The loratinib CL/F was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

Time frame: At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Population: The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1	Apparent Clearance (CL/F)	18.55 Liter per hour (L/hr)	Geometric Coefficient of Variation 37
Cohort 2	Apparent Clearance (CL/F)	14.71 Liter per hour (L/hr)	Geometric Coefficient of Variation 40

Secondary

Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau)

The loratinib AUCtau was estimated using non-compartmental analysis.

Time frame: At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1	Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau)	7310 nanogram*hour per milliliter (ng.hr/mL)	Geometric Coefficient of Variation 17
Cohort 2	Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau)	7778 nanogram*hour per milliliter (ng.hr/mL)	Geometric Coefficient of Variation 39

Secondary

Cycle 1 Day 1 Maximum Plasma Concentration (Cmax)

The loratinib Cmax was estimated using non-compartmental analysis.

Time frame: At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1	Cycle 1 Day 1 Maximum Plasma Concentration (Cmax)	1004 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 42
Cohort 2	Cycle 1 Day 1 Maximum Plasma Concentration (Cmax)	1074 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 58

Secondary

Cycle 1 Day 1 Time to Cmax (Tmax)

The loratinib Tmax was estimated using non-compartmental analysis.

Time frame: At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1

Arm	Measure	Value (MEDIAN)
Cohort 1	Cycle 1 Day 1 Time to Cmax (Tmax)	1.02 hour
Cohort 2	Cycle 1 Day 1 Time to Cmax (Tmax)	1.45 hour

Secondary

DOR Based on Investigator Assessment

DOR: time from first documentation of CR or PR to first documentation of PD or death due to any cause, whichever occurred first. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10mm. PR:\>=30% decrease in sum of longest dimensions of target lesions taking as a reference baseline sum longest dimensions. PD:\>=20 % increase in sum of longest dimensions of target lesions taking as a reference smallest sum of longest dimensions recorded since treatment started, or the appearance of one or more new lesions. In addition to relative increase of 20% sum must also demonstrate an absolute increase of at least 5 mm and for non-target lesions PD: unequivocal progression of existing non-target lesions or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at time of analysis were censored at date of last tumor assessment. Analysis was performed using Kaplan Meier method.

Time frame: From first documentation of CR or PR to documented PD by investigator, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.

Arm	Measure	Value (MEDIAN)
Cohort 1	DOR Based on Investigator Assessment	20.9 Months
Cohort 2	DOR Based on Investigator Assessment	20.8 Months

Secondary

Duration of Intracranial Response Based on ICR Assessment

Duration of intracranial response: time from first documentation of CR or PR considering only lesions having disease site=brain to first documentation of PD or death due to any cause, whichever occurred first, participants who had at least 1 intracranial lesion.CR: disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in \<10mm.PR:\>=30% decrease in the sum of the longest dimensions of target lesions taking reference the baseline sum longest dimension. PD:\>=20% increase in sum of longest dimensions of target lesion, or appearance of one or more new lesion. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm and for non-target lesion PD: unequivocal progression of existing non-target lesion, or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. Kaplan Meier method was used.

Time frame: From first documentation of CR or PR to documented progression of disease by ICR, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib. Here, 'Overall Number of Participants Analyzed' signifies participants for whom the brain lesions were chosen as RECIST target or non-target lesions at baseline and who were evaluable for this outcome measure.

Arm	Measure	Value (MEDIAN)
Cohort 1	Duration of Intracranial Response Based on ICR Assessment	NA Months
Cohort 2	Duration of Intracranial Response Based on ICR Assessment	NA Months

Secondary

Duration of Intracranial Response Based on Investigator Assessment

Duration of intracranial response: time from first documentation of CR or PR considering only lesions having disease site=brain to first documentation of PD or death due to any cause, whichever occurred first, participants who had at least 1 intracranial lesion.CR: disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in \<10mm.PR:\>=30% decrease in the sum of the longest dimensions of target lesions taking reference the baseline sum longest dimension. PD:\>=20% increase in sum of longest dimensions of target lesion or appearance of one or more new lesion. In addition to relative increase of 20% sum must also demonstrate an absolute increase of at least 5mm and for non-target lesion PD: unequivocal progression of existing non-target lesion, or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. Kaplan Meier method was used.

Time frame: From first documentation of CR or PR to documented progression of disease by investigator, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)

Arm	Measure	Value (MEDIAN)
Cohort 1	Duration of Intracranial Response Based on Investigator Assessment	NA Months
Cohort 2	Duration of Intracranial Response Based on Investigator Assessment	NA Months

Secondary

Duration of Response (DOR) Based on ICR Assessment

Arm	Measure	Value (MEDIAN)
Cohort 1	Duration of Response (DOR) Based on ICR Assessment	31.7 Months
Cohort 2	Duration of Response (DOR) Based on ICR Assessment	10.4 Months

Secondary

Number of Participants With Adverse Events (AEs)

AE:any untoward medical occurrence in a study participant administered a product or medical device;event did not necessarily have a causal relationship with treatment or usage.Serious AE:any untoward medical occurrence at any dose resulted in death;life-threatening;required inpatient or prolongation of existing hospitalization;persistent or significant disability/incapacity; congenital anomaly/birth defect or that was considered to be an important event.AEs were graded by the National Cancer Institute Common Terminology Criteria AE(NCICTCAE)v4.03 where,Grade(G)1:mild AE;G2:moderate;G3:severe;G4:life-threatening consequences,urgent intervention indicated;G5:death related to AE. Focus of AE summaries was on treatment-emergent AE(TEAE).AE was considered TEAE if the event occurred during the on-treatment period.On-treatment:time from first dose of study treatment through end of study follow-up(i.e.,up to 28 days after last dose of treatment. Participant with G3or4 and5 AEs were reported.

Time frame: From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	Number of Participants With Adverse Events (AEs)	All-causality TEAEs	67 Participants
Cohort 1	Number of Participants With Adverse Events (AEs)	Treatment-related TEAEs	67 Participants
Cohort 1	Number of Participants With Adverse Events (AEs)	All-causality serious AEs	23 Participants
Cohort 1	Number of Participants With Adverse Events (AEs)	Treatment-related serious AEs	11 Participants
Cohort 1	Number of Participants With Adverse Events (AEs)	All-causalities maximum Grade 3 or 4 AEs	49 Participants
Cohort 1	Number of Participants With Adverse Events (AEs)	Treatment-related Grade 3 or 4 AEs	46 Participants
Cohort 1	Number of Participants With Adverse Events (AEs)	All-causality Grade 5 AEs	4 Participants
Cohort 1	Number of Participants With Adverse Events (AEs)	Treatment-related Grade 5 AEs	0 Participants
Cohort 2	Number of Participants With Adverse Events (AEs)	Treatment-related Grade 5 AEs	0 Participants
Cohort 2	Number of Participants With Adverse Events (AEs)	All-causality TEAEs	42 Participants
Cohort 2	Number of Participants With Adverse Events (AEs)	All-causalities maximum Grade 3 or 4 AEs	25 Participants
Cohort 2	Number of Participants With Adverse Events (AEs)	Treatment-related TEAEs	42 Participants
Cohort 2	Number of Participants With Adverse Events (AEs)	All-causality Grade 5 AEs	7 Participants
Cohort 2	Number of Participants With Adverse Events (AEs)	All-causality serious AEs	16 Participants
Cohort 2	Number of Participants With Adverse Events (AEs)	Treatment-related Grade 3 or 4 AEs	19 Participants
Cohort 2	Number of Participants With Adverse Events (AEs)	Treatment-related serious AEs	5 Participants

Secondary

Number of Participants With Central Nervous System-Related Adverse Events

An AE was any untoward medical occurrence in a study participant administered a product or medical device; the event did not necessarily have a causal relationship with the treatment or usage. The central-nervous system-related AEs included AEs under the cluster terms of mood effects, cognitive effects, psychotic effects, and speech effects.

Time frame: From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	Number of Participants With Central Nervous System-Related Adverse Events	Cognitive Effects	2 Participants
Cohort 1	Number of Participants With Central Nervous System-Related Adverse Events	Mood Effects	1 Participants
Cohort 1	Number of Participants With Central Nervous System-Related Adverse Events	Speech Effects	0 Participants
Cohort 1	Number of Participants With Central Nervous System-Related Adverse Events	Psychotic Effects	1 Participants
Cohort 2	Number of Participants With Central Nervous System-Related Adverse Events	Psychotic Effects	0 Participants
Cohort 2	Number of Participants With Central Nervous System-Related Adverse Events	Cognitive Effects	1 Participants
Cohort 2	Number of Participants With Central Nervous System-Related Adverse Events	Speech Effects	1 Participants
Cohort 2	Number of Participants With Central Nervous System-Related Adverse Events	Mood Effects	2 Participants

Secondary

Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities

Laboratory tests included hematology, chemistry and lipids. Laboratory test results were graded according to NCI CTCAE version 4.03, where Grade 0: no AE, Grade 1 : mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Shifts from Grade \<=2 at baseline to Grade 3 or 4 post-baseline were considered clinically significant. Only categories with non-zero values were reported in this outcome measure.

Time frame: From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks

Population: The safety analysis population included all enrolled participants who received at least 1 dose of Lorlatinib. Here, Number Analyzed signifies number of participants evaluable for each row.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hyperglycemia: Grade 0 to Grade 3 or 4	6 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Aspartate aminotransferase increased:Grade 1 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hyperglycemia:Grade 1 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Lymphocyte count decreased Grade 0 to Grade 3 or 4	3 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypermagnesemia: Grade 0 to Grade 3 or 4	7 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Blood bilirubin increased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypocalcemia: Grade 0 to Grade 3 or 4	0 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Alanine aminotransferase increased: Grade 0 to Grade 3 or 4	2 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypokalemia: Grade 0 to Grade 3 or 4	2 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Blood bilirubin increased:Grade 1 to Grade 3 or 4	0 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypokalemia:Grade 2 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Anemia:Grade 2 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hyponatremia: Grade 0 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	CPK increased: Grade 0 to Grade 3 or 4	0 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hyponatremia:Grade 1 to Grade 3 or 4	0 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Alanine aminotransferase increased:Grade 1 to Grade 3 or 4	2 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypophosphatemia: Grade 0 to Grade 3 or 4	4 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	CPK increased:Grade 2 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypophosphatemia:Grade 1 to Grade 3 or 4	0 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Lymphocyte count decreased:Grade 1 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Lipase increased: Grade 0 to Grade 3 or 4	5 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Creatinine increased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Lipase increased:Grade 1 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypertriglyceridemia: Grade 0 to Grade 3 or 4	19 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Alkaline phosphatase increased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Serum amylase increased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	GGT increased: Grade 0 to Grade 3 or 4	3 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Cholesterol high: Grade 0 to Grade 3 or 4	12 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Anemia:Grade 1 to Grade 3 or 4	2 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Cholesterol high:Grade 1 to Grade 3 or 4	6 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	GGT increased:Grade 1 to Grade 3 or 4	2 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Cholesterol high:Grade 2 to Grade 3 or 4	1 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Aspartate aminotransferase increased: Grade 0 to Grade 3 or 4	2 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypercalcemia: Grade 0 to Grade 3 or 4	0 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypertriglyceridemia:Grade 1 to Grade 3 or 4	9 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Platelet count decreased: Grade 0 to Grade 3 or 4	2 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypertriglyceridemia:Grade 2 to Grade 3 or 4	3 Participants
Cohort 1	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Anemia: Grade 0 to Grade 3 or 4	3 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypertriglyceridemia:Grade 2 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Anemia: Grade 0 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Anemia:Grade 1 to Grade 3 or 4	3 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Anemia:Grade 2 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Lymphocyte count decreased Grade 0 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Lymphocyte count decreased:Grade 1 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Platelet count decreased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Alanine aminotransferase increased: Grade 0 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Alanine aminotransferase increased:Grade 1 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Alkaline phosphatase increased: Grade 0 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Aspartate aminotransferase increased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Aspartate aminotransferase increased:Grade 1 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Blood bilirubin increased: Grade 0 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Blood bilirubin increased:Grade 1 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	CPK increased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	CPK increased:Grade 2 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Creatinine increased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	GGT increased: Grade 0 to Grade 3 or 4	2 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	GGT increased:Grade 1 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypercalcemia: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hyperglycemia: Grade 0 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hyperglycemia:Grade 1 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypermagnesemia: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypocalcemia: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypokalemia: Grade 0 to Grade 3 or 4	2 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypokalemia:Grade 2 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hyponatremia: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hyponatremia:Grade 1 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypophosphatemia: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypophosphatemia:Grade 1 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Lipase increased: Grade 0 to Grade 3 or 4	2 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Lipase increased:Grade 1 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Serum amylase increased: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Cholesterol high: Grade 0 to Grade 3 or 4	1 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Cholesterol high:Grade 1 to Grade 3 or 4	3 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Cholesterol high:Grade 2 to Grade 3 or 4	0 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypertriglyceridemia: Grade 0 to Grade 3 or 4	3 Participants
Cohort 2	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Hypertriglyceridemia:Grade 1 to Grade 3 or 4	6 Participants

Secondary

Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria

The QT intervals were corrected for heart rate (QTc) using standard correction factors (ie, QTcF \[Fridericia's\], QTcB \[Bazett's\], and possibly a study-specified factor, as appropriate). The pre-specified criteria included: PR interval change \>= 50% and baseline \<200 msec, change \>=25% and baseline \>=200 msec; QRS interval change \>=50% and baseline \<100 msec, change \>=25% and baseline \>=100 msec; QTcB values \<=450 msec, 450 \< Value \<= 480 msec, 480 \< Value \<= 500 msec, value \>500 msec, change \<=30 msec, 30 \< Change \<= 60 msec, change \>60 msec; QTcF value \<=450 msec, 450 \< Value \<= 480 msec, 480 \< Value \<= 500 msec, Value \> 500 msec, change \<=30 msec, 30 \< Change \<=60 msec and change \>60 msec. . One participant can have more than one ECG data meeting pre-specified criteria.

Time frame: From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	PR interval change >=50% and baseline <200 msec	4 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	PR interval change >=25% and baseline >=200 msec	0 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QRS interval change >=50% and baseline<100 msec	1 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QRS interval change >=25% and baseline >=100 msec	2 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB value <=450 msec	27 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB 450 < Value <= 480 msec	26 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB 480 < Value <= 500 msec	5 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB value >500 msec	9 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB change <=30 msec	31 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB 30 < Change <= 60 msec	24 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB change >60 msec	12 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF value <=450 msec	49 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF 450 < Value <= 480 msec	13 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF 480 < Value <= 500 msec	1 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF value >500 msec	4 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF change <=30 msec	39 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF 30 < Change <= 60 msec	20 Participants
Cohort 1	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF change >60 msec	8 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF 480 < Value <= 500 msec	1 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	PR interval change >=50% and baseline <200 msec	1 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB 30 < Change <= 60 msec	14 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	PR interval change >=25% and baseline >=200 msec	0 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF change >60 msec	4 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QRS interval change >=50% and baseline<100 msec	1 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB change >60 msec	3 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QRS interval change >=25% and baseline >=100 msec	0 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF value >500 msec	0 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB value <=450 msec	27 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF value <=450 msec	35 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB 450 < Value <= 480 msec	9 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF 30 < Change <= 60 msec	9 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB 480 < Value <= 500 msec	3 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF 450 < Value <= 480 msec	6 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB value >500 msec	3 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcF change <=30 msec	29 Participants
Cohort 2	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	QTcB change <=30 msec	25 Participants

Secondary

Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria

Echocardiogram or multigated acquisition scan were performed to monitor LVEF. Pre-specified criteria included shift from baseline normal to post-baseline below lower limit of normal (LLN) \>=20-point decrease from baseline in LVEF% .

Time frame: From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib and who had at least 1 result of the LVEF value. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria	LVEF change from baseline normal to post-baseline below LLN	7 Participants
Cohort 1	Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria	LVEF >=20-point decrease from baseline	3 Participants
Cohort 2	Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria	LVEF change from baseline normal to post-baseline below LLN	0 Participants
Cohort 2	Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria	LVEF >=20-point decrease from baseline	0 Participants

Secondary

Number of Participants With Vital Signs Data Meeting Pre-specified Criteria

Vital signs evaluation included diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse rate and weight. Blood pressure and pulse rate were recorded in sitting position after the participant had been sitting quietly for at least 5 minutes. The pre-specified criteria included: sitting SBP change \>=40 millimeters of mercury (mmHg) increase, \>=40 mmHg decrease; sitting DBP change \>=20 mmHg increase, change \>=20 mmHg decrease, or change \>=60 mmHg increase; sitting pulse rate value \<50 beats per minute (bpm), \>120 bpm, change \>=30 bpm increase, or change \>=30 bpm decrease; weight 10% \<= change \<20% increase, change \>=20% increase or change \>=10% decrease. One participant can have more than one vital sign data meeting pre-specified criteria.

Time frame: From start of study treatment (Cycle 1 Day 1) up to 28 days after the last administration of the investigational product, up to approximately 275 weeks

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting SBP change >=40 mmHg increase	10 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting SBP change >=40 mmHg decrease	2 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting DBP change >=20 mmHg increase	26 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting DBP change >=20 mmHg decrease	12 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting DBP change >=60 mmHg increase	0 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting pulse rate value <50 bpm	0 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting pulse rate value >120 bpm	5 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting pulse rate change >=30 mmHg increase	18 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting pulse rate change >=30 mmHg decrease	5 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	weight 10% <= change <20% kg increase	43 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Weight change >=20% kg increase	14 Participants
Cohort 1	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Weight change >=10% kg decrease	3 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Weight change >=20% kg increase	6 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting SBP change >=40 mmHg increase	1 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting pulse rate value >120 bpm	3 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting SBP change >=40 mmHg decrease	0 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	weight 10% <= change <20% kg increase	22 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting DBP change >=20 mmHg increase	10 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting pulse rate change >=30 mmHg increase	5 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting DBP change >=20 mmHg decrease	7 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Weight change >=10% kg decrease	2 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting DBP change >=60 mmHg increase	0 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting pulse rate change >=30 mmHg decrease	7 Participants
Cohort 2	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Sitting pulse rate value <50 bpm	0 Participants

Secondary

Observed Accumulation Ratio (Rac)

The loratinib Rac was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

Time frame: At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1	Observed Accumulation Ratio (Rac)	0.7371 Ratio	Geometric Coefficient of Variation 47
Cohort 2	Observed Accumulation Ratio (Rac)	0.9578 Ratio	Geometric Coefficient of Variation 33

Secondary

Overall Survival

Overall survival was defined as the time from first dose to the date of death due to any cause. Analysis was performed using Kaplan Meier method.

Time frame: From first dose (Cycle 1 Day 1) to date of death due to any cause (up to 271 weeks of treatment exposure)

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Value (MEDIAN)
Cohort 1	Overall Survival	NA Months
Cohort 2	Overall Survival	21.9 Months

Secondary

Percentage of Participants With Intracranial Objective Response Based on Investigator Assessment

IC-OR: percentage of participants with a best overall confirmed intracranial response of CR or PR according to RECIST version 1.1 relative to total participants in the analysis population but limited to intra cranial lesions only in participants with central nervous system metastases. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>= 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. 95% CI was based on Clopper-Pearson method

Time frame: From first dose (Cycle 1 Day 1) to documented progression of disease by investigator (up to 271 weeks of treatment exposure)

Arm	Measure	Value (NUMBER)
Cohort 1	Percentage of Participants With Intracranial Objective Response Based on Investigator Assessment	63.4 Percentage of participants
Cohort 2	Percentage of Participants With Intracranial Objective Response Based on Investigator Assessment	33.3 Percentage of participants

Secondary

Percentage of Participants With Intracranial Objective Response (IC-OR) Based on ICR Assessment

Time frame: From first dose (Cycle 1 Day 1) to documented PD by ICR (up to 271 weeks of treatment exposure)

Arm	Measure	Value (NUMBER)
Cohort 1	Percentage of Participants With Intracranial Objective Response (IC-OR) Based on ICR Assessment	83.8 Percentage of participants
Cohort 2	Percentage of Participants With Intracranial Objective Response (IC-OR) Based on ICR Assessment	50.0 Percentage of participants

Secondary

Percentage of Participants With Objective Response (Cohort 2)

ORR was defined as the percentage of participants with a best overall confirmed response of CR or PR according to RECIST version 1.1 relative to the total participants in the analysis population. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. ICR was used for disease progression assessment.

Time frame: From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Population: The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm	Measure	Value (NUMBER)
Cohort 1	Percentage of Participants With Objective Response (Cohort 2)	47.6 Percentage of participants

Secondary

Progression-Free Survival Based on Investigator Assessment

PFS was defined as the time from first dose to first documentation of objective PD or to death due to any cause, whichever came first. PD: at least a \>=20 % increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, PD was defined as unequivocal progression of existing non-target lesions, or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. Analysis was performed using Kaplan Meier method. Investigator assessment was used for disease progression assessment.

Time frame: From first dose (Cycle 1 Day 1) to documented progression of disease by investigator, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Value (MEDIAN)
Cohort 1	Progression-Free Survival Based on Investigator Assessment	26.3 Months
Cohort 2	Progression-Free Survival Based on Investigator Assessment	6.9 Months

Secondary

Progression-Free Survival (PFS) Based on ICR Assessment

PFS was defined as the time from first dose to first documentation of objective disease progression (PD) or to death due to any cause, whichever came first. PD: at least a \>=20 percent (%) increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, PD was defined as unequivocal progression of existing non-target lesions, or the appearance of \>=1 new lesion. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. Analysis was performed using Kaplan Meier method. ICR was used for disease progression assessment.

Time frame: From first dose (Cycle 1 Day 1) to documented PD by ICR, death due to any cause or date of censoring, whichever occurred first (up to 271 weeks of treatment exposure)

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Value (MEDIAN)
Cohort 1	Progression-Free Survival (PFS) Based on ICR Assessment	26.3 Months
Cohort 2	Progression-Free Survival (PFS) Based on ICR Assessment	5.6 Months

Secondary

Steady-State AUCtau

The loratinib AUCtau was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

Time frame: At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1	Steady-State AUCtau	5388 ng*hr/mL	Geometric Coefficient of Variation 37
Cohort 2	Steady-State AUCtau	6801 ng*hr/mL	Geometric Coefficient of Variation 40

Secondary

Steady-State Cmax

The loratinib Cmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

Time frame: At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1	Steady-State Cmax	643.9 ng/mL	Geometric Coefficient of Variation 50
Cohort 2	Steady-State Cmax	795.9 ng/mL	Geometric Coefficient of Variation 40

Secondary

Steady-State Tmax

The loratinib Tmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

Time frame: At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Arm	Measure	Value (MEDIAN)
Cohort 1	Steady-State Tmax	1.53 hour
Cohort 2	Steady-State Tmax	1.88 hour

Secondary

Time to Tumor Response Based on ICR Assessment

Time to tumor response was defined as the time from first dose to first documentation of objective tumor response CR or PR. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.

Time frame: From first dose (Cycle 1 Day 1) to first documented CR or PR (up to 271 weeks of treatment exposure)

Arm	Measure	Value (MEDIAN)
Cohort 1	Time to Tumor Response Based on ICR Assessment	1.4 Months
Cohort 2	Time to Tumor Response Based on ICR Assessment	1.4 Months

Secondary

Time to Tumor Response Based on Investigator Assessment

Time frame: From first dose (Cycle 1 Day 1) to documented first CR or PR (up to 271 weeks of treatment exposure)

Arm	Measure	Value (MEDIAN)
Cohort 1	Time to Tumor Response Based on Investigator Assessment	1.4 Months
Cohort 2	Time to Tumor Response Based on Investigator Assessment	1.4 Months

Other Pre-specified

Percentage of Participants With Objective Response (Cohort 1)-Final Analysis

Time frame: From first dose (Cycle 1 Day 1) to documented disease progression by ICR (up to 271 weeks of treatment exposure)

Population: The safety analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm	Measure	Value (NUMBER)
Cohort 1	Percentage of Participants With Objective Response (Cohort 1)-Final Analysis	79.1 Percentage of participants

Source: ClinicalTrials.gov · Data processed: Feb 18, 2026

A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Other

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Percentage of Participants With Objective Response (Cohort 1)

Apparent Clearance (CL/F)

Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau)

Cycle 1 Day 1 Maximum Plasma Concentration (Cmax)

Cycle 1 Day 1 Time to Cmax (Tmax)

DOR Based on Investigator Assessment

Duration of Intracranial Response Based on ICR Assessment

Duration of Intracranial Response Based on Investigator Assessment

Duration of Response (DOR) Based on ICR Assessment

Number of Participants With Adverse Events (AEs)

Number of Participants With Central Nervous System-Related Adverse Events

Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities

Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria

Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria

Number of Participants With Vital Signs Data Meeting Pre-specified Criteria

Observed Accumulation Ratio (Rac)

Overall Survival

Percentage of Participants With Intracranial Objective Response Based on Investigator Assessment

Percentage of Participants With Intracranial Objective Response (IC-OR) Based on ICR Assessment

Percentage of Participants With Objective Response (Cohort 2)

Progression-Free Survival Based on Investigator Assessment

Progression-Free Survival (PFS) Based on ICR Assessment

Steady-State AUCtau

Steady-State Cmax

Steady-State Tmax

Time to Tumor Response Based on ICR Assessment

Time to Tumor Response Based on Investigator Assessment

Percentage of Participants With Objective Response (Cohort 1)-Final Analysis