A Study Of Lorlatinib Versus Crizotinib In First Line Treatment Of Patients With ALK-Positive NSCLC

• Sponsor: Pfizer (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03052608
• Collaborator: (none)
• Enrollment: 296
• Locations: 165
• Arms: 2
• Anticipated Duration (Months): 140.2
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

A phase 3 study to demonstrate whether lorlatinib given as monotherapy is superior to crizotinib alone in prolonging the progression-free survival in advanced ALK-positive NSCLC patients who are treatment naïve and to compare lorlatinib to crizotinib with respect to overall survival in the same population

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Lorlatinib; Drug: Crizotinib	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 296 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY OF LORLATINIB (PF-06463922) MONOTHERAPY VERSUS CRIZOTINIB MONOTHERAPY IN THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED ALK-POSITIVE NON-SMALL CELL LUNG CANCER
• Actual Study Start Date: Apr 27, 2017
• Actual Primary Completion Date: Mar 20, 2020
• Anticipated Study Completion Date: Dec 31, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lorlatinib Lorlatinib single agent, 100 mg (4 x 25 mg) oral tables, QD, continuously	Drug: Lorlatinib; ALK-positive NSCL treatment; Other Names: PF-06463922
Active Comparator: Crizotinib Crizotinib single agent, 250 mg (1 x 250) oral capsules, BID, continuously	Drug: Crizotinib; ALK-positive NSCL treatment; Other Names: Xalkori

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) Assessment [From time of Study Start up to 33 months]

   PFS was defined as the time from randomization to the date of the first documentation of progressive disease as assessed by the independent radiologist or death due to any cause, whichever occurred first. PFS (in months) was calculated as (date of event or censoring-randomization+1)/30.4375. Progressive disease is defined per RECIST version 1.1, as at least a 20% increase (including an absolute increase of at least 5 mm) 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 1 or more new lesions.

Secondary Outcome Measures

1. Overall Survival (OS) [From time of Study Start up to 33 months]

   OS was defined as the time from randomization to the date of death due to any cause. OS (in months) was calculated as (date of death or censoring - start date +1)/30.4375. Participants last known to be alive were censored at date of last contact.

2. Progression-Free Survival (PFS) Based on Investigator's Assessment [From time of Study Start up to 33 months]

   PFS was defined as the time from randomization to the date of the first documentation of progressive disease as assessed by investigator or death due to any cause, whichever occurred first. PFS (in months) was calculated as (date of event or censoring-randomization+1)/30.4375. Progressive disease is defined per RECIST version 1.1, as at least a 20% increase (including an absolute increase of at least 5 mm) 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 1 or more new lesions.

3. Objective Response Rate (ORR) - Percentage of Participants With Objective Response (OR) Based on BICR Assessment [From time of Study Start up to 33 months]

   ORR was the percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1 recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.

4. Objective Response Rate (ORR) - Percentage of Participants With Objective Response (OR) Based on Investigator's Assessment [From time of Study Start up to 33 months]

   ORR was the percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1 recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.

5. Intracranial Objective Response Rate (IC-ORR) - Percentage of Participants With Intracranial Objective Response (IC-OR) Based on BICR Assessment [From time of Study Start up to 33 months]

   IC-ORR was the percentage of participant with intracranial objective response of complete response (CR) or partial response (PR) based on intracranial disease in the subset of participants with at least 1 intracranial lesion per RECIST version 1.1 (modified) recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.

6. Intracranial Time to Progression (IC-TTP) Based on BICR Assessment [From time of Study Start up to 33 months]

   IC-TTP based on BICR assessment was defined as the time from date of randomization to the date of the first documentation of progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases.

7. Duration of Response (DR) Based on BICR Assessment [From time of Study Start up to 33 months]

   DR was defined, for participants with a confirmed objective response (OR) of complete response (CR) or partial response (PR) per RECIST version 1.1, as the time from the first documentation of OR to the first documentation of progressive disease (PD) or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) 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 1 or more new lesions.

8. Intracranial Duration of Response (IC-DR) Based on BICR Assessment [From time of Study Start up to 33 months]

   IC-DR was defined, for participants with a confirmed intracranial objective response (OR) of complete response (CR) or partial response (PR) per RECIST version 1.1, as the time from the first documentation of intracranial OR to the first documentation of intracranial progressive disease (PD) or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) 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 1 or more new lesions.

9. Time to Tumor Response (TTR) Based on BICR Assessment [From time of Study Start up to 33 months]

   TTR based on BICR assessment was defined, for participants with a confirmed objective response, as the time from the date of randomization to the first documentation of objective response (complete response or partial response) which was subsequently confirmed. Complete response was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). Partial response was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.

10. Intracranial Time to Tumor Response (IC-TTR) Based on BICR Assessment [From time of Study Start up to 33 months]

    IC-TTR was defined, for participants with a confirmed intracranial objective response, as the time from the date of randomization to the first documentation of intracranial objective response (complete response or partial response) which was subsequently confirmed. Complete response was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). Partial response was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.

11. PFS2 Based on Investigator's Assessment [From time of Study Start up to 45 months]

    PFS2 was defined as the time from randomization to the date of progression of disease on first subsequent systemic anti-cancer therapy, or death from any cause, whichever occurred first

12. Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) [From time of Study Start up to 33 months]

    An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, life-threatening experience, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. All AEs in the table below were treatment-emergent AEs. Grade 3 and 4 AEs in the table below indicated severe AE and life-threatening consequences respectively; Grade 5 indicated death due to AE. Treatment-related AEs were determined by investigators.

13. Number of Participants With Changes in Hematology Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4 [From Baseline up to 33 months]

    Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3.

14. Number of Participants With Changes in Chemistry Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4 [From Baseline up to 33 months]

    Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3.

15. Number of Participants With Changes in Lipid Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4 [From Baseline up to 33 months]

    Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3.

16. Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria [From Baseline up to 33 months]

    Vital signs data included pulse, systolic blood pressure, and diastolic blood pressure. Measurements were only provided once per timepoint. If multiple assessments were provided per timepoint, the maximum value were used for reporting. The pre-defined criteria of vital sign and body weight data were as follows: maximum pulse rate >120 beats per minute (bpm); minimum pulse rate <50 bpm; maximum increase in pulse rate ≥30 bpm; maximum decrease in pulse rate ≥30 bpm; increase in systolic blood Pressure ≥40 mmHg; decrease in systolic blood pressure ≥40 mmHg; decrease in systolic blood pressure ≥60 mmHg; increase in diastolic blood pressure ≥20 mmHg; decrease in diastolic blood pressure ≥20 mmHg; decrease in diastolic blood pressure ≥40 mmHg; increase in body weight ≥10%; increase in body weight ≥20%; decrease in body weight ≥10%.

17. Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria [From Baseline up to 33 months]

    Baseline was defined as the last assessment performed on or prior to date of the first dose of study treatment. Triplicate ECGs were collected in the study and the average of the replicate assessments were used for summary analysis. The pre-defined criteria of ECG data were as follows: change from baseline in QTcF ≥60 msec, ≥30 msec but <60 msec, <30 msec; change from baseline in QTcB ≥60 msec, ≥30 msec but <60 msec, <30 msec; PR change ≥50% if absolute baseline value was <200 msec; PR change ≥25% if absolute baseline value was ≥200 msec; QRS change ≥50% if absolute baseline value was <100 msec; QRS change ≥25% if absolute baseline value was ≥100 msec.

18. Number of Participants With Maximum Decrease From Baseline Greater Than or Equal to 20 Points in Left Ventricular Ejection Fraction (LVEF) Percentage [From Baseline up to 33 months]

    In this outcome measure, baseline was defined as the last assessment on or prior to the date of the first dose of study treatment. Decrease from baseline was an absolute difference between baseline and observed value.

19. Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time [Baseline, Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C8D1, C10D1, C12D1, C14D1, C16D1, C18D1, C20D1, C22D1, C24D1, C26D1, C28D1, C30D1, C32D1, C34D1, C36D1, C38D1 and End of Treatment]

    BDI-II (Mood Assessment) is a 21 item self-reported scale, with each item rated by participants on a 4-point scale (ranging from 0-3). The scale includes items capturing mood, (loss of pleasure, sadness, and irritability), suicidal ideation, and cognitive signs (punitive thoughts, self-criticism, self-dislike pessimism, poor concentration) as well as somatic signs (appetite, sleep, fatigue, libido). Scores were obtained by adding up the total points from the series of answers. The total score ranged from 0 to 63, with higher total scores indicating more severe depressive symptoms. The standardized cutoffs are as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression.

20. Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time [Baseline, Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C8D1, C10D1, C12D1, C14D1, C16D1, C18D1, C20D1, C22D1, C24D1, C26D1, C28D1, C30D1, C32D1, C34D1, C36D1, C38D1 and End of Treatment]

    Suicidal ideation and behaviors were assessed by the Columbia Suicide Severity Rating Scale (C-SSRS). The C-SSRS is a unique, simple and short method of assessing both behavior and ideation that tracks all suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation, and deterrents), all of which are significantly predictive of completed suicide.

21. Change From Baseline in Global Quality of Life (QOL), Functional Scales and Symptoms Scales as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) During Overall Treatment [From Baseline up to Cycle 38 Day 1]

    The EORTC QLQ C30 consists of 30 questions and includes 5 functional scales (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale; 3 symptom scales (fatigue, pain, nausea and vomiting); and 6 single items that assess additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and financial impact. All scales and single item measures range in score from 0 to 100. Higher scores on the functional scales represent higher levels of functioning. Higher scores on the global health status/quality of life scale represent higher health status/quality of life. Higher scores on symptom scales/items represent a greater presence of symptoms.

22. Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment [From Baseline up to Cycle 38 Day 1]

    The EORTC QLQ LC13 consists of 13 questions and includes 1 multi-item scale and 9 single items assessing symptoms (dyspnea, cough, haemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication use. The scale scores rang from 0 to 100, with higher scores indicating higher ("worse") level of symptoms.

23. Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time [Baseline, Day 1 of all cycles from Cycle 2 to Cycle 38, and End of Treatment]

    The EuroQol EQ-5D-5L is a participant-completed questionnaire designed to assess health status. There are 2 components to the EuroQol EQ-5D-5L: a descriptive system in which individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a VAS. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) and higher scores indicate better health state.

24. Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time [Baseline, Day 1 of all cycles from Cycle 2 to Cycle 38, and End of Treatment]

    The EuroQol EQ-5D-5L is a participant-completed questionnaire designed to assess health status. There are 2 components to the EuroQol EQ-5D-5L: a descriptive system in which individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a VAS in which participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable). EQ-5D summary index is obtained with a formula that weights each level of the 5 dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health).

25. Time to Deterioration (TTD) in Participant Reported Pain in Chest, Dyspnea, or Cough From QLQ-LC13 [From Baseline up to 33 months]

    The EORTC QLQ LC13 consists of 13 questions and includes 1 multi-item scale and 9 single items assessing symptoms (dyspnea, cough, haemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication use. The scale scores rang from 0 to 100, with higher scores indicating higher ("worse") level of symptoms. TTD in pain in chest, dyspnea, or cough was defined as the time from randomization to the first time the participant's score showed a 10 point or greater increase after baseline in any of the 3 symptoms. TTD in months was calculated as (date of deterioration or censoring - randomization date +1)/30.4375.

26. Number of Participant With ALK Domain Mutation in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 [at Screening, Cycle 2 Day 1 and Cycle 7 Day 1]

    The analysis of anaplastic lymphoma kinase (ALK) domain mutation in plasma CNA was performed by next-generation sequencing (NGS) and the number of participants with one or more ALK mutations at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 is presented here.

27. Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 [at Screening, Cycle 2 Day 1 and Cycle 7 Day 1]

    The analysis of ALK fusion variant in plasma CNA was performed by NGS and the number of participants with fusion variants at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 is presented here. In the table below, EML4-ALK is the abbreviation of echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK-positive NSCLC; at least 1 extracranial measurable target lesion not previously irradiated. CNS metastases allowed if asymptomatic and not currently requiring corticosteroid treatment.

• Availability of an archival FFPE tissue specimen.

• No prior systemic NSCLC treatment.

• ECOG PS 0, 1, or 2.

• Age ≥18 years .

• Adequate Bone Marrow, Liver, Renal, Pancreatic Function

• Negative pregnancy test for females of childbearing potential

Exclusion Criteria:

• Spinal cord compression unless good pain control attained

• Major surgery within 4 weeks prior to randomization.

• Radiation therapy within 2 weeks prior to randomization, including stereotactic or partial brain irradiation. Whole brain irradiation within 4 weeks prior to randomization

• Active bacterial, fungal, or viral infection

• Clinically significant cardiovascular disease, active or within 3 months prior to enrollment. Ongoing cardiac dysrhythmias, uncontrolled atrial fibrillation, bradycardia or congenital long QT syndrome

• Predisposing characteristics for acute pancreatitis in the last month prior to randomization.

• History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease

• Active malignancy (other than NSCLC, non melanoma skin cancer, in situ cervical cancer, papillary thyroid cancer, LCIS/DCIS of the breast, or localized prostate cancer) within the last 3 years prior to randomization.

• Concurrent use of any of the following food or drugs within 12 days prior to the first dose of lorlatinib or crizotinib.

1. known strong CYP3A inhibitors .

2. known strong CYP3A inducers

3. known P gp substrates with a narrow therapeutic index

• Concurrent use of CYP3A substrates with narrow therapeutic indices within 12 days prior to the first dose of lorlatinib or crizotinib.

• Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or interfere with the interpretation of study results

• Investigational site staff members directly involved in the conduct of the study and their family members, or Pfizer employees, including their family members, directly involved in the conduct of the study.

• Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Altamonte Springs	Florida	United States	32701
2	Florida Cancer Specialists	Brandon	Florida	United States	33511
3	Florida Cancer Specialists	Clearwater	Florida	United States	33761
4	Florida Cancer Specialists	Gainesville	Florida	United States	32605
5	Florida Cancer Specialists	Largo	Florida	United States	33770
6	Florida Cancer Specialists	Lecanto	Florida	United States	34461
7	Florida Cancer Specialists	Orange City	Florida	United States	32763
8	Florida Cancer Specialists	Orlando	Florida	United States	32806
9	Florida Cancer Specialists	Saint Petersburg	Florida	United States	33705
10	Florida Cancer Specialists	Spring Hill	Florida	United States	34608
11	Florida Cancer Specialists	Tampa	Florida	United States	33607
12	Florida Cancer Specialists	Tavares	Florida	United States	32778
13	Florida Cancer Specialists	The Villages	Florida	United States	32159
14	Florida Cancer Specialists	Winter Park	Florida	United States	32792
15	Massachusetts Eye and Ear Infirmary	Boston	Massachusetts	United States	02114
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
17	Ophthalmic Consultants of Boston Inc	Boston	Massachusetts	United States	02114
18	The William P. Beetham Eye Institute, Joslin Diabetes Center	Boston	Massachusetts	United States	02215
19	University of Rochester Cancer Center Pharmacy	Rochester	New York	United States	14642
20	University of Rochester Medical Center	Rochester	New York	United States	14642
21	Tennessee Oncology, PLLC	Dickson	Tennessee	United States	37055
22	Tennessee Oncology, PLLC	Franklin	Tennessee	United States	37067
23	Tennessee Oncology, PLLC	Gallatin	Tennessee	United States	37066
24	Tennessee Oncology, PLLC	Hermitage	Tennessee	United States	37076
25	Tennessee Oncology, PLLC	Lebanon	Tennessee	United States	37090
26	Tennessee Oncology, PLLC	Murfreesboro	Tennessee	United States	37129
27	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
28	The Sarah Cannon Research Institute.	Nashville	Tennessee	United States	37203
29	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37205
30	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37207
31	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37211
32	Tennessee Oncology, PLLC	Shelbyville	Tennessee	United States	37160
33	Tennessee Oncology, PLLC	Smyrna	Tennessee	United States	37167
34	University of Washington Medical Center	Seattle	Washington	United States	98195
35	Centro de Investigacion Pergamino SA	Pergamino	Buenos Aires	Argentina	B2700CPM
36	Centro Medico Austral	Caba		Argentina	C1019ABS
37	Bendigo Day Surgery Collection Centre and Laboratory	Bendigo	Victoria	Australia	3550
38	Bendigo Medical Imaging, Bendigo Hospital	Bendigo	Victoria	Australia	3550
39	Melbourne Pathology	Bendigo	Victoria	Australia	3550
40	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
41	Grand Hopital de Charleroi - Site Notre Dame	Charleroi		Belgium	6000
42	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
43	McGill University Health Centre	Montreal	Quebec	Canada	H4A 3J1
44	The Affiliated Hospital of Military Medical Sciences	Beijing	Beijing	China	100071
45	Jilin Provincial Cancer Hospital	Changchun	Jilin	China	130012
46	Shanghai Chest Hospital	Shanghai	Shanghai	China	200030
47	Department of Respiratory,the First Affiliated Hospital of College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China	310003
48	The Second Affiliated Hospital of Zhejiang University School of Medicine	Hangzhou	Zhejiang	China	310009
49	Zhejiang Cancer Hospital	Hangzhou	Zhejiang	China	310022
50	Beijing Cancer Hospital	Beijing		China	100142
51	Guangdong General Hospital	Guangzhou		China	510000
52	Fakultni nemocnice Olomouc, Klinika plicnich nemoci a tuberkulozy	Olomouc		Czechia	779 00
53	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	128 08
54	Hopital Haut-Léveque-Centre François Magendie	Pessac	Aquitaine	France	33604
55	Hopital de Chevilly Larue	Chevilly Larue		France	94550
56	Centre Hospitalier du Mans	Le Mans		France	72000
57	Institut Paoli-Calmettes	Marseille cedex 09		France	13273
58	Département d'Imagerie Médicale	Marseille cedex 20		France	13915
59	Hôpital Nord	Marseille cedex 20		France	13915
60	Service Ophtalmologie	Marseille cedex 20		France	13915
61	Groupe Hospitalier Bichat Claude Bernard, AP-HP	Paris		France	75018
62	CHU de Rennes Hopital Pontchaillou	Rennes cedex 9		France	35033
63	CHU de Rennes, Hopital Pontchaillou	Rennes cedex 9		France	35033
64	Hopital Foch	Suresnes		France	92150
65	Hopital Larrey	Toulouse Cedex 9		France	31059
66	Hopital Pierre Paul Riquet	Toulouse cedex 9		France	31059
67	Hôpital Larrey	Toulouse Cedex 9		France	31059
68	Department d'imagerie medicale	Villejuif		France	94805
69	Institut Gustave Roussy	Villejuif		France	94805
70	Uberortliche Radiologische Gemeinschaftspraxis Dr. med. Marc Amler	Dresden		Germany	01309
71	Technische Universitat Dresden , Medizinische Fakultat Carl Gustav Carus	Dresden		Germany	D-01307
72	Thoraxklinik Heidelberg gGmbH	Heidelberg		Germany	D-69126
73	Universitatsklinikum Heidelberg	Heidelberg		Germany	D-69126
74	Universitätsklinikum des Saarlandes, Innere Medizin V	Homburg - Saar		Germany	66421
75	Universitätsklinikum des Saarlandes	Homburg - Saar		Germany	66421
76	Universitatsklinikum Regensburg, Institut fur Rontgendiagnostik	Regensburg		Germany	93053
77	Universitatsklinikum Regensburg, Klinik und Poliklinik fur Innere Medizin II	Regensburg		Germany	93053
78	The University of Hong Kong, Department of Clinical Oncology	Hong Kong		Hong Kong
79	The University of Hong Kong, Department of Medicine	Hong Kong		Hong Kong
80	Tuen Mun Hospital	Hong Kong		Hong Kong
81	Artemis Hospital	Gurugram	Haryana	India	122001
82	Manipal Hospital	Bangalore	Karnataka	India	560017
83	Srinivasam Cancer Care Multispeciality Hospitals India Pvt Ltd	Bangalore	Karnataka	India	560072
84	Sahyadri Clinical Research and Development Centre	Pune	Maharashtra	India	411004
85	Sahyadri Specialty Hospital	Pune	Maharashtra	India	411004
86	AOU Policlinico Vittorio Emanuele-P.O.G. Rodolico	Catania	CT	Italy	95123
87	ASST Monza - A.O. San Gerardo	Monza	MB	Italy	20900
88	IRCCS Ospedale San Raffaele	Milano	MI	Italy	20132
89	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	MI	Italy	20133
90	Istituto Europeo di Oncologia	Milano	MI	Italy	20141
91	Istituto Clinico Humanitas	Rozzano	MI	Italy	20089
92	Azienda Ospedaliera di Perugia - Ospedale S. M. Misericordia	Perugia	PG	Italy	06132
93	Centro di Riferimento Oncologico-IRCCS	Pordenone	PN	Italy	33081
94	Azienda Ospedaliero-Universitaria di Parma	Parma	PR	Italy	43126
95	Istituto Nazionale Tumori Regina Elena	Roma	RM	Italy	00144
96	Az.Osp.San Camillo-Forlanini	Roma	RM	Italy	00152
97	Azienda Ospedaliera Dei Colli Ospedale Monaldi	Napoli		Italy	80131
98	Istituto Nazionale Tumori di Napoli	Napoli		Italy	80131
99	Ausl della Romagna- Ravenna	Ravenna		Italy	48121
100	Aichi cancer center central hospital	Nagoya	Aichi	Japan	464-8681
101	Nagoya University Hospital	Nagoya	Aichi	Japan	466-8560
102	National Hospital Organization Shikoku Cancer Center	Matsuyama	Ehime	Japan	791-0280
103	Kurume University Hospital	Kurume	Fukuoka	Japan	830-0011
104	National Hospital Organization Hokkaido Cancer Center	Sapporo	Hokkaido	Japan	003-0804
105	Kanazawa University Hospital	Kanazawa	Ishikawa	Japan	920-8641
106	Kanagawa Cancer Center	Yokohama	Kanagawa	Japan	241-8515
107	Sendai Kousei Hospital	Sendai	Miyagi	Japan	980-0873
108	Osaka International Cancer Institute	Osaka-shi	Osaka	Japan	541-8567
109	Kindai University Hospital	Osakasayama	Osaka	Japan	589-8511
110	Shizuoka Cancer Center	Sunto-gun	Shizuoka	Japan	411-8777
111	National Cancer Center Hospital	Chuo-Ku	Tokyo	Japan	104-0045
112	National Hospital Organization, Yamaguchi-Ube Medical Center	Ube	Yamaguchi	Japan	755-0241
113	The Cancer Institute Hospital of JFCR	Koto-ku, Tokyo		Japan	135-8550
114	Niigata Cancer Center Hospital	Niigata		Japan	951-8566
115	Okayama University Hospital	Okayama		Japan	700-8558
116	Osaka City General Hospital	Osaka		Japan	534-0021
117	Tokushima University Hospital	Tokushima		Japan	770-8503
118	Wakayama Medical University Department of Pulmonary Medicine and Oncology	Wakayama		Japan	641-8509
119	The Catholic University of Korea, St. Vincents Hospital	Suwon	Gyeonggi-do	Korea, Republic of	16247
120	Seoul National University Hospital	Seoul		Korea, Republic of	03080
121	Division of Medical Oncology, Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
122	Asan Medical Center	Seoul		Korea, Republic of	05505
123	Ulsan University Hospital	Ulsan		Korea, Republic of	44033
124	Médicos Especialistas en Cancer S.C. / San Peregrino.	Aguascalientes		Mexico	20230
125	Instituto Nacional de Cancerologia	Distrito Federal		Mexico	14080
126	Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas	Distrito Federal		Mexico	14080
127	University Medical Center Groningen	Groningen		Netherlands	9713 GZ
128	Klinika Onkologii i Radioterapii Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80-214
129	Med-Polonia Sp. z o.o.	Poznan		Poland	60-693
130	Centrum Medyczne Dom Lekarski S.A.	Szczecin		Poland	70-784
131	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytut Badawczy	Warszawa		Poland	02-781
132	RBHI Kursk Regional Clinical Oncology Dispensary	Kislino, Ryshkovsky Rural Council	Kursk Region	Russian Federation	305 524
133	Budgetary Healthcare Institution Omsk Region "Clinical Oncological Dispensary"	Omsk	OMSK Region	Russian Federation	644013
134	LEC at SBIH "Saint-Petersburg Clinical Research Practical Center of specialized types of	Pesochniy Poselok	Saint-petersburg	Russian Federation	197758
135	Private Medical Institution "Euromedservice"	Pushkin	Saint-petersburg	Russian Federation	196603
136	RBHI Kursk Regional Clinical Oncology Dispensary	Kursk		Russian Federation	305 035
137	FSBI "N.N.Blokhin Medical Research Center of Oncology"	Moscow		Russian Federation	115478
138	National University Hospital	Singapore		Singapore	119074
139	Raffles Hospital	Singapore		Singapore	188770
140	Institut Catala d'Oncologia L'Hospitalet	L'Hospitalet de Llobregat	Barcelona	Spain	08908
141	Hospital Universitario Insular de Gran Canaria	Las Palmas de Gran Canaria	Canarias	Spain	35016
142	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda	Madrid	Spain	28222
143	Complejo Hospitalario De Navarra	Pamplona	Navarra	Spain	31008
144	Hospital Teresa Herrera C.H.U.A.C.	A Coruna		Spain	15006
145	Hospital De La Santa Creu I Sant Pau	Barcelona		Spain	08025
146	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
147	Hospital Clinic i Provincial de Barcelona	Barcelona		Spain	08036
148	Hospital De La Santa Creu I Sant Pau	Barcelona		Spain	08041
149	Institut Catala d'Oncologia Girona	Girona		Spain	17007
150	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
151	Hospital Clinico San Carlos	Madrid		Spain	28040
152	Hospital Universitario Fundacion Jimenez Diaz	Madrid		Spain	28040
153	Hospital Universitario La Fe	Valencia		Spain	46026
154	National Taiwan University Hospital	Taipei	Taiwan ROC	Taiwan	10002
155	Chang Gung Memorial Hospital - Kaohsiung Branch	Kaohsiung		Taiwan	83301
156	Chung Shan Medical University Hospital	Taichung		Taiwan	402
157	Taichung Veterans General Hospital	Taichung		Taiwan	40705
158	Taipei Veterans General Hospital	Taipei		Taiwan	112
159	Cukurova University Medical Faculty	Adana		Turkey	01330
160	Istanbul University Oncology Institute	Istanbul		Turkey	34093
161	Marmara Univ Pendik Training and Research Hospital	Istanbul		Turkey	34899
162	Ege University Medical Faculty	Izmir		Turkey	35100
163	The Ipswich Hospital NHS Trust	Ipswich	Suffolk	United Kingdom	IP4 5PD
164	Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital	Birmingham	WEST Midlands	United Kingdom	B9 5SS
165	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Oct 4, 2019
• Statistical Analysis Plan - May 26, 2020

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03052608
• Other Study ID Numbers: B7461006; 2016-003315-35
• First Posted: Feb 14, 2017
• Last Update Posted: May 31, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pfizer: ALK; anaplastic lymphoma kinase; Non-Small-Cell Lung cancer; NSCLC
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Crizotinib

Study Results

Participant Flow

Recruitment Details	This phase 3, randomized, open label study was conducted at 104 sites in 23 countries. A total of 296 participants were randomized, 149 to the lorlatinib arm and 147 to the crizotinib arm.
Pre-assignment Detail	Previously untreated Stage IIIB/IV participants with ALK-positive non-small cell lung cancer were randomized in this study.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Period Title: Treatment Phase
STARTED	149	147
COMPLETED	26	83
NOT COMPLETED	123	64
Period Title: Treatment Phase
STARTED	149	147
COMPLETED	0	0
NOT COMPLETED	149	147

Baseline Characteristics

Arm/Group Title	Lorlatinib	Crizotinib	Total
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Total of all reporting groups
Overall Participants	149	147	296
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.1 (13.12)	55.6 (13.52)	57.4 (13.41)
Sex: Female, Male (Count of Participants)
Female	84 56.4%	91 61.9%	175 59.1%
Male	65 43.6%	56 38.1%	121 40.9%
Race/Ethnicity, Customized (Count of Participants)
White	72 48.3%	72 49%	144 48.6%
Black or African American	0 0%	1 0.7%	1 0.3%
Asian	65 43.6%	65 44.2%	130 43.9%
Missing	12 8.1%	9 6.1%	21 7.1%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) Assessment
Description	PFS was defined as the time from randomization to the date of the first documentation of progressive disease as assessed by the independent radiologist or death due to any cause, whichever occurred first. PFS (in months) was calculated as (date of event or censoring-randomization+1)/30.4375. Progressive disease is defined per RECIST version 1.1, as at least a 20% increase (including an absolute increase of at least 5 mm) 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 1 or more new lesions.
Time Frame	From time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

The full analysis (FA) population included all participants who were randomized, and participants were classified according to the treatment assigned at randomization.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	147
Median (95% Confidence Interval) [Months]	NA	9.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	The study was designed to test the null hypothesis H0: λ ≥1 versus the alternative hypothesis HA: λ <1, where λ is the hazard ratio (HR; Lorlatinib/Crizotinib). Evaluation of 177 PFS events was required to have at least 90% power to detect a HR of 0.611 using a one-sided stratified log-rank test at a significance level of 0.025 (one-sided), and a 2-look group-sequential design with a Lan-DeMets (O'Brien-Fleming) α-spending function to determine the efficacy boundaries.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The study was to be considered positive if the 1-sided log-rank test for PFS, stratified for baseline stratification factors (ethnicity and brain metastases) was significant at the 0.0081 level at the cutoff date of this report.
	Method	one-sided stratified log-rank
	Comments	Stratified by the presence of brain metastases (Yes/No) and ethnic origin (Asian/Non-Asian) at randomization.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; 0.191 to 0.413
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox Proportional Hazards model stratified by the presence of brain metastases and ethnic origin at randomization. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Lorlatinib.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to the date of death due to any cause. OS (in months) was calculated as (date of death or censoring - start date +1)/30.4375. Participants last known to be alive were censored at date of last contact.
Time Frame	From time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

The FA population included all participants who were randomized, and participants were classified according to the treatment assigned at randomization.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	147
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.414 to 1.249
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox Proportional Hazards model stratified by the presence of brain metastases and ethnic origin at randomization. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Lorlatinib.

3. Secondary Outcome

Title	Progression-Free Survival (PFS) Based on Investigator's Assessment
Description	PFS was defined as the time from randomization to the date of the first documentation of progressive disease as assessed by investigator or death due to any cause, whichever occurred first. PFS (in months) was calculated as (date of event or censoring-randomization+1)/30.4375. Progressive disease is defined per RECIST version 1.1, as at least a 20% increase (including an absolute increase of at least 5 mm) 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 1 or more new lesions.
Time Frame	From time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

The FA population included all participants who were randomized, and participants were classified according to the treatment assigned at randomization.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	147
Median (95% Confidence Interval) [Months]	NA	9.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	one-sided stratified log-rank
	Comments	Stratified by the presence of brain metastases (Yes/No) and ethnic origin (Asian/Non-Asian) at randomization.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; 0.144 to 0.307
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox Proportional Hazards model stratified by the presence of brain metastases and ethnic origin at randomization. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Lorlatinib.

4. Secondary Outcome

Title	Objective Response Rate (ORR) - Percentage of Participants With Objective Response (OR) Based on BICR Assessment
Description	ORR was the percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1 recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least 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 time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

The FA population included all participants who were randomized, and participants were classified according to the treatment assigned at randomization.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	147
Number (95% Confidence Interval) [Percentage of participants]	75.8 50.9%	57.8 39.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by the presence of brain metastases (Yes/No) and ethnic origin (Asian/Non-Asian) at randomization.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.254
	Confidence Interval	(2-Sided) 95%; 1.353 to 3.891
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio was estimated using Mantel-Haenszel method. An odds ratio larger than 1 indicates better outcome for Lorlatinib relative to Crizotinib. Exact CI was calculated.

5. Secondary Outcome

Title	Objective Response Rate (ORR) - Percentage of Participants With Objective Response (OR) Based on Investigator's Assessment
Description	ORR was the percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1 recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least 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 time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

The FA population included all participants who were randomized, and participants were classified according to the treatment assigned at randomization.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	147
Number (95% Confidence Interval) [Percentage of participants]	80.5 54%	61.9 42.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by the presence of brain metastases (Yes/No) and ethnic origin (Asian/Non-Asian) at randomization.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.499
	Confidence Interval	(2-Sided) 95%; 1.484 to 4.594
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio was estimated using Mantel-Haenszel method. An odds ratio larger than 1 indicates better outcome for Lorlatinib relative to Crizotinib. Exact CI was calculated.

6. Secondary Outcome

Title	Intracranial Objective Response Rate (IC-ORR) - Percentage of Participants With Intracranial Objective Response (IC-OR) Based on BICR Assessment
Description	IC-ORR was the percentage of participant with intracranial objective response of complete response (CR) or partial response (PR) based on intracranial disease in the subset of participants with at least 1 intracranial lesion per RECIST version 1.1 (modified) recorded from randomization until disease progression or start of new anti-cancer therapy. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least 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 time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

The subset of the FA population with at least 1 baseline intracranial lesion (based on BICR intracranial assessment).

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	38	40
Number (95% Confidence Interval) [Percentage of participants]	65.8 44.2%	20.0 13.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by the presence of brain metastases (Yes/No) and ethnic origin (Asian/Non-Asian) at randomization.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	8.407
	Confidence Interval	(2-Sided) 95%; 2.586 to 27.233
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio was estimated using Mantel-Haenszel method. An odds ratio larger than 1 indicates better outcome for Lorlatinib relative to Crizotinib. Exact CI was calculated.

7. Secondary Outcome

Title	Intracranial Time to Progression (IC-TTP) Based on BICR Assessment
Description	IC-TTP based on BICR assessment was defined as the time from date of randomization to the date of the first documentation of progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases.
Time Frame	From time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

The FA population included all participants who were randomized, and participants were classified according to the treatment assigned at randomization.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	147
Median (95% Confidence Interval) [Months]	NA	16.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	one-sided stratified log-rank
	Comments	Stratified by the presence of brain metastases (Yes/No) and ethnic origin (Asian/Non-Asian) at randomization.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; 0.026 to 0.170
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox Proportional Hazards model stratified by the presence of brain metastases and ethnic origin at randomization. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Lorlatinib.

8. Secondary Outcome

Title	Duration of Response (DR) Based on BICR Assessment
Description	DR was defined, for participants with a confirmed objective response (OR) of complete response (CR) or partial response (PR) per RECIST version 1.1, as the time from the first documentation of OR to the first documentation of progressive disease (PD) or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) 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 1 or more new lesions.
Time Frame	From time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

Participants with a confirmed objective response (complete response or partial response) per RECIST version 1.1 in the FA population.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	113	85
Median (95% Confidence Interval) [Months]	NA	11.0

9. Secondary Outcome

Title	Intracranial Duration of Response (IC-DR) Based on BICR Assessment
Description	IC-DR was defined, for participants with a confirmed intracranial objective response (OR) of complete response (CR) or partial response (PR) per RECIST version 1.1, as the time from the first documentation of intracranial OR to the first documentation of intracranial progressive disease (PD) or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). PR was defined as at least a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) 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 1 or more new lesions.
Time Frame	From time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

Participants with brain metastases at baseline and confirmed intracranial complete response or partial response in the FA population.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	25	8
Median (95% Confidence Interval) [Months]	NA	9.4

10. Secondary Outcome

Title	Time to Tumor Response (TTR) Based on BICR Assessment
Description	TTR based on BICR assessment was defined, for participants with a confirmed objective response, as the time from the date of randomization to the first documentation of objective response (complete response or partial response) which was subsequently confirmed. Complete response was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). Partial response was defined as at least 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 time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

Participants with confirmed complete response or partial response in the FA population.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	113	85
Median (Inter-Quartile Range) [Months]	1.8	1.8

11. Secondary Outcome

Title	Intracranial Time to Tumor Response (IC-TTR) Based on BICR Assessment
Description	IC-TTR was defined, for participants with a confirmed intracranial objective response, as the time from the date of randomization to the first documentation of intracranial objective response (complete response or partial response) which was subsequently confirmed. Complete response was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). Partial response was defined as at least 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 time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

Participants with brain metastases at baseline and confirmed intracranial complete response or partial response in the FA population.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	25	8
Median (Inter-Quartile Range) [Months]	1.9	1.8

12. Secondary Outcome

Title	PFS2 Based on Investigator's Assessment
Description	PFS2 was defined as the time from randomization to the date of progression of disease on first subsequent systemic anti-cancer therapy, or death from any cause, whichever occurred first
Time Frame	From time of Study Start up to 45 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related)
Description	An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, life-threatening experience, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. All AEs in the table below were treatment-emergent AEs. Grade 3 and 4 AEs in the table below indicated severe AE and life-threatening consequences respectively; Grade 5 indicated death due to AE. Treatment-related AEs were determined by investigators.
Time Frame	From time of Study Start up to 33 months

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of study drug. Participants were classified according to the treatment assigned at randomization unless the incorrect treatment(s) were received throughout the dosing period, in which case participants were classified according to the first study treatment received.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	142
AEs (all-causality)	149 100%	140 95.2%
AEs (treatment-related)	144 96.6%	133 90.5%
SAEs (all-causality)	51 34.2%	39 26.5%
SAEs (treatment-related)	12 8.1%	7 4.8%
Maximum Grade 3 or 4 AEs (all-causality)	108 72.5%	79 53.7%
Maximum Grade 3 or 4 AEs (treatment-related)	83 55.7%	52 35.4%
Maximum Grade 5 AEs (all-causality)	7 4.7%	7 4.8%
Maximum Grade 5 AEs (treatment-related)	2 1.3%	0 0%
AEs causing study discontinuation (all-causality)	7 4.7%	8 5.4%
AEs causing study discontinuation (treatment-related)	2 1.3%	0 0%
AEs causing study treatment discontinuation (all-causality)	10 6.7%	13 8.8%
AEs causing study treatment discontinuation (treatment-related)	7 4.7%	7 4.8%
AEs causing dose reduction or temporary discontinuation (all-causality)	79 53%	71 48.3%
AEs causing dose reduction or temporary discontinuation (treatment-related)	60 40.3%	54 36.7%

14. Secondary Outcome

Title	Number of Participants With Changes in Hematology Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4
Description	Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3.
Time Frame	From Baseline up to 33 months

Outcome Measure Data

Analysis Population Description

Participants in the safety analysis population who had at least one on-study assessment for the parameter of interest.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	141
Anemia (Postbaseline Maximum Grade 3)	3 2%	4 2.7%
Anemia (Postbaseline Maximum Grade 4)	NA NaN	NA NaN
Hemoglobin increased (Postbaseline Maximum Grade 3)	0 0%	0 0%
Hemoglobin increased (Postbaseline Maximum Grade 4)	NA NaN	NA NaN
Lymphocyte count decreased (Postbaseline Maximum Grade 3)	2 1.3%	7 4.8%
Lymphocyte count decreased (Postbaseline Maximum Grade 4)	2 1.3%	1 0.7%
Lymphocyte count increased (Postbaseline Maximum Grade 3)	0 0%	0 0%
Lymphocyte count increased (Postbaseline Maximum Grade 4)	NA NaN	NA NaN
Neutrophil count decreased (Postbaseline Maximum Grade 3)	1 0.7%	19 12.9%
Neutrophil count decreased (Postbaseline Maximum Grade 4)	1 0.7%	4 2.7%
Platelet count decreased (Postbaseline Maximum Grade 3)	0 0%	1 0.7%
Platelet count decreased (Postbaseline Maximum Grade 4)	0 0%	0 0%
White blood cell decreased (Postbaseline Maximum Grade 3)	0 0%	5 3.4%
White blood cell decreased (Postbaseline Maximum Grade 4)	0 0%	0 0%

15. Secondary Outcome

Title	Number of Participants With Changes in Chemistry Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4
Description	Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3.
Time Frame	From Baseline up to 33 months

Outcome Measure Data

Analysis Population Description

Participants in the safety analysis population who had at least one on-study assessment for the parameter of interest.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	141
Alanine aminotransferase increased (Postbaseline Maximum Grade 3)	4 2.7%	5 3.4%
Alanine aminotransferase increased (Postbaseline Maximum Grade 4)	0 0%	1 0.7%
Alkaline phosphate increased (Postbaseline Maximum Grade 3)	0 0%	1 0.7%
Alkaline phosphate increased (Postbaseline Maximum Grade 4)	0 0%	0 0%
Aspartate aminotransferase increased (Postbaseline Maximum Grade 3)	3 2%	4 2.7%
Aspartate aminotransferase increased (Postbaseline Maximum Grade 4)	0 0%	1 0.7%
Blood bilirubin increased (Postbaseline Maximum Grade 3)	0 0%	0 0%
Blood bilirubin increased (Postbaseline Maximum Grade 4)	0 0%	0 0%
Creatine kinase increased (Postbaseline Maximum Grade 3)	3 2%	5 3.4%
Creatine kinase increased (Postbaseline Maximum Grade 4)	0 0%	2 1.4%
Creatinine increased (Postbaseline Maximum Grade 3)	1 0.7%	3 2%
Creatinine increased (Postbaseline Maximum Grade 4)	0 0%	0 0%
Gamma glutamyl transferase increased (Postbaseline Maximum Grade 3)	9 6%	8 5.4%
Gamma glutamyl transferase increased (Postbaseline Maximum Grade 4)	0 0%	1 0.7%
Hypercalcemia (Postbaseline Maximum Grade 3)	0 0%	0 0%
Hypercalcemia (Postbaseline Maximum Grade 4)	0 0%	0 0%
Hyperglycemia (Postbaseline Maximum Grade 3)	9 6%	3 2%
Hyperglycemia (Postbaseline Maximum Grade 4)	1 0.7%	0 0%
Hyperkalemia (Postbaseline Maximum Grade 3)	2 1.3%	3 2%
Hyperkalemia (Postbaseline Maximum Grade 4)	0 0%	0 0%
Hypermagnesemia (Postbaseline Maximum Grade 3)	2 1.3%	1 0.7%
Hypermagnesemia (Postbaseline Maximum Grade 4)	0 0%	0 0%
Hypernatremia (Postbaseline Maximum Grade 3)	0 0%	0 0%
Hypernatremia (Postbaseline Maximum Grade 4)	0 0%	0 0%
Hypoalbuminemia (Postbaseline Maximum Grade 3)	1 0.7%	9 6.1%
Hypoalbuminemia (Postbaseline Maximum Grade 4)	NA NaN	NA NaN
Hypocalcemia (Postbaseline Maximum Grade 3)	1 0.7%	0 0%
Hypocalcemia (Postbaseline Maximum Grade 4)	0 0%	0 0%
Hypoglycemia (Postbaseline Maximum Grade 3)	0 0%	0 0%
Hypoglycemia (Postbaseline Maximum Grade 4)	0 0%	1 0.7%
Hypokalemia (Postbaseline Maximum Grade 3)	0 0%	3 2%
Hypokalemia (Postbaseline Maximum Grade 4)	0 0%	0 0%
Hypomagnesemia (Postbaseline Maximum Grade 3)	0 0%	0 0%
Hypomagnesemia (Postbaseline Maximum Grade 4)	0 0%	0 0%
Hyponatremia (Postbaseline Maximum Grade 3)	5 3.4%	10 6.8%
Hyponatremia (Postbaseline Maximum Grade 4)	0 0%	1 0.7%
Hypophosphatemia (Postbaseline Maximum Grade 3)	3 2%	4 2.7%
Hypophosphatemia (Postbaseline Maximum Grade 4)	0 0%	0 0%
Lipase increased (Postbaseline Maximum Grade 3)	8 5.4%	6 4.1%
Lipase increased (Postbaseline Maximum Grade 4)	3 2%	1 0.7%
Serum amylase increased (Postbaseline Maximum Grade 3)	1 0.7%	2 1.4%
Serum amylase increased (Postbaseline Maximum Grade 4)	0 0%	0 0%

16. Secondary Outcome

Title	Number of Participants With Changes in Lipid Laboratory Parameters From Baseline Maximum NCI-CTCAE Grade Lower Than 3 to Postbaseline Maximum Grade 3 or Grade 4
Description	Laboratory test results were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grades 1 and 2 indicate mild and moderate AE, respectively; Grades 3 and 4 indicate severe AE and life-threatening consequences respectively; Grade 5 indicates death due to AE. Participants with laboratory test abnormalities were summarized according to the worst grade for each laboratory test result. All participants meeting the postbaseline grade criteria in the table below had baseline maximum grades lower than 3.
Time Frame	From Baseline up to 33 months

Outcome Measure Data

Analysis Population Description

Participants in the safety analysis population who had at least one on-study assessment for the parameter of interest.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	141
Cholesterol high (Postbaseline Maximum Grade 3)	26 17.4%	0 0%
Cholesterol high (Postbaseline Maximum Grade 4)	3 2%	0 0%
Hypertriglyceridemia (Postbaseline Maximum Grade 3)	20 13.4%	0 0%
Hypertriglyceridemia (Postbaseline Maximum Grade 4)	13 8.7%	0 0%

17. Secondary Outcome

Title	Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria
Description	Vital signs data included pulse, systolic blood pressure, and diastolic blood pressure. Measurements were only provided once per timepoint. If multiple assessments were provided per timepoint, the maximum value were used for reporting. The pre-defined criteria of vital sign and body weight data were as follows: maximum pulse rate >120 beats per minute (bpm); minimum pulse rate <50 bpm; maximum increase in pulse rate ≥30 bpm; maximum decrease in pulse rate ≥30 bpm; increase in systolic blood Pressure ≥40 mmHg; decrease in systolic blood pressure ≥40 mmHg; decrease in systolic blood pressure ≥60 mmHg; increase in diastolic blood pressure ≥20 mmHg; decrease in diastolic blood pressure ≥20 mmHg; decrease in diastolic blood pressure ≥40 mmHg; increase in body weight ≥10%; increase in body weight ≥20%; decrease in body weight ≥10%.
Time Frame	From Baseline up to 33 months

Outcome Measure Data

Analysis Population Description

"Number of Participants Analyzed" included all participants in the safety analysis population. "Number Analyzed" included all participants in the safety analysis population with evaluable data against the pre-defined criteria.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	142
Sitting pulse rate: pulse >120 bpm	7 4.7%	1 0.7%
Sitting pulse rate: pulse <50 bpm	4 2.7%	22 15%
Sitting pulse rate: change ≥30 bpm increase	24 16.1%	3 2%
Sitting pulse rate: change ≥30 bpm decrease	17 11.4%	47 32%
Sitting systolic blood pressure: change ≥40 mmHg increase	22 14.8%	3 2%
Sitting systolic blood pressure: change ≥40 mmHg decrease	6 4%	14 9.5%
Sitting systolic blood pressure: change ≥60 mmHg decrease	0 0%	1 0.7%
Sitting diastolic blood pressure: change ≥20 mmHg increase	41 27.5%	18 12.2%
Sitting diastolic blood pressure: change ≥20 mmHg decrease	26 17.4%	52 35.4%
Sitting diastolic blood pressure: change ≥40 mmHg decrease	0 0%	1 0.7%
Body weight (kg): percent change from baseline ≥10% increase	99 66.4%	39 26.5%
Body weight (kg): percent change from baseline ≥20% increase	35 23.5%	3 2%
Body weight (kg): percent change from baseline ≥10% decrease	6 4%	12 8.2%

18. Secondary Outcome

Title	Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria
Description	Baseline was defined as the last assessment performed on or prior to date of the first dose of study treatment. Triplicate ECGs were collected in the study and the average of the replicate assessments were used for summary analysis. The pre-defined criteria of ECG data were as follows: change from baseline in QTcF ≥60 msec, ≥30 msec but <60 msec, <30 msec; change from baseline in QTcB ≥60 msec, ≥30 msec but <60 msec, <30 msec; PR change ≥50% if absolute baseline value was <200 msec; PR change ≥25% if absolute baseline value was ≥200 msec; QRS change ≥50% if absolute baseline value was <100 msec; QRS change ≥25% if absolute baseline value was ≥100 msec.
Time Frame	From Baseline up to 33 months

Outcome Measure Data

Analysis Population Description

"Number of Participants Analyzed" included all participants in the safety analysis population. "Number Analyzed" included all participants in the safety analysis population with evaluable data against the pre-defined criteria.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	142
Change of QTcF ≥60 msec	5 3.4%	16 10.9%
30 msec ≤ Change of QTcF <60 msec	49 32.9%	41 27.9%
Change of QTcF <30 msec	92 61.7%	81 55.1%
Change of QTcB ≥60 msec	10 6.7%	15 10.2%
30 msec ≤ Change of QTcB <60 msec	49 32.9%	26 17.7%
Change of QTcB <30 msec	90 60.4%	100 68%
PR change ≥50% if absolute baseline value was <200 msec	8 5.4%	4 2.7%
PR change ≥25% if absolute baseline value was ≥200 msec	0 0%	0 0%
QRS change ≥50% if absolute baseline value was <100 msec	2 1.3%	3 2%
QRS change ≥25% if absolute baseline value was ≥100 msec	2 1.3%	0 0%

19. Secondary Outcome

Title	Number of Participants With Maximum Decrease From Baseline Greater Than or Equal to 20 Points in Left Ventricular Ejection Fraction (LVEF) Percentage
Description	In this outcome measure, baseline was defined as the last assessment on or prior to the date of the first dose of study treatment. Decrease from baseline was an absolute difference between baseline and observed value.
Time Frame	From Baseline up to 33 months

Outcome Measure Data

Analysis Population Description

All participants in the safety analysis population who had at least one on-study assessment for the parameter of interest.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	143	133
Count of Participants [Participants]	2 1.3%	1 0.7%

20. Secondary Outcome

Title	Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time
Description	BDI-II (Mood Assessment) is a 21 item self-reported scale, with each item rated by participants on a 4-point scale (ranging from 0-3). The scale includes items capturing mood, (loss of pleasure, sadness, and irritability), suicidal ideation, and cognitive signs (punitive thoughts, self-criticism, self-dislike pessimism, poor concentration) as well as somatic signs (appetite, sleep, fatigue, libido). Scores were obtained by adding up the total points from the series of answers. The total score ranged from 0 to 63, with higher total scores indicating more severe depressive symptoms. The standardized cutoffs are as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression.
Time Frame	Baseline, Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C8D1, C10D1, C12D1, C14D1, C16D1, C18D1, C20D1, C22D1, C24D1, C26D1, C28D1, C30D1, C32D1, C34D1, C36D1, C38D1 and End of Treatment

Outcome Measure Data

Analysis Population Description

"Number of Participants Analyzed" included all participants in the safety analysis population within each treatment group. "Number Analyzed" included all participants with at least a baseline and postbaseline assessment at the visit.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	147
Cycle 2 Day 1	-1.8 (5.52)	-1.2 (5.62)
Cycle 3 Day 1	-2.5 (5.85)	-2.7 (5.78)
Cycle 4 Day 1	-2.9 (5.73)	-3.6 (6.60)
Cycle 5 Day 1	-2.5 (6.28)	-3.0 (6.24)
Cycle 6 Day 1	-2.6 (6.61)	-2.9 (6.65)
Cycle 8 Day 1	-3.2 (6.18)	-1.9 (6.56)
Cycle 10 Day 1	-3.0 (6.30)	-2.6 (5.98)
Cycle 12 Day 1	-3.6 (6.05)	-2.1 (6.23)
Cycle 14 Day 1	-3.3 (6.82)	-2.5 (5.57)
Cycle 16 Day 1	-3.3 (6.87)	-2.3 (5.77)
Cycle 18 Day 1	-3.7 (7.26)	-2.6 (4.30)
Cycle 20 Day 1	-3.3 (6.24)	-2.4 (4.62)
Cycle 22 Day 1	-3.2 (6.95)	-2.5 (4.82)
Cycle 24 Day 1	-3.1 (5.97)	2.3 (9.31)
Cycle 26 Day 1	-3.2 (6.87)	-0.8 (3.81)
Cycle 28 Day 1	-3.0 (6.53)	0.2 (7.65)
Cycle 30 Day 1	-4.8 (8.00)	1.3 (3.20)
Cycle 32 Day 1	-5.0 (14.14)	7.5 (9.19)
Cycle 34 Day 1	-2.3 (12.42)	0.0
Cycle 36 Day 1	0.0
End of Treatment	0.8 (4.49)	-0.2 (7.45)

21. Secondary Outcome

Title	Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time
Description	Suicidal ideation and behaviors were assessed by the Columbia Suicide Severity Rating Scale (C-SSRS). The C-SSRS is a unique, simple and short method of assessing both behavior and ideation that tracks all suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation, and deterrents), all of which are significantly predictive of completed suicide.
Time Frame	Baseline, Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C8D1, C10D1, C12D1, C14D1, C16D1, C18D1, C20D1, C22D1, C24D1, C26D1, C28D1, C30D1, C32D1, C34D1, C36D1, C38D1 and End of Treatment

Outcome Measure Data

Analysis Population Description

"Number of Participants Analyzed" included all participants in the safety analysis population within each treatment group. "Number Analyzed" included all participants with assessment scores at each specified time point.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	149	142
Baseline	3 2%	7 4.8%
Cycle 2 Day 1	0 0%	5 3.4%
Cycle 3 Day 1	1 0.7%	1 0.7%
Cycle 4 Day 1	0 0%	1 0.7%
Cycle 5 Day 1	0 0%	1 0.7%
Cycle 6 Day 1	0 0%	2 1.4%
Cycle 8 Day 1	0 0%	2 1.4%
Cycle 10 Day 1	0 0%	1 0.7%
Cycle 12 Day 1	0 0%	0 0%
Cycle 14 Day 1	0 0%	0 0%
Cycle 16 Day 1	0 0%	0 0%
Cycle 18 Day 1	0 0%	0 0%
Cycle 20 Day 1	0 0%	0 0%
Cycle 22 Day 1	0 0%	0 0%
Cycle 24 Day 1	0 0%	1 0.7%
Cycle 26 Day 1	1 0.7%	0 0%
Cycle 28 Day 1	0 0%	0 0%
Cycle 30 Day 1	0 0%	0 0%
Cycle 32 Day 1	0 0%	0 0%
Cycle 34 Day 1	0 0%	0 0%
Cycle 36 Day 1	0 0%	0 0%
Cycle 38 Day 1	0 0%
End of Treatment	0 0%	0 0%

22. Secondary Outcome

Title	Change From Baseline in Global Quality of Life (QOL), Functional Scales and Symptoms Scales as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) During Overall Treatment
Description	The EORTC QLQ C30 consists of 30 questions and includes 5 functional scales (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale; 3 symptom scales (fatigue, pain, nausea and vomiting); and 6 single items that assess additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and financial impact. All scales and single item measures range in score from 0 to 100. Higher scores on the functional scales represent higher levels of functioning. Higher scores on the global health status/quality of life scale represent higher health status/quality of life. Higher scores on symptom scales/items represent a greater presence of symptoms.
Time Frame	From Baseline up to Cycle 38 Day 1

Outcome Measure Data

Analysis Population Description

Participants from the FA population who completed a baseline (last patient-reported outcome (PRO) assessment prior to the first dose of study treatment) and at least 1 post-baseline PRO assessment.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	148	140
Global QOL	8.60	3.95
Physical Functioning	4.84	2.82
Role Functioning	6.86	4.78
Emotional Functioning	8.77	6.20
Cognitive Functioning	-4.20	-1.02
Social Functioning	7.00	4.72
Fatigue	-9.93	-4.26
Nausea and Vomiting	-4.35	3.51
Pain	-4.60	-5.76
Dyspnoea	-7.02	-8.75
Insomnia	-17.34	-9.39
Appetite Loss	-13.15	-3.95
Constipation	-2.40	2.53
Diarrhea	-0.92	11.12
Financial Difficulties	-6.79	-5.74

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Global QOL. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0096
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.65
	Confidence Interval	(2-Sided) 95%; 1.14 to 8.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Physical Functioning. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1897
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 95%; -1.01 to 5.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Role Functioning. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2999
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.09
	Confidence Interval	(2-Sided) 95%; -1.87 to 6.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Emotional Functioning. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0553
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.58
	Confidence Interval	(2-Sided) 95%; -0.06 to 5.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Cognitive Functioning. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0588
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.18
	Confidence Interval	(2-Sided) 95%; -6.47 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Social Functioning. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2118
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.27
	Confidence Interval	(2-Sided) 95%; -1.30 to 5.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Fatigue. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0032
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.67
	Confidence Interval	(2-Sided) 95%; -9.42 to -1.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Nausea and Vomiting. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.86
	Confidence Interval	(2-Sided) 95%; -9.86 to -5.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Pain. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5310
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; -2.49 to 4.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Dyspnoea. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3602
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.72
	Confidence Interval	(2-Sided) 95%; -1.98 to 5.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Insomnia. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.95
	Confidence Interval	(2-Sided) 95%; -11.25 to -4.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Appetite Loss. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.21
	Confidence Interval	(2-Sided) 95%; -11.80 to -6.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Constipation. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0198
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.93
	Confidence Interval	(2-Sided) 95%; -9.07 to -0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Diarrhea. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-12.03
	Confidence Interval	(2-Sided) 95%; -15.49 to -8.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-C30 Financial Difficulties. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5947
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.04
	Confidence Interval	(2-Sided) 95%; -4.90 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment
Description	The EORTC QLQ LC13 consists of 13 questions and includes 1 multi-item scale and 9 single items assessing symptoms (dyspnea, cough, haemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication use. The scale scores rang from 0 to 100, with higher scores indicating higher ("worse") level of symptoms.
Time Frame	From Baseline up to Cycle 38 Day 1

Outcome Measure Data

Analysis Population Description

Participants from the FA population who completed a baseline (last patient-reported outcome (PRO) assessment prior to the first dose of study treatment) and at least 1 post-baseline PRO assessment.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	146	139
Dyspnoea	-4.36	-4.90
Coughing	-21.21	-16.66
Haemoptysis	-2.53	-2.65
Sore Mouth	0.56	-0.60
Dysphagia	-1.35	0.16
Peripheral Neuropathy	11.56	6.20
Alopecia	1.61	1.81
Pain in Chest	-9.54	-9.01
Pain in Arm or Shoulder	-6.93	-7.38
Pain in Other Parts	-2.31	-5.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Dyspnoea. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7254
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; -2.51 to 3.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Coughing. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0115
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.55
	Confidence Interval	(2-Sided) 95%; -8.06 to -1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Haemoptysis. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7824
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.75 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Sore Mouth. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2988
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; -1.04 to 3.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Dysphagia. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1916
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.51
	Confidence Interval	(2-Sided) 95%; -3.79 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Peripheral Neuropathy. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0279
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.37
	Confidence Interval	(2-Sided) 95%; 0.59 to 10.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Alopecia. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9162
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -3.89 to 3.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Pain in Chest. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6698
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 95%; -2.96 to 1.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Pain in Arm or Shoulder. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8035
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; -3.13 to 4.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	This is the analysis for QLQ-LC13 Pain in Other Parts. Estimated change from baseline was based on random intercept random slope mixed-effects model with an intercept term, treatment, time (as a continuous variable), treatment-by-time, baseline and randomization stratification factors as covariates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1143
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.36
	Confidence Interval	(2-Sided) 95%; -0.82 to 7.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time
Description	The EuroQol EQ-5D-5L is a participant-completed questionnaire designed to assess health status. There are 2 components to the EuroQol EQ-5D-5L: a descriptive system in which individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a VAS. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) and higher scores indicate better health state.
Time Frame	Baseline, Day 1 of all cycles from Cycle 2 to Cycle 38, and End of Treatment

Outcome Measure Data

Analysis Population Description

"Number of Participants Analyzed" included all participants in the EQ-5D-5L PRO analysis population within each treatment group. "Number Analyzed" included all participants with at least a baseline and postbaseline assessment at the visit.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	147	138
Cycle 2 Day 1	6.0	3.1
Cycle 3 Day 1	6.0	5.3
Cycle 4 Day 1	7.1	5.6
Cycle 5 Day 1	4.3	5.1
Cycle 6 Day 1	6.5	4.5
Cycle 7 Day 1	5.5	4.0
Cycle 8 Day 1	6.7	4.2
Cycle 9 Day 1	6.4	3.9
Cycle 10 Day 1	7.2	3.9
Cycle 11 Day 1	8.1	2.0
Cycle 12 Day 1	7.6	4.8
Cycle 13 Day 1	7.5	5.8
Cycle 14 Day 1	6.7	2.3
Cycle 15 Day 1	6.1	1.5
Cycle 16 Day 1	6.9	2.4
Cycle 17 Day 1	8.3	1.1
Cycle 18 Day 1	8.7	1.3
Cycle 19 Day 1	6.8	2.8
Cycle 20 Day 1	7.9	3.4
Cycle 21 Day 1	7.2	3.3
Cycle 22 Day 1	4.5	1.9
Cycle 23 Day 1	5.2	-0.6
Cycle 24 Day 1	4.9	-3.0
Cycle 25 Day 1	4.0	1.4
Cycle 26 Day 1	7.9	2.0
Cycle 27 Day 1	4.6	3.0
Cycle 28 Day 1	6.0	2.7
Cycle 29Day 1	7.4	8.2
Cycle 30 Day 1	9.1	2.8
Cycle 31 Day 1	7.8	0.0
Cycle 32 Day 1	7.9	2.5
Cycle 33 Day 1	4.4	-2.5
Cycle 34 Day 1	-0.5	20.0
Cycle 35 Day 1	0.0	20.0
Cycle 36 Day 1	-4.5	15.0
Cycle 37 Day 1	-17.5
Cycle 38 Day 1	25.0
End of Treatment	-3.7	-1.3

25. Secondary Outcome

Title	Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time
Description	The EuroQol EQ-5D-5L is a participant-completed questionnaire designed to assess health status. There are 2 components to the EuroQol EQ-5D-5L: a descriptive system in which individuals rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a VAS in which participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable). EQ-5D summary index is obtained with a formula that weights each level of the 5 dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health).
Time Frame	Baseline, Day 1 of all cycles from Cycle 2 to Cycle 38, and End of Treatment

Outcome Measure Data

Analysis Population Description

"Number of Participants Analyzed" included all participants in the PRO analysis population within each treatment group. "Number Analyzed" included all participants with at least a baseline and postbaseline assessment at the visit.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	148	140
Cycle 2 Day 1	0.078	0.064
Cycle 3 Day 1	0.071	0.101
Cycle 4 Day 1	0.089	0.098
Cycle 5 Day 1	0.047	0.100
Cycle 6 Day 1	0.077	0.070
Cycle 7 Day 1	0.062	0.046
Cycle 8 Day 1	0.074	0.061
Cycle 9 Day 1	0.060	0.050
Cycle 10 Day 1	0.074	0.050
Cycle 11 Day 1	0.083	0.057
Cycle 12 Day 1	0.080	0.049
Cycle 13 Day 1	0.081	0.055
Cycle 14 Day 1	0.091	0.021
Cycle 15 Day 1	0.077	0.036
Cycle 16 Day 1	0.091	0.051
Cycle 17 Day 1	0.098	-0.016
Cycle 18 Day 1	0.103	0.021
Cycle 19 Day 1	0.100	0.027
Cycle 20 Day 1	0.103	0.025
Cycle 21 Day 1	0.068	0.040
Cycle 22 Day 1	0.079	0.052
Cycle 23 Day 1	0.060	0.006
Cycle 24 Day 1	0.082	-0.053
Cycle 25 Day 1	0.047	0.045
Cycle 26 Day 1	0.065	0.039
Cycle 27 Day 1	0.042	0.021
Cycle 28 Day 1	0.024	-0.040
Cycle 29 Day 1	0.046	0.041
Cycle 30 Day 1	0.099	-0.028
Cycle 31 Day 1	0.086	-0.024
Cycle 32 Day 1	0.058	-0.139
Cycle 33 Day 1	0.058	-0.024
Cycle 34 Day 1	0.062	0.042
Cycle 35 Day 1	0.129	0.042
Cycle 36 Day 1	-0.027	0.042
Cycle 37 Day 1	0.056
Cycle 38 Day 1	0.232
End of Treatment	-0.033	0.001

26. Secondary Outcome

Title	Time to Deterioration (TTD) in Participant Reported Pain in Chest, Dyspnea, or Cough From QLQ-LC13
Description	The EORTC QLQ LC13 consists of 13 questions and includes 1 multi-item scale and 9 single items assessing symptoms (dyspnea, cough, haemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication use. The scale scores rang from 0 to 100, with higher scores indicating higher ("worse") level of symptoms. TTD in pain in chest, dyspnea, or cough was defined as the time from randomization to the first time the participant's score showed a 10 point or greater increase after baseline in any of the 3 symptoms. TTD in months was calculated as (date of deterioration or censoring - randomization date +1)/30.4375.
Time Frame	From Baseline up to 33 months

Outcome Measure Data

Analysis Population Description

Participants in the EORTC QLQ-LC13 PRO analysis population with change from baseline scores within each treatment group and subscale.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	146	139
Median (95% Confidence Interval) [Months]	3.3	3.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7293
	Comments
	Method	one-sided stratified log-rank
	Comments	Stratified by the presence of brain metastases (Yes/No) and ethnic origin (Asian/Non-Asian) at randomization.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.822 to 1.444
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox Proportional Hazards model stratified by the presence of brain metastases and ethnic origin at randomization. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Lorlatinib.

27. Secondary Outcome

Title	Number of Participant With ALK Domain Mutation in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1
Description	The analysis of anaplastic lymphoma kinase (ALK) domain mutation in plasma CNA was performed by next-generation sequencing (NGS) and the number of participants with one or more ALK mutations at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 is presented here.
Time Frame	at Screening, Cycle 2 Day 1 and Cycle 7 Day 1

Outcome Measure Data

Analysis Population Description

"Number of Participants Analyzed" included all participants in the plasma CNA analysis population within each treatment group at screening. "Number Analyzed" included all participants in the plasma CNA analysis population within each treatment group at the specified visit.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	130	125
≥1 ALK Mutation Detected	5 3.4%	6 4.1%
No ALK Mutation Detected	88 59.1%	91 61.9%
No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	32 21.5%	25 17%
Other (Sample failed analysis, uninformative, or not analyzed.)	5 3.4%	3 2%
≥1 ALK Mutation Detected	2 1.3%	3 2%
No ALK Mutation Detected	66 44.3%	55 37.4%
No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	53 35.6%	58 39.5%
Other (Sample failed analysis, uninformative, or not analyzed.)	4 2.7%	2 1.4%
≥1 ALK Mutation Detected	3 2%	5 3.4%
No ALK Mutation Detected	45 30.2%	42 28.6%
No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	52 34.9%	35 23.8%
Other (Sample failed analysis, uninformative, or not analyzed.)	3 2%	2 1.4%

28. Secondary Outcome

Title	Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1
Description	The analysis of ALK fusion variant in plasma CNA was performed by NGS and the number of participants with fusion variants at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 is presented here. In the table below, EML4-ALK is the abbreviation of echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase.
Time Frame	at Screening, Cycle 2 Day 1 and Cycle 7 Day 1

Outcome Measure Data

Analysis Population Description

"Number of Participants Analyzed" included all participants in the plasma CNA analysis population within each treatment group at screening. "Number Analyzed" included all participants in the plasma CNA analysis population within each treatment group at the specified visit.

Arm/Group Title	Lorlatinib	Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.	Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
Measure Participants	130	125
EML4-ALK Variant 1	19 12.8%	25 17%
EML4-ALK Variant 2	7 4.7%	2 1.4%
EML4-ALK Variant 3	18 12.1%	21 14.3%
EML4-ALK Other	15 10.1%	9 6.1%
ALK Rearrangement Other	2 1.3%	4 2.7%
ALK Rearrangement Not Detected	32 21.5%	36 24.5%
No cfDNA Detected	32 21.5%	25 17%
Other (Sample failed analysis, uninformative, or not analyzed.)	5 3.4%	3 2%
EML4-ALK Variant 1	1 0.7%	7 4.8%
EML4-ALK Variant 2	2 1.3%	0 0%
EML4-ALK Variant 3	2 1.3%	2 1.4%
EML4-ALK Other	2 1.3%	1 0.7%
ALK Rearrangement Other	0 0%	0 0%
ALK Rearrangement Not Detected	61 40.9%	48 32.7%
No cfDNA Detected	53 35.6%	58 39.5%
Other (Sample failed analysis, uninformative, or not analyzed.)	4 2.7%	2 1.4%
EML4-ALK Variant 1	0 0%	5 3.4%
EML4-ALK Variant 2	0 0%	1 0.7%
EML4-ALK Variant 3	0 0%	4 2.7%
EML4-ALK Other	0 0%	1 0.7%
ALK Rearrangement Other	0 0%	2 1.4%
ALK Rearrangement Not Detected	48 32.2%	34 23.1%
No cfDNA Detected	52 34.9%	35 23.8%
Other (Sample failed analysis, uninformative, or not analyzed.)	3 2%	2 1.4%

Adverse Events

Time Frame	From the first dose of study treatment through end of study follow-up (infinite lag) or start of new anti-cancer therapy, whichever occurred first (assessed up to 33 months).
Adverse Event Reporting Description	The analysis of adverse events included all participants who received at least 1 dose of study drug. Participants were classified according to the treatment assigned at randomization. Totals number of participants at a higher level were not necessarily the sum of those at the lower levels since a participant may report two or more different adverse events within the higher level category.
Arm/Group Title	Lorlatinib		Crizotinib
Arm/Group Description	Lorlatinib monotherapy at the recommended Phase 2 dose of 100 mg, was administered orally once daily (QD) at approximately the same time of the day on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.		Crizotinib monotherapy at the registered dose of 250 mg, was administered orally twice daily (BID) at approximately the same time in the morning and evening (12 hours apart) on a continuous daily dosing schedule. Each treatment cycle was defined as 28 days. Treatment continued until confirmation of RECIST version 1.1 defined disease progression assessed by the blinded independent central review (unless clinical benefit was still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, death, or the study was terminated by the sponsor, whichever occurred first.
All Cause Mortality
	Lorlatinib		Crizotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/149 (15.4%)		28/142 (19.7%)
Serious Adverse Events
	Lorlatinib		Crizotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/149 (34.2%)		39/142 (27.5%)
Blood and lymphatic system disorders
Anaemia	1/149 (0.7%)		0/142 (0%)
Cardiac disorders
Cardiac disorder	1/149 (0.7%)		0/142 (0%)
Cardiac failure	2/149 (1.3%)		1/142 (0.7%)
Cardiac failure acute	1/149 (0.7%)		0/142 (0%)
Cardiac tamponade	1/149 (0.7%)		0/142 (0%)
Left ventricular dysfunction	1/149 (0.7%)		0/142 (0%)
Pericardial effusion	2/149 (1.3%)		1/142 (0.7%)
Sinus node dysfunction	0/149 (0%)		1/142 (0.7%)
Eye disorders
Blindness cortical	0/149 (0%)		1/142 (0.7%)
Retinal detachment	0/149 (0%)		1/142 (0.7%)
Gastrointestinal disorders
Constipation	0/149 (0%)		1/142 (0.7%)
Diarrhoea	1/149 (0.7%)		0/142 (0%)
Dyspepsia	0/149 (0%)		1/142 (0.7%)
Oesophagitis	0/149 (0%)		1/142 (0.7%)
Pancreatitis	1/149 (0.7%)		0/142 (0%)
General disorders
Death	1/149 (0.7%)		1/142 (0.7%)
Disease progression	1/149 (0.7%)		1/142 (0.7%)
Generalised oedema	1/149 (0.7%)		0/142 (0%)
Pyrexia	3/149 (2%)		3/142 (2.1%)
Hepatobiliary disorders
Cholecystitis chronic	0/149 (0%)		1/142 (0.7%)
Hepatic function abnormal	0/149 (0%)		1/142 (0.7%)
Liver injury	0/149 (0%)		1/142 (0.7%)
Immune system disorders
Anaphylactic reaction	1/149 (0.7%)		0/142 (0%)
Infections and infestations
Bacterial infection	0/149 (0%)		1/142 (0.7%)
Bronchitis	2/149 (1.3%)		0/142 (0%)
Clostridium difficile colitis	0/149 (0%)		1/142 (0.7%)
Gastroenteritis	0/149 (0%)		1/142 (0.7%)
Haemophilus infection	1/149 (0.7%)		0/142 (0%)
Lung abscess	1/149 (0.7%)		0/142 (0%)
Pharyngeal abscess	0/149 (0%)		1/142 (0.7%)
Pharyngitis	1/149 (0.7%)		0/142 (0%)
Pneumonia	7/149 (4.7%)		5/142 (3.5%)
Pneumonia cryptococcal	1/149 (0.7%)		0/142 (0%)
Respiratory tract infection	1/149 (0.7%)		0/142 (0%)
Sepsis	2/149 (1.3%)		0/142 (0%)
Tuberculosis	0/149 (0%)		1/142 (0.7%)
Upper respiratory tract infection	1/149 (0.7%)		1/142 (0.7%)
Urinary tract infection	1/149 (0.7%)		0/142 (0%)
Injury, poisoning and procedural complications
Femoral neck fracture	0/149 (0%)		1/142 (0.7%)
Femur fracture	0/149 (0%)		1/142 (0.7%)
Fracture	1/149 (0.7%)		0/142 (0%)
Hip fracture	1/149 (0.7%)		0/142 (0%)
Lower limb fracture	1/149 (0.7%)		0/142 (0%)
Multiple injuries	1/149 (0.7%)		0/142 (0%)
Pelvic fracture	0/149 (0%)		1/142 (0.7%)
Skin laceration	1/149 (0.7%)		0/142 (0%)
Investigations
Blood triglycerides increased	1/149 (0.7%)		0/142 (0%)
Haemoglobin decreased	1/149 (0.7%)		0/142 (0%)
Neutrophil count decreased	0/149 (0%)		1/142 (0.7%)
Platelet count decreased	0/149 (0%)		1/142 (0.7%)
Metabolism and nutrition disorders
Diabetes mellitus	1/149 (0.7%)		0/142 (0%)
Hypercholesterolaemia	1/149 (0.7%)		0/142 (0%)
Hypertriglyceridaemia	1/149 (0.7%)		0/142 (0%)
Hypocalcaemia	0/149 (0%)		1/142 (0.7%)
Hyponatraemia	1/149 (0.7%)		1/142 (0.7%)
Musculoskeletal and connective tissue disorders
Back pain	2/149 (1.3%)		0/142 (0%)
Muscular weakness	0/149 (0%)		1/142 (0.7%)
Osteoarthritis	1/149 (0.7%)		0/142 (0%)
Pain in extremity	1/149 (0.7%)		0/142 (0%)
Rotator cuff syndrome	1/149 (0.7%)		0/142 (0%)
Spondylitis	1/149 (0.7%)		0/142 (0%)
Tenosynovitis	1/149 (0.7%)		0/142 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial adenocarcinoma	1/149 (0.7%)		0/142 (0%)
Follicle centre lymphoma, follicular grade I, II, III	1/149 (0.7%)		0/142 (0%)
Lung neoplasm malignant	1/149 (0.7%)		0/142 (0%)
Malignant neoplasm progression	0/149 (0%)		2/142 (1.4%)
Neoplasm progression	0/149 (0%)		1/142 (0.7%)
Nervous system disorders
Carpal tunnel syndrome	1/149 (0.7%)		0/142 (0%)
Cerebral infarction	0/149 (0%)		1/142 (0.7%)
Cognitive disorder	1/149 (0.7%)		0/142 (0%)
Ischaemic stroke	0/149 (0%)		1/142 (0.7%)
Speech disorder	1/149 (0.7%)		0/142 (0%)
Thalamus haemorrhage	1/149 (0.7%)		0/142 (0%)
Psychiatric disorders
Confusional state	1/149 (0.7%)		0/142 (0%)
Delirium	1/149 (0.7%)		0/142 (0%)
Intentional self-injury	1/149 (0.7%)		0/142 (0%)
Renal and urinary disorders
Renal failure	1/149 (0.7%)		0/142 (0%)
Urinary retention	0/149 (0%)		1/142 (0.7%)
Urinary tract disorder	1/149 (0.7%)		0/142 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/149 (0.7%)		0/142 (0%)
Dyspnoea	4/149 (2.7%)		0/142 (0%)
Epistaxis	0/149 (0%)		1/142 (0.7%)
Pleural effusion	2/149 (1.3%)		2/142 (1.4%)
Pneumonitis	2/149 (1.3%)		2/142 (1.4%)
Pneumothorax	1/149 (0.7%)		0/142 (0%)
Pulmonary embolism	1/149 (0.7%)		2/142 (1.4%)
Respiratory failure	4/149 (2.7%)		0/142 (0%)
Surgical and medical procedures
Radiotherapy to bone	1/149 (0.7%)		0/142 (0%)
Vascular disorders
Aortitis	0/149 (0%)		1/142 (0.7%)
Hypertensive crisis	1/149 (0.7%)		0/142 (0%)
Thrombosis	0/149 (0%)		1/142 (0.7%)
Other (Not Including Serious) Adverse Events
	Lorlatinib		Crizotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	148/149 (99.3%)		140/142 (98.6%)
Blood and lymphatic system disorders
Anaemia	29/149 (19.5%)		11/142 (7.7%)
Neutropenia	10/149 (6.7%)		21/142 (14.8%)
Cardiac disorders
Bradycardia	2/149 (1.3%)		17/142 (12%)
Sinus bradycardia	4/149 (2.7%)		15/142 (10.6%)
Ear and labyrinth disorders
Tinnitus	9/149 (6%)		1/142 (0.7%)
Eye disorders
Photopsia	1/149 (0.7%)		24/142 (16.9%)
Vision blurred	11/149 (7.4%)		4/142 (2.8%)
Visual impairment	10/149 (6.7%)		16/142 (11.3%)
Gastrointestinal disorders
Abdominal distension	9/149 (6%)		3/142 (2.1%)
Abdominal pain	7/149 (4.7%)		11/142 (7.7%)
Constipation	26/149 (17.4%)		41/142 (28.9%)
Diarrhoea	32/149 (21.5%)		74/142 (52.1%)
Flatulence	11/149 (7.4%)		3/142 (2.1%)
Nausea	22/149 (14.8%)		74/142 (52.1%)
Vomiting	19/149 (12.8%)		55/142 (38.7%)
General disorders
Asthenia	20/149 (13.4%)		27/142 (19%)
Chest pain	16/149 (10.7%)		20/142 (14.1%)
Fatigue	11/149 (7.4%)		24/142 (16.9%)
Oedema	16/149 (10.7%)		13/142 (9.2%)
Oedema peripheral	65/149 (43.6%)		44/142 (31%)
Pain	5/149 (3.4%)		8/142 (5.6%)
Pyrexia	22/149 (14.8%)		16/142 (11.3%)
Infections and infestations
Bronchitis	9/149 (6%)		3/142 (2.1%)
Nasopharyngitis	8/149 (5.4%)		10/142 (7%)
Pneumonia	5/149 (3.4%)		8/142 (5.6%)
Respiratory tract infection	12/149 (8.1%)		6/142 (4.2%)
Upper respiratory tract infection	16/149 (10.7%)		11/142 (7.7%)
Urinary tract infection	6/149 (4%)		10/142 (7%)
Investigations
Alanine aminotransferase increased	26/149 (17.4%)		48/142 (33.8%)
Amylase increased	13/149 (8.7%)		16/142 (11.3%)
Aspartate aminotransferase increased	21/149 (14.1%)		39/142 (27.5%)
Blood alkaline phosphatase increased	7/149 (4.7%)		18/142 (12.7%)
Blood cholesterol increased	59/149 (39.6%)		4/142 (2.8%)
Blood creatine phosphokinase increased	16/149 (10.7%)		24/142 (16.9%)
Blood creatinine increased	9/149 (6%)		19/142 (13.4%)
Blood lactate dehydrogenase increased	3/149 (2%)		15/142 (10.6%)
Blood triglycerides increased	19/149 (12.8%)		2/142 (1.4%)
Electrocardiogram QT prolonged	5/149 (3.4%)		8/142 (5.6%)
Gamma-glutamyltransferase increased	22/149 (14.8%)		22/142 (15.5%)
Lipase increased	14/149 (9.4%)		17/142 (12%)
Neutrophil count decreased	3/149 (2%)		16/142 (11.3%)
Weight decreased	4/149 (2.7%)		10/142 (7%)
Weight increased	57/149 (38.3%)		18/142 (12.7%)
White blood cell count decreased	1/149 (0.7%)		11/142 (7.7%)
Metabolism and nutrition disorders
Decreased appetite	5/149 (3.4%)		35/142 (24.6%)
Dyslipidaemia	9/149 (6%)		0/142 (0%)
Hypercholesterolaemia	53/149 (35.6%)		1/142 (0.7%)
Hyperglycaemia	15/149 (10.1%)		5/142 (3.5%)
Hyperlipidaemia	16/149 (10.7%)		0/142 (0%)
Hypertriglyceridaemia	78/149 (52.3%)		6/142 (4.2%)
Hyperuricaemia	12/149 (8.1%)		4/142 (2.8%)
Hypoalbuminaemia	8/149 (5.4%)		18/142 (12.7%)
Hypocalcaemia	2/149 (1.3%)		8/142 (5.6%)
Hypokalaemia	9/149 (6%)		4/142 (2.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	28/149 (18.8%)		16/142 (11.3%)
Back pain	22/149 (14.8%)		16/142 (11.3%)
Musculoskeletal pain	8/149 (5.4%)		5/142 (3.5%)
Myalgia	16/149 (10.7%)		5/142 (3.5%)
Pain in extremity	25/149 (16.8%)		12/142 (8.5%)
Nervous system disorders
Dizziness	16/149 (10.7%)		20/142 (14.1%)
Dysgeusia	8/149 (5.4%)		23/142 (16.2%)
Headache	25/149 (16.8%)		25/142 (17.6%)
Hypoaesthesia	8/149 (5.4%)		7/142 (4.9%)
Memory impairment	13/149 (8.7%)		3/142 (2.1%)
Neuropathy peripheral	13/149 (8.7%)		0/142 (0%)
Paraesthesia	18/149 (12.1%)		7/142 (4.9%)
Peripheral sensory neuropathy	10/149 (6.7%)		1/142 (0.7%)
Psychiatric disorders
Anxiety	10/149 (6.7%)		3/142 (2.1%)
Insomnia	14/149 (9.4%)		13/142 (9.2%)
Renal and urinary disorders
Proteinuria	9/149 (6%)		1/142 (0.7%)
Respiratory, thoracic and mediastinal disorders
Cough	24/149 (16.1%)		26/142 (18.3%)
Dyspnoea	28/149 (18.8%)		23/142 (16.2%)
Oropharyngeal pain	9/149 (6%)		8/142 (5.6%)
Productive cough	12/149 (8.1%)		4/142 (2.8%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	8/149 (5.4%)		0/142 (0%)
Rash	15/149 (10.1%)		11/142 (7.7%)
Vascular disorders
Hypertension	27/149 (18.1%)		3/142 (2.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.