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

• ClinicalTrials.gov Identifier: NCT03052608
• Recruitment Status: Active, not recruiting
• First Posted: February 14, 2017
• Results First Posted: April 1, 2021
• Last Update Posted: February 20, 2024
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Non-Small-Cell Lung
• Interventions: Drug: Lorlatinib; Drug: Crizotinib
• Enrollment: 296

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 Details	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 [1]	26	83
Not Completed	123	64
Reason Not Completed
Adverse Event	10	12
Death	6	4
Withdrawal by Subject	4	12
Global Deterioration of Health Status	0	3
Subject decided to continue study treatment as per clinical practice in another hospital.	0	1
Subject didn't receive study treatment.	0	1
Ongoing	103	31
[1] "Completed" refers to participants with confirmed RECIST version 1.1 defined disease progression assessed by the blinded independent central review or investigator.
Period Title: Long-Term Follow-up Phase
Started [1]	149	147
Completed	0	0
Not Completed	149	147
Reason Not Completed
Death	23	28
Lost to Follow-up	0	2
Withdrawal by Subject	4	18
Ongoing	122	99
[1] The long-term follow-up phase included the post-treatment follow-up and the survival follow-up. Participants who started the long-term follow-up phase consisted of participants in both the post-treatment follow-up and the survival follow-up.

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 Number of Baseline Participants		149	147	296
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	149 participants	147 participants	296 participants
		59.1 (13.12)	55.6 (13.52)	57.4 (13.41)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	149 participants	147 participants	296 participants
	Female	84 56.4%	91 61.9%	175 59.1%
	Male	65 43.6%	56 38.1%	121 40.9%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	149 participants	147 participants	296 participants
	White	72 48.3%	72 49.0%	144 48.6%
	Black or African American	0 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.
Overall Number of Participants Analyzed	149	147
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	9.3; (7.6 to 11.1)

[1]

The values were not estimable because there were insufficient events to estimate the median PFS time and 95% confidence interval.

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	[Not Specified]
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
	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.
Overall Number of Participants Analyzed	149	147
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

The values were not estimable because there were insufficient events to estimate the median OS time and 95% confidence interval.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.414 to 1.249
	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.
Overall Number of Participants Analyzed	149	147
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	9.1; (7.4 to 10.9)

[1]

The values were not estimable because there were insufficient events to estimate the median PFS time and 95% confidence interval.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	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
	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.
Overall Number of Participants Analyzed	149	147
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	75.8; (68.2 to 82.5)	57.8; (49.4 to 65.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	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
	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.
Overall Number of Participants Analyzed	149	147
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	80.5; (73.3 to 86.6)	61.9; (53.5 to 69.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	[Not Specified]
	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
	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.
Overall Number of Participants Analyzed	38	40
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	65.8; (48.6 to 80.4)	20.0; (9.1 to 35.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	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
	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.
Overall Number of Participants Analyzed	149	147
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	16.6 [2]; (11.1 to NA)

[1]

The values were not estimable because there were insufficient events to estimate the median IC-TTP time and 95% confidence interval.

[2]

The value was not estimable because there were insufficient events to estimate the upper bound of the 95% confidence interval.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	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
	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.
Overall Number of Participants Analyzed	113	85
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	11.0; (9.0 to 12.9)

[1]

The values were not estimable because there were insufficient events to estimate the median DR time and the 95% confidence interval.

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.
Overall Number of Participants Analyzed	25	8
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	9.4; (6.0 to 11.1)

[1]

The values were not estimable because there were insufficient events to estimate the median IC-DR time and the 95% confidence interval.

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.
Overall Number of Participants Analyzed	113	85
Median (Inter-Quartile Range); Unit of Measure: Months
	1.8; (1.7 to 1.9)	1.8; (1.7 to 1.9)

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.
Overall Number of Participants Analyzed	25	8
Median (Inter-Quartile Range); Unit of Measure: Months
	1.9; (1.8 to 3.7)	1.8; (1.7 to 2.7)

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 Not Reported

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.
Overall Number of Participants Analyzed	149	142
Measure Type: Count of Participants; Unit of Measure: Participants
AEs (all-causality)	149 100.0%	140 98.6%
AEs (treatment-related)	144 96.6%	133 93.7%
SAEs (all-causality)	51 34.2%	39 27.5%
SAEs (treatment-related)	12 8.1%	7 4.9%
Maximum Grade 3 or 4 AEs (all-causality)	108 72.5%	79 55.6%
Maximum Grade 3 or 4 AEs (treatment-related)	83 55.7%	52 36.6%
Maximum Grade 5 AEs (all-causality)	7 4.7%	7 4.9%
Maximum Grade 5 AEs (treatment-related)	2 1.3%	0 0.0%
AEs causing study discontinuation (all-causality)	7 4.7%	8 5.6%
AEs causing study discontinuation (treatment-related)	2 1.3%	0 0.0%
AEs causing study treatment discontinuation (all-causality)	10 6.7%	13 9.2%
AEs causing study treatment discontinuation (treatment-related)	7 4.7%	7 4.9%
AEs causing dose reduction or temporary discontinuation (all-causality)	79 53.0%	71 50.0%
AEs causing dose reduction or temporary discontinuation (treatment-related)	60 40.3%	54 38.0%

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.
Overall Number of Participants Analyzed	149	141
Measure Type: Count of Participants; Unit of Measure: Participants
Anemia (Postbaseline Maximum Grade 3)	3 2.0%	4 2.8%
Anemia (Postbaseline Maximum Grade 4)	NA [1]	NA [1]
Hemoglobin increased (Postbaseline Maximum Grade 3)	0 0.0%	0 0.0%
Hemoglobin increased (Postbaseline Maximum Grade 4)	NA [1]	NA [1]
Lymphocyte count decreased (Postbaseline Maximum Grade 3)	2 1.3%	7 5.0%
Lymphocyte count decreased (Postbaseline Maximum Grade 4)	2 1.3%	1 0.7%
Lymphocyte count increased (Postbaseline Maximum Grade 3)	0 0.0%	0 0.0%
Lymphocyte count increased (Postbaseline Maximum Grade 4)	NA [1]	NA [1]
Neutrophil count decreased (Postbaseline Maximum Grade 3)	1 0.7%	19 13.5%
Neutrophil count decreased (Postbaseline Maximum Grade 4)	1 0.7%	4 2.8%
Platelet count decreased (Postbaseline Maximum Grade 3)	0 0.0%	1 0.7%
Platelet count decreased (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
White blood cell decreased (Postbaseline Maximum Grade 3)	0 0.0%	5 3.5%
White blood cell decreased (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%

[1]

CTCAE grade not defined.

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.
Overall Number of Participants Analyzed	149	141
Measure Type: Count of Participants; Unit of Measure: Participants
Alanine aminotransferase increased (Postbaseline Maximum Grade 3)	4 2.7%	5 3.5%
Alanine aminotransferase increased (Postbaseline Maximum Grade 4)	0 0.0%	1 0.7%
Alkaline phosphate increased (Postbaseline Maximum Grade 3)	0 0.0%	1 0.7%
Alkaline phosphate increased (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Aspartate aminotransferase increased (Postbaseline Maximum Grade 3)	3 2.0%	4 2.8%
Aspartate aminotransferase increased (Postbaseline Maximum Grade 4)	0 0.0%	1 0.7%
Blood bilirubin increased (Postbaseline Maximum Grade 3)	0 0.0%	0 0.0%
Blood bilirubin increased (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Creatine kinase increased (Postbaseline Maximum Grade 3)	3 2.0%	5 3.5%
Creatine kinase increased (Postbaseline Maximum Grade 4)	0 0.0%	2 1.4%
Creatinine increased (Postbaseline Maximum Grade 3)	1 0.7%	3 2.1%
Creatinine increased (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Gamma glutamyl transferase increased (Postbaseline Maximum Grade 3)	9 6.0%	8 5.7%
Gamma glutamyl transferase increased (Postbaseline Maximum Grade 4)	0 0.0%	1 0.7%
Hypercalcemia (Postbaseline Maximum Grade 3)	0 0.0%	0 0.0%
Hypercalcemia (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Hyperglycemia (Postbaseline Maximum Grade 3)	9 6.0%	3 2.1%
Hyperglycemia (Postbaseline Maximum Grade 4)	1 0.7%	0 0.0%
Hyperkalemia (Postbaseline Maximum Grade 3)	2 1.3%	3 2.1%
Hyperkalemia (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Hypermagnesemia (Postbaseline Maximum Grade 3)	2 1.3%	1 0.7%
Hypermagnesemia (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Hypernatremia (Postbaseline Maximum Grade 3)	0 0.0%	0 0.0%
Hypernatremia (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Hypoalbuminemia (Postbaseline Maximum Grade 3)	1 0.7%	9 6.4%
Hypoalbuminemia (Postbaseline Maximum Grade 4)	NA [1]	NA [1]
Hypocalcemia (Postbaseline Maximum Grade 3)	1 0.7%	0 0.0%
Hypocalcemia (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Hypoglycemia (Postbaseline Maximum Grade 3)	0 0.0%	0 0.0%
Hypoglycemia (Postbaseline Maximum Grade 4)	0 0.0%	1 0.7%
Hypokalemia (Postbaseline Maximum Grade 3)	0 0.0%	3 2.1%
Hypokalemia (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Hypomagnesemia (Postbaseline Maximum Grade 3)	0 0.0%	0 0.0%
Hypomagnesemia (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Hyponatremia (Postbaseline Maximum Grade 3)	5 3.4%	10 7.1%
Hyponatremia (Postbaseline Maximum Grade 4)	0 0.0%	1 0.7%
Hypophosphatemia (Postbaseline Maximum Grade 3)	3 2.0%	4 2.8%
Hypophosphatemia (Postbaseline Maximum Grade 4)	0 0.0%	0 0.0%
Lipase increased (Postbaseline Maximum Grade 3)	8 5.4%	6 4.3%
Lipase increased (Postbaseline Maximum Grade 4)	3 2.0%	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 0.0%

[1]

CTCAE grade not defined.

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.
Overall Number of Participants Analyzed	149	141
Measure Type: Count of Participants; Unit of Measure: Participants
Cholesterol high (Postbaseline Maximum Grade 3)	26 17.4%	0 0.0%
Cholesterol high (Postbaseline Maximum Grade 4)	3 2.0%	0 0.0%
Hypertriglyceridemia (Postbaseline Maximum Grade 3)	20 13.4%	0 0.0%
Hypertriglyceridemia (Postbaseline Maximum Grade 4)	13 8.7%	0 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.
Overall Number of Participants Analyzed		149	142
Measure Type: Count of Participants; Unit of Measure: Participants
Sitting pulse rate: pulse >120 bpm	Number Analyzed	149 participants	142 participants
		7 4.7%	1 0.7%
Sitting pulse rate: pulse <50 bpm	Number Analyzed	149 participants	142 participants
		4 2.7%	22 15.5%
Sitting pulse rate: change ≥30 bpm increase	Number Analyzed	147 participants	142 participants
		24 16.3%	3 2.1%
Sitting pulse rate: change ≥30 bpm decrease	Number Analyzed	147 participants	142 participants
		17 11.6%	47 33.1%
Sitting systolic blood pressure: change ≥40 mmHg increase	Number Analyzed	147 participants	142 participants
		22 15.0%	3 2.1%
Sitting systolic blood pressure: change ≥40 mmHg decrease	Number Analyzed	147 participants	142 participants
		6 4.1%	14 9.9%
Sitting systolic blood pressure: change ≥60 mmHg decrease	Number Analyzed	147 participants	142 participants
		0 0.0%	1 0.7%
Sitting diastolic blood pressure: change ≥20 mmHg increase	Number Analyzed	147 participants	142 participants
		41 27.9%	18 12.7%
Sitting diastolic blood pressure: change ≥20 mmHg decrease	Number Analyzed	147 participants	142 participants
		26 17.7%	52 36.6%
Sitting diastolic blood pressure: change ≥40 mmHg decrease	Number Analyzed	147 participants	142 participants
		0 0.0%	1 0.7%
Body weight (kg): percent change from baseline ≥10% increase	Number Analyzed	146 participants	137 participants
		99 67.8%	39 28.5%
Body weight (kg): percent change from baseline ≥20% increase	Number Analyzed	146 participants	137 participants
		35 24.0%	3 2.2%
Body weight (kg): percent change from baseline ≥10% decrease	Number Analyzed	146 participants	137 participants
		6 4.1%	12 8.8%

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.
Overall Number of Participants Analyzed		149	142
Measure Type: Count of Participants; Unit of Measure: Participants
Change of QTcF ≥60 msec	Number Analyzed	146 participants	138 participants
		5 3.4%	16 11.6%
30 msec ≤ Change of QTcF <60 msec	Number Analyzed	146 participants	138 participants
		49 33.6%	41 29.7%
Change of QTcF <30 msec	Number Analyzed	146 participants	138 participants
		92 63.0%	81 58.7%
Change of QTcB ≥60 msec	Number Analyzed	149 participants	141 participants
		10 6.7%	15 10.6%
30 msec ≤ Change of QTcB <60 msec	Number Analyzed	149 participants	141 participants
		49 32.9%	26 18.4%
Change of QTcB <30 msec	Number Analyzed	149 participants	141 participants
		90 60.4%	100 70.9%
PR change ≥50% if absolute baseline value was <200 msec	Number Analyzed	146 participants	140 participants
		8 5.5%	4 2.9%
PR change ≥25% if absolute baseline value was ≥200 msec	Number Analyzed	146 participants	140 participants
		0 0.0%	0 0.0%
QRS change ≥50% if absolute baseline value was <100 msec	Number Analyzed	149 participants	141 participants
		2 1.3%	3 2.1%
QRS change ≥25% if absolute baseline value was ≥100 msec	Number Analyzed	149 participants	141 participants
		2 1.3%	0 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.
Overall Number of Participants Analyzed	143	133
Measure Type: Count of Participants; Unit of Measure: Participants
	2 1.4%	1 0.8%

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.
Overall Number of Participants Analyzed		149	147
Mean (Standard Deviation); Unit of Measure: Units on a scale
Cycle 2 Day 1	Number Analyzed	139 participants	120 participants
		-1.8 (5.52)	-1.2 (5.62)
Cycle 3 Day 1	Number Analyzed	135 participants	115 participants
		-2.5 (5.85)	-2.7 (5.78)
Cycle 4 Day 1	Number Analyzed	127 participants	110 participants
		-2.9 (5.73)	-3.6 (6.60)
Cycle 5 Day 1	Number Analyzed	126 participants	106 participants
		-2.5 (6.28)	-3.0 (6.24)
Cycle 6 Day 1	Number Analyzed	123 participants	96 participants
		-2.6 (6.61)	-2.9 (6.65)
Cycle 8 Day 1	Number Analyzed	123 participants	87 participants
		-3.2 (6.18)	-1.9 (6.56)
Cycle 10 Day 1	Number Analyzed	115 participants	72 participants
		-3.0 (6.30)	-2.6 (5.98)
Cycle 12 Day 1	Number Analyzed	113 participants	58 participants
		-3.6 (6.05)	-2.1 (6.23)
Cycle 14 Day 1	Number Analyzed	108 participants	47 participants
		-3.3 (6.82)	-2.5 (5.57)
Cycle 16 Day 1	Number Analyzed	102 participants	39 participants
		-3.3 (6.87)	-2.3 (5.77)
Cycle 18 Day 1	Number Analyzed	83 participants	28 participants
		-3.7 (7.26)	-2.6 (4.30)
Cycle 20 Day 1	Number Analyzed	67 participants	17 participants
		-3.3 (6.24)	-2.4 (4.62)
Cycle 22 Day 1	Number Analyzed	54 participants	13 participants
		-3.2 (6.95)	-2.5 (4.82)
Cycle 24 Day 1	Number Analyzed	41 participants	9 participants
		-3.1 (5.97)	2.3 (9.31)
Cycle 26 Day 1	Number Analyzed	33 participants	8 participants
		-3.2 (6.87)	-0.8 (3.81)
Cycle 28 Day 1	Number Analyzed	21 participants	6 participants
		-3.0 (6.53)	0.2 (7.65)
Cycle 30 Day 1	Number Analyzed	12 participants	4 participants
		-4.8 (8.00)	1.3 (3.20)
Cycle 32 Day 1	Number Analyzed	8 participants	2 participants
		-5.0 (14.14)	7.5 (9.19)
Cycle 34 Day 1	Number Analyzed	4 participants	1 participants
		-2.3 (12.42)	0.0
Cycle 36 Day 1	Number Analyzed	0 participants	1 participants
			0.0
Cycle 38 Day 1	Number Analyzed	0 participants	0 participants
End of Treatment	Number Analyzed	20 participants	60 participants
		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.
Overall Number of Participants Analyzed		149	142
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline	Number Analyzed	147 participants	121 participants
		3 2.0%	7 5.8%
Cycle 2 Day 1	Number Analyzed	138 participants	119 participants
		0 0.0%	5 4.2%
Cycle 3 Day 1	Number Analyzed	137 participants	113 participants
		1 0.7%	1 0.9%
Cycle 4 Day 1	Number Analyzed	131 participants	109 participants
		0 0.0%	1 0.9%
Cycle 5 Day 1	Number Analyzed	128 participants	103 participants
		0 0.0%	1 1.0%
Cycle 6 Day 1	Number Analyzed	123 participants	93 participants
		0 0.0%	2 2.2%
Cycle 8 Day 1	Number Analyzed	122 participants	85 participants
		0 0.0%	2 2.4%
Cycle 10 Day 1	Number Analyzed	115 participants	68 participants
		0 0.0%	1 1.5%
Cycle 12 Day 1	Number Analyzed	114 participants	55 participants
		0 0.0%	0 0.0%
Cycle 14 Day 1	Number Analyzed	109 participants	44 participants
		0 0.0%	0 0.0%
Cycle 16 Day 1	Number Analyzed	103 participants	35 participants
		0 0.0%	0 0.0%
Cycle 18 Day 1	Number Analyzed	81 participants	25 participants
		0 0.0%	0 0.0%
Cycle 20 Day 1	Number Analyzed	67 participants	15 participants
		0 0.0%	0 0.0%
Cycle 22 Day 1	Number Analyzed	54 participants	13 participants
		0 0.0%	0 0.0%
Cycle 24 Day 1	Number Analyzed	41 participants	9 participants
		0 0.0%	1 11.1%
Cycle 26 Day 1	Number Analyzed	33 participants	8 participants
		1 3.0%	0 0.0%
Cycle 28 Day 1	Number Analyzed	23 participants	6 participants
		0 0.0%	0 0.0%
Cycle 30 Day 1	Number Analyzed	14 participants	4 participants
		0 0.0%	0 0.0%
Cycle 32 Day 1	Number Analyzed	10 participants	2 participants
		0 0.0%	0 0.0%
Cycle 34 Day 1	Number Analyzed	6 participants	1 participants
		0 0.0%	0 0.0%
Cycle 36 Day 1	Number Analyzed	2 participants	1 participants
		0 0.0%	0 0.0%
Cycle 38 Day 1	Number Analyzed	1 participants	0 participants
		0 0.0%
End of Treatment	Number Analyzed	20 participants	62 participants
		0 0.0%	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.
Overall Number of Participants Analyzed	148	140
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
Global QOL	8.60; (6.09 to 11.11)	3.95; (1.15 to 6.76)
Physical Functioning	4.84; (2.67 to 7.01)	2.82; (0.42 to 5.22)
Role Functioning	6.86; (4.05 to 9.68)	4.78; (1.61 to 7.95)
Emotional Functioning	8.77; (6.88 to 10.67)	6.20; (4.09 to 8.30)
Cognitive Functioning	-4.20; (-6.56 to -1.84)	-1.02; (-3.64 to 1.60)
Social Functioning	7.00; (4.48 to 9.52)	4.72; (1.87 to 7.57)
Fatigue	-9.93; (-12.61 to -7.26)	-4.26; (-7.28 to -1.25)
Nausea and Vomiting	-4.35; (-5.79 to -2.90)	3.51; (1.89 to 5.14)
Pain	-4.60; (-7.17 to -2.02)	-5.76; (-8.67 to -2.85)
Dyspnoea	-7.02; (-9.66 to -4.39)	-8.75; (-11.76 to -5.74)
Insomnia	-17.34; (-19.71 to -14.96)	-9.39; (-12.07 to -6.71)
Appetite Loss	-13.15; (-15.00 to -11.30)	-3.95; (-6.01 to -1.88)
Constipation	-2.40; (-5.33 to 0.54)	2.53; (-0.83 to 5.90)
Diarrhea	-0.92; (-3.42 to 1.59)	11.12; (8.33 to 13.91)
Financial Difficulties	-6.79; (-9.52 to -4.05)	-5.74; (-8.80 to -2.68)

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0096
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.65
	Confidence Interval	(2-Sided) 95%; 1.14 to 8.16
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1897
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 95%; -1.01 to 5.05
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2999
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.09
	Confidence Interval	(2-Sided) 95%; -1.87 to 6.04
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0553
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.58
	Confidence Interval	(2-Sided) 95%; -0.06 to 5.22
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0588
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.18
	Confidence Interval	(2-Sided) 95%; -6.47 to 0.12
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2118
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.27
	Confidence Interval	(2-Sided) 95%; -1.30 to 5.85
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0032
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.67
	Confidence Interval	(2-Sided) 95%; -9.42 to -1.92
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.86
	Confidence Interval	(2-Sided) 95%; -9.86 to -5.86
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5310
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; -2.49 to 4.82
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3602
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.72
	Confidence Interval	(2-Sided) 95%; -1.98 to 5.43
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.95
	Confidence Interval	(2-Sided) 95%; -11.25 to -4.64
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.21
	Confidence Interval	(2-Sided) 95%; -11.80 to -6.62
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0198
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.93
	Confidence Interval	(2-Sided) 95%; -9.07 to -0.79
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-12.03
	Confidence Interval	(2-Sided) 95%; -15.49 to -8.58
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5947
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.04
	Confidence Interval	(2-Sided) 95%; -4.90 to 2.82
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed	146	139
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
Dyspnoea	-4.36; (-6.55 to -2.17)	-4.90; (-7.34 to -2.47)
Coughing	-21.21; (-23.71 to -18.70)	-16.66; (-19.48 to -13.84)
Haemoptysis	-2.53; (-3.12 to -1.94)	-2.65; (-3.34 to -1.97)
Sore Mouth	0.56; (-0.98 to 2.10)	-0.60; (-2.39 to 1.19)
Dysphagia	-1.35; (-2.95 to 0.25)	0.16; (-1.68 to 2.00)
Peripheral Neuropathy	11.56; (8.21 to 14.91)	6.20; (2.39 to 10.00)
Alopecia	1.61; (-0.97 to 4.20)	1.81; (-1.08 to 4.70)
Pain in Chest	-9.54; (-11.27 to -7.80)	-9.01; (-10.97 to -7.05)
Pain in Arm or Shoulder	-6.93; (-9.43 to -4.43)	-7.38; (-10.24 to -4.52)
Pain in Other Parts	-2.31; (-5.28 to 0.66)	-5.67; (-8.97 to -2.38)

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7254
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; -2.51 to 3.60
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0115
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.55
	Confidence Interval	(2-Sided) 95%; -8.06 to -1.03
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7824
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.75 to 0.99
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2988
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; -1.04 to 3.36
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1916
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.51
	Confidence Interval	(2-Sided) 95%; -3.79 to 0.76
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0279
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.37
	Confidence Interval	(2-Sided) 95%; 0.59 to 10.15
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9162
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -3.89 to 3.49
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6698
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 95%; -2.96 to 1.90
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8035
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; -3.13 to 4.04
	Estimation Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1143
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.36
	Confidence Interval	(2-Sided) 95%; -0.82 to 7.55
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		147	138
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
Cycle 2 Day 1	Number Analyzed	143 participants	133 participants
		6.0; (3.33 to 8.72)	3.1; (0.19 to 5.92)
Cycle 3 Day 1	Number Analyzed	137 participants	124 participants
		6.0; (3.30 to 8.75)	5.3; (2.37 to 8.18)
Cycle 4 Day 1	Number Analyzed	133 participants	122 participants
		7.1; (3.71 to 10.41)	5.6; (2.77 to 8.47)
Cycle 5 Day 1	Number Analyzed	130 participants	115 participants
		4.3; (0.39 to 8.13)	5.1; (1.88 to 8.26)
Cycle 6 Day 1	Number Analyzed	127 participants	105 participants
		6.5; (3.11 to 9.85)	4.5; (1.08 to 7.91)
Cycle 7 Day 1	Number Analyzed	122 participants	100 participants
		5.5; (1.95 to 9.13)	4.0; (0.35 to 7.55)
Cycle 8 Day 1	Number Analyzed	125 participants	94 participants
		6.7; (2.95 to 10.37)	4.2; (0.63 to 7.68)
Cycle 9 Day 1	Number Analyzed	120 participants	82 participants
		6.4; (2.47 to 10.33)	3.9; (0.09 to 7.69)
Cycle 10 Day 1	Number Analyzed	116 participants	74 participants
		7.2; (3.22 to 11.20)	3.9; (-0.02 to 7.75)
Cycle 11 Day 1	Number Analyzed	117 participants	73 participants
		8.1; (4.27 to 11.83)	2.0; (-1.62 to 5.59)
Cycle 12 Day 1	Number Analyzed	117 participants	61 participants
		7.6; (3.82 to 11.41)	4.8; (0.95 to 8.59)
Cycle 13 Day 1	Number Analyzed	114 participants	56 participants
		7.5; (3.91 to 11.11)	5.8; (1.99 to 9.51)
Cycle 14 Day 1	Number Analyzed	110 participants	48 participants
		6.7; (3.06 to 10.32)	2.3; (-1.33 to 5.91)
Cycle 15 Day 1	Number Analyzed	111 participants	43 participants
		6.1; (2.33 to 9.96)	1.5; (-3.14 to 6.07)
Cycle 16 Day 1	Number Analyzed	104 participants	39 participants
		6.9; (2.71 to 11.04)	2.4; (-2.89 to 7.71)
Cycle 17 Day 1	Number Analyzed	93 participants	32 participants
		8.3; (4.08 to 12.46)	1.1; (-5.05 to 7.17)
Cycle 18 Day 1	Number Analyzed	83 participants	29 participants
		8.7; (4.17 to 13.28)	1.3; (-5.01 to 7.56)
Cycle 19 Day 1	Number Analyzed	78 participants	23 participants
		6.8; (1.86 to 11.70)	2.8; (-2.79 to 8.44)
Cycle 20 Day 1	Number Analyzed	69 participants	19 participants
		7.9; (2.83 to 13.06)	3.4; (-3.59 to 10.44)
Cycle 21 Day 1	Number Analyzed	65 participants	17 participants
		7.2; (1.96 to 12.44)	3.3; (-4.06 to 10.64)
Cycle 22 Day 1	Number Analyzed	56 participants	14 participants
		4.5; (-0.51 to 9.48)	1.9; (-6.69 to 10.54)
Cycle 23 Day 1	Number Analyzed	48 participants	12 participants
		5.2; (-0.68 to 11.14)	-0.6; (-10.97 to 9.81)
Cycle 24 Day 1	Number Analyzed	44 participants	10 participants
		4.9; (-1.22 to 11.09)	-3.0; (-21.43 to 15.43)
Cycle 25 Day 1	Number Analyzed	39 participants	9 participants
		4.0; (-2.13 to 10.18)	1.4; (-11.86 to 14.75)
Cycle 26 Day 1	Number Analyzed	35 participants	9 participants
		7.9; (1.00 to 14.77)	2.0; (-11.84 to 15.84)
Cycle 27 Day 1	Number Analyzed	30 participants	7 participants
		4.6; (-2.37 to 11.57)	3.0; (-12.79 to 18.79)
Cycle 28 Day 1	Number Analyzed	23 participants	6 participants
		6.0; (-3.75 to 15.66)	2.7; (-13.20 to 18.54)
Cycle 29Day 1	Number Analyzed	20 participants	5 participants
		7.4; (-3.78 to 18.48)	8.2; (-11.18 to 27.58)
Cycle 30 Day 1	Number Analyzed	14 participants	4 participants
		9.1; (-5.66 to 23.95)	2.8; (-22.92 to 28.42)
Cycle 31 Day 1	Number Analyzed	12 participants	2 participants
		7.8; (-11.84 to 27.51)	0.0; (-190.59 to 190.59)
Cycle 32 Day 1	Number Analyzed	10 participants	2 participants
		7.9; (-11.65 to 27.45)	2.5; (-156.33 to 161.33)
Cycle 33 Day 1	Number Analyzed	8 participants	2 participants
		4.4; (-21.74 to 30.49)	-2.5; (-224.86 to 219.86)
Cycle 34 Day 1	Number Analyzed	6 participants	1 participants
		-0.5; (-32.20 to 31.20)	20.0
Cycle 35 Day 1	Number Analyzed	4 participants	1 participants
		0.0; (-32.48 to 32.48)	20.0
Cycle 36 Day 1	Number Analyzed	2 participants	1 participants
		-4.5; (-315.80 to 306.80)	15.0
Cycle 37 Day 1	Number Analyzed	2 participants	0 participants
		-17.5; (-176.33 to 141.33)
Cycle 38 Day 1	Number Analyzed	1 participants	0 participants
		25.0
End of Treatment	Number Analyzed	27 participants	82 participants
		-3.7; (-13.66 to 6.33)	-1.3; (-5.43 to 2.80)

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.
Overall Number of Participants Analyzed		148	140
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
Cycle 2 Day 1	Number Analyzed	141 participants	133 participants
		0.078; (0.0475 to 0.1092)	0.064; (0.0258 to 0.1021)
Cycle 3 Day 1	Number Analyzed	138 participants	124 participants
		0.071; (0.0327 to 0.1097)	0.101; (0.0665 to 0.1353)
Cycle 4 Day 1	Number Analyzed	131 participants	121 participants
		0.089; (0.0520 to 0.1254)	0.098; (0.0619 to 0.1338)
Cycle 5 Day 1	Number Analyzed	130 participants	114 participants
		0.047; (0.0061 to 0.0887)	0.100; (0.0626 to 0.1373)
Cycle 6 Day 1	Number Analyzed	126 participants	104 participants
		0.077; (0.0407 to 0.1124)	0.070; (0.0324 to 0.1077)
Cycle 7 Day 1	Number Analyzed	121 participants	99 participants
		0.062; (0.0180 to 0.1052)	0.046; (0.0002 to 0.0910)
Cycle 8 Day 1	Number Analyzed	124 participants	93 participants
		0.074; (0.0340 to 0.1133)	0.061; (0.0201 to 0.1011)
Cycle 9 Day 1	Number Analyzed	118 participants	82 participants
		0.060; (0.0175 to 0.1028)	0.050; (0.0082 to 0.0919)
Cycle 10 Day 1	Number Analyzed	115 participants	75 participants
		0.074; (0.0303 to 0.1179)	0.050; (0.0168 to 0.0826)
Cycle 11 Day 1	Number Analyzed	116 participants	73 participants
		0.083; (0.0418 to 0.1237)	0.057; (0.0222 to 0.0914)
Cycle 12 Day 1	Number Analyzed	116 participants	61 participants
		0.080; (0.0390 to 0.1201)	0.049; (0.0118 to 0.0864)
Cycle 13 Day 1	Number Analyzed	113 participants	56 participants
		0.081; (0.0365 to 0.1259)	0.055; (0.0165 to 0.0931)
Cycle 14 Day 1	Number Analyzed	110 participants	48 participants
		0.091; (0.0490 to 0.1322)	0.021; (-0.0157 to 0.0576)
Cycle 15 Day 1	Number Analyzed	110 participants	43 participants
		0.077; (0.0314 to 0.1217)	0.036; (-0.0100 to 0.0811)
Cycle 16 Day 1	Number Analyzed	103 participants	39 participants
		0.091; (0.0469 to 0.1347)	0.051; (0.0070 to 0.0953)
Cycle 17 Day 1	Number Analyzed	91 participants	31 participants
		0.098; (0.0523 to 0.1434)	-0.016; (-0.1000 to 0.0685)
Cycle 18 Day 1	Number Analyzed	84 participants	28 participants
		0.103; (0.0520 to 0.1531)	0.021; (-0.0296 to 0.0716)
Cycle 19 Day 1	Number Analyzed	79 participants	21 participants
		0.100; (0.0481 to 0.1518)	0.027; (-0.0246 to 0.0793)
Cycle 20 Day 1	Number Analyzed	69 participants	18 participants
		0.103; (0.0459 to 0.1596)	0.025; (-0.0593 to 0.1090)
Cycle 21 Day 1	Number Analyzed	65 participants	17 participants
		0.068; (0.0091 to 0.1276)	0.040; (-0.0187 to 0.0989)
Cycle 22 Day 1	Number Analyzed	56 participants	14 participants
		0.079; (0.0134 to 0.1447)	0.052; (-0.0249 to 0.1289)
Cycle 23 Day 1	Number Analyzed	48 participants	12 participants
		0.060; (-0.0127 to 0.1324)	0.006; (-0.2020 to 0.2133)
Cycle 24 Day 1	Number Analyzed	44 participants	10 participants
		0.082; (0.0104 to 0.1531)	-0.053; (-0.2793 to 0.1731)
Cycle 25 Day 1	Number Analyzed	39 participants	9 participants
		0.047; (-0.0287 to 0.1231)	0.045; (-0.0289 to 0.1194)
Cycle 26 Day 1	Number Analyzed	35 participants	9 participants
		0.065; (-0.0218 to 0.1519)	0.039; (-0.0200 to 0.0978)
Cycle 27 Day 1	Number Analyzed	30 participants	7 participants
		0.042; (-0.0603 to 0.1434)	0.021; (-0.0867 to 0.1292)
Cycle 28 Day 1	Number Analyzed	23 participants	6 participants
		0.024; (-0.0911 to 0.1399)	-0.040; (-0.1640 to 0.0836)
Cycle 29 Day 1	Number Analyzed	20 participants	5 participants
		0.046; (-0.0836 to 0.1755)	0.041; (-0.0108 to 0.0928)
Cycle 30 Day 1	Number Analyzed	14 participants	4 participants
		0.099; (-0.0355 to 0.2306)	-0.028; (-0.1740 to 0.1190)
Cycle 31 Day 1	Number Analyzed	12 participants	2 participants
		0.086; (-0.0957 to 0.2683)	-0.024; (-0.8558 to 0.8088)
Cycle 32 Day 1	Number Analyzed	10 participants	2 participants
		0.058; (-0.1601 to 0.2767)	-0.139; (-2.4320 to 2.1550)
Cycle 33 Day 1	Number Analyzed	8 participants	2 participants
		0.058; (-0.2006 to 0.3163)	-0.024; (-0.8558 to 0.8088)
Cycle 34 Day 1	Number Analyzed	6 participants	1 participants
		0.062; (-0.2820 to 0.4057)	0.042
Cycle 35 Day 1	Number Analyzed	4 participants	1 participants
		0.129; (-0.1098 to 0.3668)	0.042
Cycle 36 Day 1	Number Analyzed	2 participants	1 participants
		-0.027; (-1.7736 to 1.7206)	0.042
Cycle 37 Day 1	Number Analyzed	2 participants	0 participants
		0.056; (-0.6497 to 0.7607)
Cycle 38 Day 1	Number Analyzed	1 participants	0 participants
		0.232
End of Treatment	Number Analyzed	27 participants	79 participants
		-0.033; (-0.1513 to 0.0852)	0.001; (-0.0769 to 0.0782)

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.
Overall Number of Participants Analyzed	146	139
Median (95% Confidence Interval); Unit of Measure: Months
	3.3; (2.1 to 4.7)	3.7; (2.0 to 5.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lorlatinib, Crizotinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7293
	Comments	[Not Specified]
	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
	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.
Overall Number of Participants Analyzed		130	125
Measure Type: Count of Participants; Unit of Measure: Participants
at Screening	Number Analyzed	130 participants	125 participants
	≥1 ALK Mutation Detected	5 3.8%	6 4.8%
	No ALK Mutation Detected	88 67.7%	91 72.8%
	No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	32 24.6%	25 20.0%
	Other (Sample failed analysis, uninformative, or not analyzed.)	5 3.8%	3 2.4%
Cycle 2 Day 1	Number Analyzed	125 participants	118 participants
	≥1 ALK Mutation Detected	2 1.6%	3 2.5%
	No ALK Mutation Detected	66 52.8%	55 46.6%
	No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	53 42.4%	58 49.2%
	Other (Sample failed analysis, uninformative, or not analyzed.)	4 3.2%	2 1.7%
Cycle 7 Day 1	Number Analyzed	103 participants	84 participants
	≥1 ALK Mutation Detected	3 2.9%	5 6.0%
	No ALK Mutation Detected	45 43.7%	42 50.0%
	No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	52 50.5%	35 41.7%
	Other (Sample failed analysis, uninformative, or not analyzed.)	3 2.9%	2 2.4%

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.
Overall Number of Participants Analyzed		130	125
Measure Type: Count of Participants; Unit of Measure: Participants
at Screening	Number Analyzed	130 participants	125 participants
	EML4-ALK Variant 1	19 14.6%	25 20.0%
	EML4-ALK Variant 2	7 5.4%	2 1.6%
	EML4-ALK Variant 3	18 13.8%	21 16.8%
	EML4-ALK Other	15 11.5%	9 7.2%
	ALK Rearrangement Other	2 1.5%	4 3.2%
	ALK Rearrangement Not Detected	32 24.6%	36 28.8%
	No cfDNA Detected	32 24.6%	25 20.0%
	Other (Sample failed analysis, uninformative, or not analyzed.)	5 3.8%	3 2.4%
Cycle 2 Day 1	Number Analyzed	125 participants	118 participants
	EML4-ALK Variant 1	1 0.8%	7 5.9%
	EML4-ALK Variant 2	2 1.6%	0 0.0%
	EML4-ALK Variant 3	2 1.6%	2 1.7%
	EML4-ALK Other	2 1.6%	1 0.8%
	ALK Rearrangement Other	0 0.0%	0 0.0%
	ALK Rearrangement Not Detected	61 48.8%	48 40.7%
	No cfDNA Detected	53 42.4%	58 49.2%
	Other (Sample failed analysis, uninformative, or not analyzed.)	4 3.2%	2 1.7%
Cycle 7 Day 1	Number Analyzed	103 participants	84 participants
	EML4-ALK Variant 1	0 0.0%	5 6.0%
	EML4-ALK Variant 2	0 0.0%	1 1.2%
	EML4-ALK Variant 3	0 0.0%	4 4.8%
	EML4-ALK Other	0 0.0%	1 1.2%
	ALK Rearrangement Other	0 0.0%	2 2.4%
	ALK Rearrangement Not Detected	48 46.6%	34 40.5%
	No cfDNA Detected	52 50.5%	35 41.7%
	Other (Sample failed analysis, uninformative, or not analyzed.)	3 2.9%	2 2.4%

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 (%)	Affected / at Risk (%)
Total	23/149 (15.44%)	28/142 (19.72%)
Serious Adverse Events
	Lorlatinib	Crizotinib
	Affected / at Risk (%)	Affected / at Risk (%)
Total	51/149 (34.23%)	39/142 (27.46%)
Blood and lymphatic system disorders
Anaemia * 1	1/149 (0.67%)	0/142 (0.00%)
Cardiac disorders
Cardiac disorder * 1	1/149 (0.67%)	0/142 (0.00%)
Cardiac failure * 1	2/149 (1.34%)	1/142 (0.70%)
Cardiac failure acute * 1	1/149 (0.67%)	0/142 (0.00%)
Cardiac tamponade * 1	1/149 (0.67%)	0/142 (0.00%)
Left ventricular dysfunction * 1	1/149 (0.67%)	0/142 (0.00%)
Pericardial effusion * 1	2/149 (1.34%)	1/142 (0.70%)
Sinus node dysfunction * 1	0/149 (0.00%)	1/142 (0.70%)
Eye disorders
Blindness cortical * 1	0/149 (0.00%)	1/142 (0.70%)
Retinal detachment * 1	0/149 (0.00%)	1/142 (0.70%)
Gastrointestinal disorders
Constipation * 1	0/149 (0.00%)	1/142 (0.70%)
Diarrhoea * 1	1/149 (0.67%)	0/142 (0.00%)
Dyspepsia * 1	0/149 (0.00%)	1/142 (0.70%)
Oesophagitis * 1	0/149 (0.00%)	1/142 (0.70%)
Pancreatitis * 1	1/149 (0.67%)	0/142 (0.00%)
General disorders
Death * 1	1/149 (0.67%)	1/142 (0.70%)
Disease progression * 1	1/149 (0.67%)	1/142 (0.70%)
Generalised oedema * 1	1/149 (0.67%)	0/142 (0.00%)
Pyrexia * 1	3/149 (2.01%)	3/142 (2.11%)
Hepatobiliary disorders
Cholecystitis chronic * 1	0/149 (0.00%)	1/142 (0.70%)
Hepatic function abnormal * 1	0/149 (0.00%)	1/142 (0.70%)
Liver injury * 1	0/149 (0.00%)	1/142 (0.70%)
Immune system disorders
Anaphylactic reaction * 1	1/149 (0.67%)	0/142 (0.00%)
Infections and infestations
Bacterial infection * 1	0/149 (0.00%)	1/142 (0.70%)
Bronchitis * 1	2/149 (1.34%)	0/142 (0.00%)
Clostridium difficile colitis * 1	0/149 (0.00%)	1/142 (0.70%)
Gastroenteritis * 1	0/149 (0.00%)	1/142 (0.70%)
Haemophilus infection * 1	1/149 (0.67%)	0/142 (0.00%)
Lung abscess * 1	1/149 (0.67%)	0/142 (0.00%)
Pharyngeal abscess * 1	0/149 (0.00%)	1/142 (0.70%)
Pharyngitis * 1	1/149 (0.67%)	0/142 (0.00%)
Pneumonia * 1	7/149 (4.70%)	5/142 (3.52%)
Pneumonia cryptococcal * 1	1/149 (0.67%)	0/142 (0.00%)
Respiratory tract infection * 1	1/149 (0.67%)	0/142 (0.00%)
Sepsis * 1	2/149 (1.34%)	0/142 (0.00%)
Tuberculosis * 1	0/149 (0.00%)	1/142 (0.70%)
Upper respiratory tract infection * 1	1/149 (0.67%)	1/142 (0.70%)
Urinary tract infection * 1	1/149 (0.67%)	0/142 (0.00%)
Injury, poisoning and procedural complications
Femoral neck fracture * 1	0/149 (0.00%)	1/142 (0.70%)
Femur fracture * 1	0/149 (0.00%)	1/142 (0.70%)
Fracture * 1	1/149 (0.67%)	0/142 (0.00%)
Hip fracture * 1	1/149 (0.67%)	0/142 (0.00%)
Lower limb fracture * 1	1/149 (0.67%)	0/142 (0.00%)
Multiple injuries * 1	1/149 (0.67%)	0/142 (0.00%)
Pelvic fracture * 1	0/149 (0.00%)	1/142 (0.70%)
Skin laceration * 1	1/149 (0.67%)	0/142 (0.00%)
Investigations
Blood triglycerides increased * 1	1/149 (0.67%)	0/142 (0.00%)
Haemoglobin decreased * 1	1/149 (0.67%)	0/142 (0.00%)
Neutrophil count decreased * 1	0/149 (0.00%)	1/142 (0.70%)
Platelet count decreased * 1	0/149 (0.00%)	1/142 (0.70%)
Metabolism and nutrition disorders
Diabetes mellitus * 1	1/149 (0.67%)	0/142 (0.00%)
Hypercholesterolaemia * 1	1/149 (0.67%)	0/142 (0.00%)
Hypertriglyceridaemia * 1	1/149 (0.67%)	0/142 (0.00%)
Hypocalcaemia * 1	0/149 (0.00%)	1/142 (0.70%)
Hyponatraemia * 1	1/149 (0.67%)	1/142 (0.70%)
Musculoskeletal and connective tissue disorders
Back pain * 1	2/149 (1.34%)	0/142 (0.00%)
Muscular weakness * 1	0/149 (0.00%)	1/142 (0.70%)
Osteoarthritis * 1	1/149 (0.67%)	0/142 (0.00%)
Pain in extremity * 1	1/149 (0.67%)	0/142 (0.00%)
Rotator cuff syndrome * 1	1/149 (0.67%)	0/142 (0.00%)
Spondylitis * 1	1/149 (0.67%)	0/142 (0.00%)
Tenosynovitis * 1	1/149 (0.67%)	0/142 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial adenocarcinoma * 1	1/149 (0.67%)	0/142 (0.00%)
Follicle centre lymphoma, follicular grade I, II, III * 1	1/149 (0.67%)	0/142 (0.00%)
Lung neoplasm malignant * 1	1/149 (0.67%)	0/142 (0.00%)
Malignant neoplasm progression * 1	0/149 (0.00%)	2/142 (1.41%)
Neoplasm progression * 1	0/149 (0.00%)	1/142 (0.70%)
Nervous system disorders
Carpal tunnel syndrome * 1	1/149 (0.67%)	0/142 (0.00%)
Cerebral infarction * 1	0/149 (0.00%)	1/142 (0.70%)
Cognitive disorder * 1	1/149 (0.67%)	0/142 (0.00%)
Ischaemic stroke * 1	0/149 (0.00%)	1/142 (0.70%)
Speech disorder * 1	1/149 (0.67%)	0/142 (0.00%)
Thalamus haemorrhage * 1	1/149 (0.67%)	0/142 (0.00%)
Psychiatric disorders
Confusional state * 1	1/149 (0.67%)	0/142 (0.00%)
Delirium * 1	1/149 (0.67%)	0/142 (0.00%)
Intentional self-injury * 1	1/149 (0.67%)	0/142 (0.00%)
Renal and urinary disorders
Renal failure * 1	1/149 (0.67%)	0/142 (0.00%)
Urinary retention * 1	0/149 (0.00%)	1/142 (0.70%)
Urinary tract disorder * 1	1/149 (0.67%)	0/142 (0.00%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease * 1	1/149 (0.67%)	0/142 (0.00%)
Dyspnoea * 1	4/149 (2.68%)	0/142 (0.00%)
Epistaxis * 1	0/149 (0.00%)	1/142 (0.70%)
Pleural effusion * 1	2/149 (1.34%)	2/142 (1.41%)
Pneumonitis * 1	2/149 (1.34%)	2/142 (1.41%)
Pneumothorax * 1	1/149 (0.67%)	0/142 (0.00%)
Pulmonary embolism * 1	1/149 (0.67%)	2/142 (1.41%)
Respiratory failure * 1	4/149 (2.68%)	0/142 (0.00%)
Surgical and medical procedures
Radiotherapy to bone * 1	1/149 (0.67%)	0/142 (0.00%)
Vascular disorders
Aortitis * 1	0/149 (0.00%)	1/142 (0.70%)
Hypertensive crisis * 1	1/149 (0.67%)	0/142 (0.00%)
Thrombosis * 1	0/149 (0.00%)	1/142 (0.70%)
1 Term from vocabulary, MedDRA v23.0; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Lorlatinib	Crizotinib
	Affected / at Risk (%)	Affected / at Risk (%)
Total	148/149 (99.33%)	140/142 (98.59%)
Blood and lymphatic system disorders
Anaemia * 1	29/149 (19.46%)	11/142 (7.75%)
Neutropenia * 1	10/149 (6.71%)	21/142 (14.79%)
Cardiac disorders
Bradycardia * 1	2/149 (1.34%)	17/142 (11.97%)
Sinus bradycardia * 1	4/149 (2.68%)	15/142 (10.56%)
Ear and labyrinth disorders
Tinnitus * 1	9/149 (6.04%)	1/142 (0.70%)
Eye disorders
Photopsia * 1	1/149 (0.67%)	24/142 (16.90%)
Vision blurred * 1	11/149 (7.38%)	4/142 (2.82%)
Visual impairment * 1	10/149 (6.71%)	16/142 (11.27%)
Gastrointestinal disorders
Abdominal distension * 1	9/149 (6.04%)	3/142 (2.11%)
Abdominal pain * 1	7/149 (4.70%)	11/142 (7.75%)
Constipation * 1	26/149 (17.45%)	41/142 (28.87%)
Diarrhoea * 1	32/149 (21.48%)	74/142 (52.11%)
Flatulence * 1	11/149 (7.38%)	3/142 (2.11%)
Nausea * 1	22/149 (14.77%)	74/142 (52.11%)
Vomiting * 1	19/149 (12.75%)	55/142 (38.73%)
General disorders
Asthenia * 1	20/149 (13.42%)	27/142 (19.01%)
Chest pain * 1	16/149 (10.74%)	20/142 (14.08%)
Fatigue * 1	11/149 (7.38%)	24/142 (16.90%)
Oedema * 1	16/149 (10.74%)	13/142 (9.15%)
Oedema peripheral * 1	65/149 (43.62%)	44/142 (30.99%)
Pain * 1	5/149 (3.36%)	8/142 (5.63%)
Pyrexia * 1	22/149 (14.77%)	16/142 (11.27%)
Infections and infestations
Bronchitis * 1	9/149 (6.04%)	3/142 (2.11%)
Nasopharyngitis * 1	8/149 (5.37%)	10/142 (7.04%)
Pneumonia * 1	5/149 (3.36%)	8/142 (5.63%)
Respiratory tract infection * 1	12/149 (8.05%)	6/142 (4.23%)
Upper respiratory tract infection * 1	16/149 (10.74%)	11/142 (7.75%)
Urinary tract infection * 1	6/149 (4.03%)	10/142 (7.04%)
Investigations
Alanine aminotransferase increased * 1	26/149 (17.45%)	48/142 (33.80%)
Amylase increased * 1	13/149 (8.72%)	16/142 (11.27%)
Aspartate aminotransferase increased * 1	21/149 (14.09%)	39/142 (27.46%)
Blood alkaline phosphatase increased * 1	7/149 (4.70%)	18/142 (12.68%)
Blood cholesterol increased * 1	59/149 (39.60%)	4/142 (2.82%)
Blood creatine phosphokinase increased * 1	16/149 (10.74%)	24/142 (16.90%)
Blood creatinine increased * 1	9/149 (6.04%)	19/142 (13.38%)
Blood lactate dehydrogenase increased * 1	3/149 (2.01%)	15/142 (10.56%)
Blood triglycerides increased * 1	19/149 (12.75%)	2/142 (1.41%)
Electrocardiogram QT prolonged * 1	5/149 (3.36%)	8/142 (5.63%)
Gamma-glutamyltransferase increased * 1	22/149 (14.77%)	22/142 (15.49%)
Lipase increased * 1	14/149 (9.40%)	17/142 (11.97%)
Neutrophil count decreased * 1	3/149 (2.01%)	16/142 (11.27%)
Weight decreased * 1	4/149 (2.68%)	10/142 (7.04%)
Weight increased * 1	57/149 (38.26%)	18/142 (12.68%)
White blood cell count decreased * 1	1/149 (0.67%)	11/142 (7.75%)
Metabolism and nutrition disorders
Decreased appetite * 1	5/149 (3.36%)	35/142 (24.65%)
Dyslipidaemia * 1	9/149 (6.04%)	0/142 (0.00%)
Hypercholesterolaemia * 1	53/149 (35.57%)	1/142 (0.70%)
Hyperglycaemia * 1	15/149 (10.07%)	5/142 (3.52%)
Hyperlipidaemia * 1	16/149 (10.74%)	0/142 (0.00%)
Hypertriglyceridaemia * 1	78/149 (52.35%)	6/142 (4.23%)
Hyperuricaemia * 1	12/149 (8.05%)	4/142 (2.82%)
Hypoalbuminaemia * 1	8/149 (5.37%)	18/142 (12.68%)
Hypocalcaemia * 1	2/149 (1.34%)	8/142 (5.63%)
Hypokalaemia * 1	9/149 (6.04%)	4/142 (2.82%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	28/149 (18.79%)	16/142 (11.27%)
Back pain * 1	22/149 (14.77%)	16/142 (11.27%)
Musculoskeletal pain * 1	8/149 (5.37%)	5/142 (3.52%)
Myalgia * 1	16/149 (10.74%)	5/142 (3.52%)
Pain in extremity * 1	25/149 (16.78%)	12/142 (8.45%)
Nervous system disorders
Dizziness * 1	16/149 (10.74%)	20/142 (14.08%)
Dysgeusia * 1	8/149 (5.37%)	23/142 (16.20%)
Headache * 1	25/149 (16.78%)	25/142 (17.61%)
Hypoaesthesia * 1	8/149 (5.37%)	7/142 (4.93%)
Memory impairment * 1	13/149 (8.72%)	3/142 (2.11%)
Neuropathy peripheral * 1	13/149 (8.72%)	0/142 (0.00%)
Paraesthesia * 1	18/149 (12.08%)	7/142 (4.93%)
Peripheral sensory neuropathy * 1	10/149 (6.71%)	1/142 (0.70%)
Psychiatric disorders
Anxiety * 1	10/149 (6.71%)	3/142 (2.11%)
Insomnia * 1	14/149 (9.40%)	13/142 (9.15%)
Renal and urinary disorders
Proteinuria * 1	9/149 (6.04%)	1/142 (0.70%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	24/149 (16.11%)	26/142 (18.31%)
Dyspnoea * 1	28/149 (18.79%)	23/142 (16.20%)
Oropharyngeal pain * 1	9/149 (6.04%)	8/142 (5.63%)
Productive cough * 1	12/149 (8.05%)	4/142 (2.82%)
Skin and subcutaneous tissue disorders
Hyperhidrosis * 1	8/149 (5.37%)	0/142 (0.00%)
Rash * 1	15/149 (10.07%)	11/142 (7.75%)
Vascular disorders
Hypertension * 1	27/149 (18.12%)	3/142 (2.11%)
1 Term from vocabulary, MedDRA v23.0; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Solomon BJ, Bauer TM, Ignatius Ou SH, Liu G, Hayashi H, Bearz A, Penkov K, Wu YL, Arrieta O, Jassem J, Calella AM, Peltz G, Polli A, Thurm H, Mok T. Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study. J Clin Oncol. 2022 Nov 1;40(31):3593-3602. doi: 10.1200/JCO.21.02278. Epub 2022 May 23.

Solomon BJ, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, Mazieres J, Kim DW, Mok T, Polli A, Thurm H, Calella AM, Peltz G, Shaw AT. Plain language summary of the CROWN study comparing lorlatinib with crizotinib for people with untreated non-small cell lung cancer. Future Oncol. 2021 Dec 1;17(34):4649-4656. doi: 10.2217/fon-2021-0904. Epub 2021 Sep 29.

Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, Mazieres J, Kim DW, Mok T, Polli A, Thurm H, Calella AM, Peltz G, Solomon BJ; CROWN Trial Investigators. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020 Nov 19;383(21):2018-2029. doi: 10.1056/NEJMoa2027187.

Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, Gainor JF, Johnson M, Dietrich J, James LP, Clancy JS, Chen J, Martini JF, Abbattista A, Solomon BJ. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017 Dec;18(12):1590-1599. doi: 10.1016/S1470-2045(17)30680-0. Epub 2017 Oct 23.

Gainor JF, Shaw AT. J-ALEX: alectinib versus crizotinib in ALK-positive lung cancer. Lancet. 2017 Jul 1;390(10089):3-4. doi: 10.1016/S0140-6736(17)31074-7. Epub 2017 May 10. No abstract available.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03052608
• Other Study ID Numbers: B7461006; 2016-003315-35 ( EudraCT Number )
• First Submitted: January 20, 2017
• First Posted: February 14, 2017
• Results First Submitted: March 5, 2021
• Results First Posted: April 1, 2021
• Last Update Posted: February 20, 2024