Trial Outcomes & Findings for A Study Of Lorlatinib Versus Crizotinib In First Line Treatment Of Patients With ALK-Positive NSCLC (NCT NCT03052608)

Last Updated: 2024-12-24

Results Overview

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.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

296 participants

Primary outcome timeframe

From time of Study Start up to 33 months

Results posted on

2024-12-24

Participant Flow

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.

Previously untreated Stage IIIB/IV participants with ALK-positive non-small cell lung cancer were randomized in this study.

Participant milestones

Participant milestones
Measure	Lorlatinib 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 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.
Treatment Phase STARTED	149	147
Treatment Phase COMPLETED	26	83
Treatment Phase NOT COMPLETED	123	64
Long-Term Follow-up Phase STARTED	149	147
Long-Term Follow-up Phase COMPLETED	0	0
Long-Term Follow-up Phase NOT COMPLETED	149	147

Reasons for withdrawal

Reasons for withdrawal
Measure	Lorlatinib 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 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.
Treatment Phase Adverse Event	10	12
Treatment Phase Death	6	4
Treatment Phase Withdrawal by Subject	4	12
Treatment Phase Global Deterioration of Health Status	0	3
Treatment Phase Subject decided to continue study treatment as per clinical practice in another hospital.	0	1
Treatment Phase Subject didn't receive study treatment.	0	1
Treatment Phase Ongoing	103	31
Long-Term Follow-up Phase Death	23	28
Long-Term Follow-up Phase Lost to Follow-up	0	2
Long-Term Follow-up Phase Withdrawal by Subject	4	18
Long-Term Follow-up Phase Ongoing	122	99

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lorlatinib n=149 Participants 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 n=147 Participants 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 n=296 Participants Total of all reporting groups
Age, Continuous	59.1 Years STANDARD_DEVIATION 13.12 • n=5 Participants	55.6 Years STANDARD_DEVIATION 13.52 • n=7 Participants	57.4 Years STANDARD_DEVIATION 13.41 • n=5 Participants
Sex: Female, Male Female	84 Participants n=5 Participants	91 Participants n=7 Participants	175 Participants n=5 Participants
Sex: Female, Male Male	65 Participants n=5 Participants	56 Participants n=7 Participants	121 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	72 Participants n=5 Participants	72 Participants n=7 Participants	144 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	65 Participants n=5 Participants	65 Participants n=7 Participants	130 Participants n=5 Participants
Race/Ethnicity, Customized Race · Missing	12 Participants n=5 Participants	9 Participants n=7 Participants	21 Participants n=5 Participants

PRIMARY outcome

Timeframe: From time of Study Start up to 33 months

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

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=147 Participants 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.
Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) Assessment	NA Months The values were not estimable because there were insufficient events to estimate the median PFS time and 95% confidence interval.	9.3 Months Interval 7.6 to 11.1

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=147 Participants 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 Survival (OS)	NA Months The values were not estimable because there were insufficient events to estimate the median OS time and 95% confidence interval.	NA Months The values were not estimable because there were insufficient events to estimate the median OS time and 95% confidence interval.

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=147 Participants 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.
Progression-Free Survival (PFS) Based on Investigator's Assessment	NA Months The values were not estimable because there were insufficient events to estimate the median PFS time and 95% confidence interval.	9.1 Months Interval 7.4 to 10.9

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=147 Participants 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.
Objective Response Rate (ORR) - Percentage of Participants With Objective Response (OR) Based on BICR Assessment	75.8 Percentage of participants Interval 68.2 to 82.5	57.8 Percentage of participants Interval 49.4 to 65.9

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=147 Participants 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.
Objective Response Rate (ORR) - Percentage of Participants With Objective Response (OR) Based on Investigator's Assessment	80.5 Percentage of participants Interval 73.3 to 86.6	61.9 Percentage of participants Interval 53.5 to 69.8

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=38 Participants 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 n=40 Participants 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.
Intracranial Objective Response Rate (IC-ORR) - Percentage of Participants With Intracranial Objective Response (IC-OR) Based on BICR Assessment	65.8 Percentage of participants Interval 48.6 to 80.4	20.0 Percentage of participants Interval 9.1 to 35.6

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=147 Participants 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.
Intracranial Time to Progression (IC-TTP) Based on BICR Assessment	NA Months The values were not estimable because there were insufficient events to estimate the median IC-TTP time and 95% confidence interval.	16.6 Months Interval 11.1 to The value was not estimable because there were insufficient events to estimate the upper bound of the 95% confidence interval.

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=113 Participants 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 n=85 Participants 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.
Duration of Response (DR) Based on BICR Assessment	NA Months The values were not estimable because there were insufficient events to estimate the median DR time and the 95% confidence interval.	11.0 Months Interval 9.0 to 12.9

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=25 Participants 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 n=8 Participants 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.
Intracranial Duration of Response (IC-DR) Based on BICR Assessment	NA Months The values were not estimable because there were insufficient events to estimate the median IC-DR time and the 95% confidence interval.	9.4 Months Interval 6.0 to 11.1

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=113 Participants 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 n=85 Participants 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.
Time to Tumor Response (TTR) Based on BICR Assessment	1.8 Months Interval 1.7 to 1.9	1.8 Months Interval 1.7 to 1.9

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=25 Participants 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 n=8 Participants 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.
Intracranial Time to Tumor Response (IC-TTR) Based on BICR Assessment	1.9 Months Interval 1.8 to 3.7	1.8 Months Interval 1.7 to 2.7

SECONDARY outcome

Timeframe: From time of Study Start up to 45 months

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From time of Study Start up to 33 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=142 Participants 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.
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) AEs (all-causality)	149 Participants	140 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) AEs (treatment-related)	144 Participants	133 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) SAEs (all-causality)	51 Participants	39 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) SAEs (treatment-related)	12 Participants	7 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) Maximum Grade 3 or 4 AEs (all-causality)	108 Participants	79 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) Maximum Grade 3 or 4 AEs (treatment-related)	83 Participants	52 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) Maximum Grade 5 AEs (all-causality)	7 Participants	7 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) Maximum Grade 5 AEs (treatment-related)	2 Participants	0 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) AEs causing study discontinuation (all-causality)	7 Participants	8 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) AEs causing study discontinuation (treatment-related)	2 Participants	0 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) AEs causing study treatment discontinuation (all-causality)	10 Participants	13 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) AEs causing study treatment discontinuation (treatment-related)	7 Participants	7 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) AEs causing dose reduction or temporary discontinuation (all-causality)	79 Participants	71 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs; All-Causality and Treatment-Related) AEs causing dose reduction or temporary discontinuation (treatment-related)	60 Participants	54 Participants

SECONDARY outcome

Timeframe: From Baseline up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=141 Participants 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.
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 Anemia (Postbaseline Maximum Grade 3)	3 Participants	4 Participants
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 Anemia (Postbaseline Maximum Grade 4)	NA Participants CTCAE grade not defined.	NA Participants CTCAE grade not defined.
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 Hemoglobin increased (Postbaseline Maximum Grade 3)	0 Participants	0 Participants
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 Hemoglobin increased (Postbaseline Maximum Grade 4)	NA Participants CTCAE grade not defined.	NA Participants CTCAE grade not defined.
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 Lymphocyte count decreased (Postbaseline Maximum Grade 3)	2 Participants	7 Participants
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 Lymphocyte count decreased (Postbaseline Maximum Grade 4)	2 Participants	1 Participants
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 Lymphocyte count increased (Postbaseline Maximum Grade 3)	0 Participants	0 Participants
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 Lymphocyte count increased (Postbaseline Maximum Grade 4)	NA Participants CTCAE grade not defined.	NA Participants CTCAE grade not defined.
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 Neutrophil count decreased (Postbaseline Maximum Grade 3)	1 Participants	19 Participants
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 Neutrophil count decreased (Postbaseline Maximum Grade 4)	1 Participants	4 Participants
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 Platelet count decreased (Postbaseline Maximum Grade 3)	0 Participants	1 Participants
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 Platelet count decreased (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 White blood cell decreased (Postbaseline Maximum Grade 3)	0 Participants	5 Participants
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 White blood cell decreased (Postbaseline Maximum Grade 4)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From Baseline up to 33 months

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

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=141 Participants 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.
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 Alanine aminotransferase increased (Postbaseline Maximum Grade 3)	4 Participants	5 Participants
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 Alanine aminotransferase increased (Postbaseline Maximum Grade 4)	0 Participants	1 Participants
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 Alkaline phosphate increased (Postbaseline Maximum Grade 3)	0 Participants	1 Participants
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 Alkaline phosphate increased (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Aspartate aminotransferase increased (Postbaseline Maximum Grade 3)	3 Participants	4 Participants
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 Aspartate aminotransferase increased (Postbaseline Maximum Grade 4)	0 Participants	1 Participants
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 Blood bilirubin increased (Postbaseline Maximum Grade 3)	0 Participants	0 Participants
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 Blood bilirubin increased (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Creatine kinase increased (Postbaseline Maximum Grade 3)	3 Participants	5 Participants
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 Creatine kinase increased (Postbaseline Maximum Grade 4)	0 Participants	2 Participants
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 Creatinine increased (Postbaseline Maximum Grade 3)	1 Participants	3 Participants
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 Creatinine increased (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Gamma glutamyl transferase increased (Postbaseline Maximum Grade 3)	9 Participants	8 Participants
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 Gamma glutamyl transferase increased (Postbaseline Maximum Grade 4)	0 Participants	1 Participants
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 Hypercalcemia (Postbaseline Maximum Grade 3)	0 Participants	0 Participants
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 Hypercalcemia (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Hyperglycemia (Postbaseline Maximum Grade 3)	9 Participants	3 Participants
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 Hyperglycemia (Postbaseline Maximum Grade 4)	1 Participants	0 Participants
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 Hyperkalemia (Postbaseline Maximum Grade 3)	2 Participants	3 Participants
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 Hyperkalemia (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Hypermagnesemia (Postbaseline Maximum Grade 3)	2 Participants	1 Participants
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 Hypermagnesemia (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Hypernatremia (Postbaseline Maximum Grade 3)	0 Participants	0 Participants
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 Hypernatremia (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Hypoalbuminemia (Postbaseline Maximum Grade 3)	1 Participants	9 Participants
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 Hypoalbuminemia (Postbaseline Maximum Grade 4)	NA Participants CTCAE grade not defined.	NA Participants CTCAE grade not defined.
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 Hypocalcemia (Postbaseline Maximum Grade 3)	1 Participants	0 Participants
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 Hypocalcemia (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Hypoglycemia (Postbaseline Maximum Grade 3)	0 Participants	0 Participants
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 Hypoglycemia (Postbaseline Maximum Grade 4)	0 Participants	1 Participants
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 Hypokalemia (Postbaseline Maximum Grade 3)	0 Participants	3 Participants
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 Hypokalemia (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Hypomagnesemia (Postbaseline Maximum Grade 3)	0 Participants	0 Participants
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 Hypomagnesemia (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Hyponatremia (Postbaseline Maximum Grade 3)	5 Participants	10 Participants
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 Hyponatremia (Postbaseline Maximum Grade 4)	0 Participants	1 Participants
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 Hypophosphatemia (Postbaseline Maximum Grade 3)	3 Participants	4 Participants
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 Hypophosphatemia (Postbaseline Maximum Grade 4)	0 Participants	0 Participants
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 Lipase increased (Postbaseline Maximum Grade 3)	8 Participants	6 Participants
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 Lipase increased (Postbaseline Maximum Grade 4)	3 Participants	1 Participants
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 Serum amylase increased (Postbaseline Maximum Grade 3)	1 Participants	2 Participants
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 Serum amylase increased (Postbaseline Maximum Grade 4)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From Baseline up to 33 months

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

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=141 Participants 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.
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 Cholesterol high (Postbaseline Maximum Grade 3)	26 Participants	0 Participants
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 Cholesterol high (Postbaseline Maximum Grade 4)	3 Participants	0 Participants
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 Hypertriglyceridemia (Postbaseline Maximum Grade 3)	20 Participants	0 Participants
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 Hypertriglyceridemia (Postbaseline Maximum Grade 4)	13 Participants	0 Participants

SECONDARY outcome

Timeframe: From Baseline up to 33 months

Population: "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.

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%.

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=142 Participants 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.
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting pulse rate: pulse >120 bpm	7 Participants	1 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting pulse rate: pulse <50 bpm	4 Participants	22 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting pulse rate: change ≥30 bpm increase	24 Participants	3 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting pulse rate: change ≥30 bpm decrease	17 Participants	47 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting systolic blood pressure: change ≥40 mmHg increase	22 Participants	3 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting systolic blood pressure: change ≥40 mmHg decrease	6 Participants	14 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting systolic blood pressure: change ≥60 mmHg decrease	0 Participants	1 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting diastolic blood pressure: change ≥20 mmHg increase	41 Participants	18 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting diastolic blood pressure: change ≥40 mmHg decrease	0 Participants	1 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Body weight (kg): percent change from baseline ≥10% increase	99 Participants	39 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Body weight (kg): percent change from baseline ≥20% increase	35 Participants	3 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Body weight (kg): percent change from baseline ≥10% decrease	6 Participants	12 Participants
Number of Participant With Vital Signs and Body Weight Data Meeting Pre-defined Criteria Sitting diastolic blood pressure: change ≥20 mmHg decrease	26 Participants	52 Participants

SECONDARY outcome

Timeframe: From Baseline up to 33 months

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

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=142 Participants 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.
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria Change of QTcF ≥60 msec	5 Participants	16 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria 30 msec ≤ Change of QTcF <60 msec	49 Participants	41 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria Change of QTcF <30 msec	92 Participants	81 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria Change of QTcB ≥60 msec	10 Participants	15 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria 30 msec ≤ Change of QTcB <60 msec	49 Participants	26 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria Change of QTcB <30 msec	90 Participants	100 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria PR change ≥50% if absolute baseline value was <200 msec	8 Participants	4 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria PR change ≥25% if absolute baseline value was ≥200 msec	0 Participants	0 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria QRS change ≥50% if absolute baseline value was <100 msec	2 Participants	3 Participants
Number of Participant With Maximum Increase From Baseline in Electrocardiogram (ECG) Data Meeting Pre-defined Criteria QRS change ≥25% if absolute baseline value was ≥100 msec	2 Participants	0 Participants

SECONDARY outcome

Timeframe: From Baseline up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=143 Participants 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 n=133 Participants 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.
Number of Participants With Maximum Decrease From Baseline Greater Than or Equal to 20 Points in Left Ventricular Ejection Fraction (LVEF) Percentage	2 Participants	1 Participants

SECONDARY outcome

Timeframe: 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

Population: "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.

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=147 Participants 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.
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 8 Day 1	-3.2 Units on a scale Standard Deviation 6.18	-1.9 Units on a scale Standard Deviation 6.56
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 10 Day 1	-3.0 Units on a scale Standard Deviation 6.30	-2.6 Units on a scale Standard Deviation 5.98
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 12 Day 1	-3.6 Units on a scale Standard Deviation 6.05	-2.1 Units on a scale Standard Deviation 6.23
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 14 Day 1	-3.3 Units on a scale Standard Deviation 6.82	-2.5 Units on a scale Standard Deviation 5.57
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 16 Day 1	-3.3 Units on a scale Standard Deviation 6.87	-2.3 Units on a scale Standard Deviation 5.77
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 18 Day 1	-3.7 Units on a scale Standard Deviation 7.26	-2.6 Units on a scale Standard Deviation 4.30
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 20 Day 1	-3.3 Units on a scale Standard Deviation 6.24	-2.4 Units on a scale Standard Deviation 4.62
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 22 Day 1	-3.2 Units on a scale Standard Deviation 6.95	-2.5 Units on a scale Standard Deviation 4.82
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 24 Day 1	-3.1 Units on a scale Standard Deviation 5.97	2.3 Units on a scale Standard Deviation 9.31
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 26 Day 1	-3.2 Units on a scale Standard Deviation 6.87	-0.8 Units on a scale Standard Deviation 3.81
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 28 Day 1	-3.0 Units on a scale Standard Deviation 6.53	0.2 Units on a scale Standard Deviation 7.65
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 30 Day 1	-4.8 Units on a scale Standard Deviation 8.00	1.3 Units on a scale Standard Deviation 3.20
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 32 Day 1	-5.0 Units on a scale Standard Deviation 14.14	7.5 Units on a scale Standard Deviation 9.19
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 34 Day 1	-2.3 Units on a scale Standard Deviation 12.42	0.0 Units on a scale
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 36 Day 1	—	0.0 Units on a scale
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time End of Treatment	0.8 Units on a scale Standard Deviation 4.49	-0.2 Units on a scale Standard Deviation 7.45
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 2 Day 1	-1.8 Units on a scale Standard Deviation 5.52	-1.2 Units on a scale Standard Deviation 5.62
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 3 Day 1	-2.5 Units on a scale Standard Deviation 5.85	-2.7 Units on a scale Standard Deviation 5.78
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 4 Day 1	-2.9 Units on a scale Standard Deviation 5.73	-3.6 Units on a scale Standard Deviation 6.60
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 5 Day 1	-2.5 Units on a scale Standard Deviation 6.28	-3.0 Units on a scale Standard Deviation 6.24
Change From Baseline in Total Scores of Beck Depression Inventory (BDI)-II (Mood Assessment) Across Time Cycle 6 Day 1	-2.6 Units on a scale Standard Deviation 6.61	-2.9 Units on a scale Standard Deviation 6.65

SECONDARY outcome

Timeframe: Baseline, Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C8D1, C10D1, C12D1, C14D1, C16D1, C18D1, C20D1, C22D1, C24D1, C26D1, C28D1, C30D1, C32D1, C34D1, C36D1, C38D1 and End of Treatment

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

Outcome measures

Outcome measures
Measure	Lorlatinib n=149 Participants 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 n=142 Participants 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.
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Baseline	3 Participants	7 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 2 Day 1	0 Participants	5 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 3 Day 1	1 Participants	1 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 4 Day 1	0 Participants	1 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 5 Day 1	0 Participants	1 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 6 Day 1	0 Participants	2 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 8 Day 1	0 Participants	2 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 10 Day 1	0 Participants	1 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 12 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 14 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 16 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 18 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 20 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 22 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 24 Day 1	0 Participants	1 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 26 Day 1	1 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 28 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 30 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 32 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 34 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 36 Day 1	0 Participants	0 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time Cycle 38 Day 1	0 Participants	—
Number of Participants With Suicidal Ideation and Suicidal Behavior Across Time End of Treatment	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From Baseline up to Cycle 38 Day 1

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=148 Participants 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 n=140 Participants 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.
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 Global QOL	8.60 Units on a scale Interval 6.09 to 11.11	3.95 Units on a scale Interval 1.15 to 6.76
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 Physical Functioning	4.84 Units on a scale Interval 2.67 to 7.01	2.82 Units on a scale Interval 0.42 to 5.22
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 Role Functioning	6.86 Units on a scale Interval 4.05 to 9.68	4.78 Units on a scale Interval 1.61 to 7.95
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 Emotional Functioning	8.77 Units on a scale Interval 6.88 to 10.67	6.20 Units on a scale Interval 4.09 to 8.3
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 Cognitive Functioning	-4.20 Units on a scale Interval -6.56 to -1.84	-1.02 Units on a scale Interval -3.64 to 1.6
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 Social Functioning	7.00 Units on a scale Interval 4.48 to 9.52	4.72 Units on a scale Interval 1.87 to 7.57
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 Fatigue	-9.93 Units on a scale Interval -12.61 to -7.26	-4.26 Units on a scale Interval -7.28 to -1.25
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 Nausea and Vomiting	-4.35 Units on a scale Interval -5.79 to -2.9	3.51 Units on a scale Interval 1.89 to 5.14
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 Pain	-4.60 Units on a scale Interval -7.17 to -2.02	-5.76 Units on a scale Interval -8.67 to -2.85
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 Dyspnoea	-7.02 Units on a scale Interval -9.66 to -4.39	-8.75 Units on a scale Interval -11.76 to -5.74
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 Insomnia	-17.34 Units on a scale Interval -19.71 to -14.96	-9.39 Units on a scale Interval -12.07 to -6.71
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 Appetite Loss	-13.15 Units on a scale Interval -15.0 to -11.3	-3.95 Units on a scale Interval -6.01 to -1.88
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 Constipation	-2.40 Units on a scale Interval -5.33 to 0.54	2.53 Units on a scale Interval -0.83 to 5.9
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 Diarrhea	-0.92 Units on a scale Interval -3.42 to 1.59	11.12 Units on a scale Interval 8.33 to 13.91
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 Financial Difficulties	-6.79 Units on a scale Interval -9.52 to -4.05	-5.74 Units on a scale Interval -8.8 to -2.68

SECONDARY outcome

Timeframe: From Baseline up to Cycle 38 Day 1

Outcome measures

Outcome measures
Measure	Lorlatinib n=146 Participants 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 n=139 Participants 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.
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Dyspnoea	-4.36 Units on a scale Interval -6.55 to -2.17	-4.90 Units on a scale Interval -7.34 to -2.47
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Coughing	-21.21 Units on a scale Interval -23.71 to -18.7	-16.66 Units on a scale Interval -19.48 to -13.84
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Haemoptysis	-2.53 Units on a scale Interval -3.12 to -1.94	-2.65 Units on a scale Interval -3.34 to -1.97
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Sore Mouth	0.56 Units on a scale Interval -0.98 to 2.1	-0.60 Units on a scale Interval -2.39 to 1.19
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Dysphagia	-1.35 Units on a scale Interval -2.95 to 0.25	0.16 Units on a scale Interval -1.68 to 2.0
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Peripheral Neuropathy	11.56 Units on a scale Interval 8.21 to 14.91	6.20 Units on a scale Interval 2.39 to 10.0
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Alopecia	1.61 Units on a scale Interval -0.97 to 4.2	1.81 Units on a scale Interval -1.08 to 4.7
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Pain in Chest	-9.54 Units on a scale Interval -11.27 to -7.8	-9.01 Units on a scale Interval -10.97 to -7.05
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Pain in Arm or Shoulder	-6.93 Units on a scale Interval -9.43 to -4.43	-7.38 Units on a scale Interval -10.24 to -4.52
Change From Baseline in Lung Cancer Symptoms as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) During Overall Treatment Pain in Other Parts	-2.31 Units on a scale Interval -5.28 to 0.66	-5.67 Units on a scale Interval -8.97 to -2.38

SECONDARY outcome

Timeframe: Baseline, Day 1 of all cycles from Cycle 2 to Cycle 38, and End of Treatment

Population: "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.

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=147 Participants 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 n=138 Participants 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.
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 2 Day 1	6.0 Units on a scale Interval 3.33 to 8.72	3.1 Units on a scale Interval 0.19 to 5.92
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 3 Day 1	6.0 Units on a scale Interval 3.3 to 8.75	5.3 Units on a scale Interval 2.37 to 8.18
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 4 Day 1	7.1 Units on a scale Interval 3.71 to 10.41	5.6 Units on a scale Interval 2.77 to 8.47
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 5 Day 1	4.3 Units on a scale Interval 0.39 to 8.13	5.1 Units on a scale Interval 1.88 to 8.26
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 6 Day 1	6.5 Units on a scale Interval 3.11 to 9.85	4.5 Units on a scale Interval 1.08 to 7.91
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 7 Day 1	5.5 Units on a scale Interval 1.95 to 9.13	4.0 Units on a scale Interval 0.35 to 7.55
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 8 Day 1	6.7 Units on a scale Interval 2.95 to 10.37	4.2 Units on a scale Interval 0.63 to 7.68
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 9 Day 1	6.4 Units on a scale Interval 2.47 to 10.33	3.9 Units on a scale Interval 0.09 to 7.69
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 10 Day 1	7.2 Units on a scale Interval 3.22 to 11.2	3.9 Units on a scale Interval -0.02 to 7.75
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 11 Day 1	8.1 Units on a scale Interval 4.27 to 11.83	2.0 Units on a scale Interval -1.62 to 5.59
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 12 Day 1	7.6 Units on a scale Interval 3.82 to 11.41	4.8 Units on a scale Interval 0.95 to 8.59
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 13 Day 1	7.5 Units on a scale Interval 3.91 to 11.11	5.8 Units on a scale Interval 1.99 to 9.51
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 14 Day 1	6.7 Units on a scale Interval 3.06 to 10.32	2.3 Units on a scale Interval -1.33 to 5.91
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 15 Day 1	6.1 Units on a scale Interval 2.33 to 9.96	1.5 Units on a scale Interval -3.14 to 6.07
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 16 Day 1	6.9 Units on a scale Interval 2.71 to 11.04	2.4 Units on a scale Interval -2.89 to 7.71
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 17 Day 1	8.3 Units on a scale Interval 4.08 to 12.46	1.1 Units on a scale Interval -5.05 to 7.17
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 18 Day 1	8.7 Units on a scale Interval 4.17 to 13.28	1.3 Units on a scale Interval -5.01 to 7.56
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 19 Day 1	6.8 Units on a scale Interval 1.86 to 11.7	2.8 Units on a scale Interval -2.79 to 8.44
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 20 Day 1	7.9 Units on a scale Interval 2.83 to 13.06	3.4 Units on a scale Interval -3.59 to 10.44
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 21 Day 1	7.2 Units on a scale Interval 1.96 to 12.44	3.3 Units on a scale Interval -4.06 to 10.64
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 22 Day 1	4.5 Units on a scale Interval -0.51 to 9.48	1.9 Units on a scale Interval -6.69 to 10.54
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 23 Day 1	5.2 Units on a scale Interval -0.68 to 11.14	-0.6 Units on a scale Interval -10.97 to 9.81
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 24 Day 1	4.9 Units on a scale Interval -1.22 to 11.09	-3.0 Units on a scale Interval -21.43 to 15.43
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 25 Day 1	4.0 Units on a scale Interval -2.13 to 10.18	1.4 Units on a scale Interval -11.86 to 14.75
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 26 Day 1	7.9 Units on a scale Interval 1.0 to 14.77	2.0 Units on a scale Interval -11.84 to 15.84
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 27 Day 1	4.6 Units on a scale Interval -2.37 to 11.57	3.0 Units on a scale Interval -12.79 to 18.79
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 28 Day 1	6.0 Units on a scale Interval -3.75 to 15.66	2.7 Units on a scale Interval -13.2 to 18.54
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 29Day 1	7.4 Units on a scale Interval -3.78 to 18.48	8.2 Units on a scale Interval -11.18 to 27.58
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 30 Day 1	9.1 Units on a scale Interval -5.66 to 23.95	2.8 Units on a scale Interval -22.92 to 28.42
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 31 Day 1	7.8 Units on a scale Interval -11.84 to 27.51	0.0 Units on a scale Interval -190.59 to 190.59
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 32 Day 1	7.9 Units on a scale Interval -11.65 to 27.45	2.5 Units on a scale Interval -156.33 to 161.33
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 33 Day 1	4.4 Units on a scale Interval -21.74 to 30.49	-2.5 Units on a scale Interval -224.86 to 219.86
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 34 Day 1	-0.5 Units on a scale Interval -32.2 to 31.2	20.0 Units on a scale
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 35 Day 1	0.0 Units on a scale Interval -32.48 to 32.48	20.0 Units on a scale
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 36 Day 1	-4.5 Units on a scale Interval -315.8 to 306.8	15.0 Units on a scale
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 37 Day 1	-17.5 Units on a scale Interval -176.33 to 141.33	—
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time Cycle 38 Day 1	25.0 Units on a scale	—
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Visual Analogue Scale (VAS) Across Time End of Treatment	-3.7 Units on a scale Interval -13.66 to 6.33	-1.3 Units on a scale Interval -5.43 to 2.8

SECONDARY outcome

Timeframe: Baseline, Day 1 of all cycles from Cycle 2 to Cycle 38, and End of Treatment

Population: "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.

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).

Outcome measures

Outcome measures
Measure	Lorlatinib n=148 Participants 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 n=140 Participants 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.
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 30 Day 1	0.099 Units on a scale Interval -0.0355 to 0.2306	-0.028 Units on a scale Interval -0.174 to 0.119
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 31 Day 1	0.086 Units on a scale Interval -0.0957 to 0.2683	-0.024 Units on a scale Interval -0.8558 to 0.8088
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 32 Day 1	0.058 Units on a scale Interval -0.1601 to 0.2767	-0.139 Units on a scale Interval -2.432 to 2.155
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 33 Day 1	0.058 Units on a scale Interval -0.2006 to 0.3163	-0.024 Units on a scale Interval -0.8558 to 0.8088
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 34 Day 1	0.062 Units on a scale Interval -0.282 to 0.4057	0.042 Units on a scale
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 35 Day 1	0.129 Units on a scale Interval -0.1098 to 0.3668	0.042 Units on a scale
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 36 Day 1	-0.027 Units on a scale Interval -1.7736 to 1.7206	0.042 Units on a scale
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 37 Day 1	0.056 Units on a scale Interval -0.6497 to 0.7607	—
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 38 Day 1	0.232 Units on a scale	—
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time End of Treatment	-0.033 Units on a scale Interval -0.1513 to 0.0852	0.001 Units on a scale Interval -0.0769 to 0.0782
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 29 Day 1	0.046 Units on a scale Interval -0.0836 to 0.1755	0.041 Units on a scale Interval -0.0108 to 0.0928
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 2 Day 1	0.078 Units on a scale Interval 0.0475 to 0.1092	0.064 Units on a scale Interval 0.0258 to 0.1021
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 3 Day 1	0.071 Units on a scale Interval 0.0327 to 0.1097	0.101 Units on a scale Interval 0.0665 to 0.1353
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 4 Day 1	0.089 Units on a scale Interval 0.052 to 0.1254	0.098 Units on a scale Interval 0.0619 to 0.1338
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 5 Day 1	0.047 Units on a scale Interval 0.0061 to 0.0887	0.100 Units on a scale Interval 0.0626 to 0.1373
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 6 Day 1	0.077 Units on a scale Interval 0.0407 to 0.1124	0.070 Units on a scale Interval 0.0324 to 0.1077
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 7 Day 1	0.062 Units on a scale Interval 0.018 to 0.1052	0.046 Units on a scale Interval 0.0002 to 0.091
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 8 Day 1	0.074 Units on a scale Interval 0.034 to 0.1133	0.061 Units on a scale Interval 0.0201 to 0.1011
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 9 Day 1	0.060 Units on a scale Interval 0.0175 to 0.1028	0.050 Units on a scale Interval 0.0082 to 0.0919
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 10 Day 1	0.074 Units on a scale Interval 0.0303 to 0.1179	0.050 Units on a scale Interval 0.0168 to 0.0826
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 11 Day 1	0.083 Units on a scale Interval 0.0418 to 0.1237	0.057 Units on a scale Interval 0.0222 to 0.0914
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 12 Day 1	0.080 Units on a scale Interval 0.039 to 0.1201	0.049 Units on a scale Interval 0.0118 to 0.0864
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 13 Day 1	0.081 Units on a scale Interval 0.0365 to 0.1259	0.055 Units on a scale Interval 0.0165 to 0.0931
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 14 Day 1	0.091 Units on a scale Interval 0.049 to 0.1322	0.021 Units on a scale Interval -0.0157 to 0.0576
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 15 Day 1	0.077 Units on a scale Interval 0.0314 to 0.1217	0.036 Units on a scale Interval -0.01 to 0.0811
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 16 Day 1	0.091 Units on a scale Interval 0.0469 to 0.1347	0.051 Units on a scale Interval 0.007 to 0.0953
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 17 Day 1	0.098 Units on a scale Interval 0.0523 to 0.1434	-0.016 Units on a scale Interval -0.1 to 0.0685
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 18 Day 1	0.103 Units on a scale Interval 0.052 to 0.1531	0.021 Units on a scale Interval -0.0296 to 0.0716
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 19 Day 1	0.100 Units on a scale Interval 0.0481 to 0.1518	0.027 Units on a scale Interval -0.0246 to 0.0793
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 20 Day 1	0.103 Units on a scale Interval 0.0459 to 0.1596	0.025 Units on a scale Interval -0.0593 to 0.109
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 21 Day 1	0.068 Units on a scale Interval 0.0091 to 0.1276	0.040 Units on a scale Interval -0.0187 to 0.0989
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 22 Day 1	0.079 Units on a scale Interval 0.0134 to 0.1447	0.052 Units on a scale Interval -0.0249 to 0.1289
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 23 Day 1	0.060 Units on a scale Interval -0.0127 to 0.1324	0.006 Units on a scale Interval -0.202 to 0.2133
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 24 Day 1	0.082 Units on a scale Interval 0.0104 to 0.1531	-0.053 Units on a scale Interval -0.2793 to 0.1731
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 25 Day 1	0.047 Units on a scale Interval -0.0287 to 0.1231	0.045 Units on a scale Interval -0.0289 to 0.1194
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 26 Day 1	0.065 Units on a scale Interval -0.0218 to 0.1519	0.039 Units on a scale Interval -0.02 to 0.0978
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 27 Day 1	0.042 Units on a scale Interval -0.0603 to 0.1434	0.021 Units on a scale Interval -0.0867 to 0.1292
Change From Baseline in Health Status as Assessed by EuroQol 5 Dimension 5 Level (EQ-5D-5L) - Index Across Time Cycle 28 Day 1	0.024 Units on a scale Interval -0.0911 to 0.1399	-0.040 Units on a scale Interval -0.164 to 0.0836

SECONDARY outcome

Timeframe: From Baseline up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=146 Participants 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 n=139 Participants 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.
Time to Deterioration (TTD) in Participant Reported Pain in Chest, Dyspnea, or Cough From QLQ-LC13	3.3 Months Interval 2.1 to 4.7	3.7 Months Interval 2.0 to 5.5

SECONDARY outcome

Timeframe: at Screening, Cycle 2 Day 1 and Cycle 7 Day 1

Population: "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.

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.

Outcome measures

Outcome measures
Measure	Lorlatinib n=130 Participants 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 n=125 Participants 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.
Number of Participant With ALK Domain Mutation in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · ≥1 ALK Mutation Detected	5 Participants	6 Participants
Number of Participant With ALK Domain Mutation in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · No ALK Mutation Detected	88 Participants	91 Participants
Number of Participant With ALK Domain Mutation in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	32 Participants	25 Participants
Number of Participant With ALK Domain Mutation in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · Other (Sample failed analysis, uninformative, or not analyzed.)	5 Participants	3 Participants
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 Cycle 2 Day 1 · ≥1 ALK Mutation Detected	2 Participants	3 Participants
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 Cycle 2 Day 1 · No ALK Mutation Detected	66 Participants	55 Participants
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 Cycle 2 Day 1 · No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	53 Participants	58 Participants
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 Cycle 2 Day 1 · Other (Sample failed analysis, uninformative, or not analyzed.)	4 Participants	2 Participants
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 Cycle 7 Day 1 · ≥1 ALK Mutation Detected	3 Participants	5 Participants
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 Cycle 7 Day 1 · No ALK Mutation Detected	45 Participants	42 Participants
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 Cycle 7 Day 1 · No Circulating Free Deoxyribonucleic Acid (cfDNA) Detected	52 Participants	35 Participants
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 Cycle 7 Day 1 · Other (Sample failed analysis, uninformative, or not analyzed.)	3 Participants	2 Participants

SECONDARY outcome

Timeframe: at Screening, Cycle 2 Day 1 and Cycle 7 Day 1

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

Outcome measures

Outcome measures
Measure	Lorlatinib n=130 Participants 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 n=125 Participants 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.
Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · EML4-ALK Variant 1	19 Participants	25 Participants
Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · EML4-ALK Variant 2	7 Participants	2 Participants
Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · EML4-ALK Variant 3	18 Participants	21 Participants
Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · EML4-ALK Other	15 Participants	9 Participants
Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · ALK Rearrangement Other	2 Participants	4 Participants
Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · ALK Rearrangement Not Detected	32 Participants	36 Participants
Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · No cfDNA Detected	32 Participants	25 Participants
Number of Participant With ALK Fusion Variant in Plasma Circulating Nucleic Acid (CNA) Analysis at Screening, Cycle 2 Day 1 and Cycle 7 Day 1 at Screening · Other (Sample failed analysis, uninformative, or not analyzed.)	5 Participants	3 Participants
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 Cycle 2 Day 1 · EML4-ALK Variant 1	1 Participants	7 Participants
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 Cycle 2 Day 1 · EML4-ALK Variant 2	2 Participants	0 Participants
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 Cycle 2 Day 1 · EML4-ALK Variant 3	2 Participants	2 Participants
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 Cycle 2 Day 1 · EML4-ALK Other	2 Participants	1 Participants
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 Cycle 2 Day 1 · ALK Rearrangement Other	0 Participants	0 Participants
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 Cycle 2 Day 1 · ALK Rearrangement Not Detected	61 Participants	48 Participants
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 Cycle 2 Day 1 · No cfDNA Detected	53 Participants	58 Participants
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 Cycle 2 Day 1 · Other (Sample failed analysis, uninformative, or not analyzed.)	4 Participants	2 Participants
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 Cycle 7 Day 1 · EML4-ALK Variant 1	0 Participants	5 Participants
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 Cycle 7 Day 1 · EML4-ALK Variant 2	0 Participants	1 Participants
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 Cycle 7 Day 1 · EML4-ALK Variant 3	0 Participants	4 Participants
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 Cycle 7 Day 1 · EML4-ALK Other	0 Participants	1 Participants
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 Cycle 7 Day 1 · ALK Rearrangement Other	0 Participants	2 Participants
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 Cycle 7 Day 1 · ALK Rearrangement Not Detected	48 Participants	34 Participants
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 Cycle 7 Day 1 · No cfDNA Detected	52 Participants	35 Participants
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 Cycle 7 Day 1 · Other (Sample failed analysis, uninformative, or not analyzed.)	3 Participants	2 Participants

Adverse Events

Lorlatinib

Serious events: 51 serious events

Other events: 148 other events

Deaths: 23 deaths

Crizotinib

Serious events: 39 serious events

Other events: 140 other events

Deaths: 28 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER