Trial Outcomes & Findings for A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China (NCT NCT03909971)

Last Updated: 2025-11-05

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

109 participants

Primary outcome timeframe

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

Results posted on

2025-11-05

Participant Flow

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

Participant milestones

Participant milestones
Measure	Cohort 1 Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Overall Study STARTED	67	42
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	67	42

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Overall Study Participant transition to rollover study	26	9
Overall Study Global Deterioration of Health Status	2	2
Overall Study Progressive Disease	28	21
Overall Study Death	6	6
Overall Study Adverse Event	1	2
Overall Study Withdrawal by Subject	2	1
Overall Study Participant was unwilling to come to site visit	0	1
Overall Study No longer benefit from Lorlatinib	2	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Total n=109 Participants Total of all reporting groups
Age, Continuous	50.4 Years STANDARD_DEVIATION 10.85 • n=15 Participants	52.1 Years STANDARD_DEVIATION 13.36 • n=161 Participants	51.0 Years STANDARD_DEVIATION 11.84 • n=100 Participants
Age, Customized <18 years	0 Participants n=15 Participants	0 Participants n=161 Participants	0 Participants n=100 Participants
Age, Customized Between 18 and 65 years	61 Participants n=15 Participants	35 Participants n=161 Participants	96 Participants n=100 Participants
Age, Customized >65 years	6 Participants n=15 Participants	7 Participants n=161 Participants	13 Participants n=100 Participants
Sex: Female, Male Female	33 Participants n=15 Participants	23 Participants n=161 Participants	56 Participants n=100 Participants
Sex: Female, Male Male	34 Participants n=15 Participants	19 Participants n=161 Participants	53 Participants n=100 Participants
Race/Ethnicity, Customized Asian · Chinese	67 Participants n=15 Participants	42 Participants n=161 Participants	109 Participants n=100 Participants

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Percentage of Participants With Objective Response (Cohort 1)	70.1 Percentage of participants Interval 57.7 to 80.7	—

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=42 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Percentage of Participants With Objective Response (Cohort 2)	47.6 Percentage of participants Interval 32.0 to 63.6	—

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Progression-Free Survival (PFS) Based on ICR Assessment	26.3 Months Interval 16.6 to Upper limit of 95% confidence interval (CI) could not be estimated due to insufficient number of participants with events.	5.6 Months Interval 2.9 to 12.4

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Progression-Free Survival Based on Investigator Assessment	26.3 Months Interval 15.2 to 52.4	6.9 Months Interval 4.2 to 13.7

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Overall Survival	NA Months Interval 42.7 to Median and upper limit of 95% CI could not be estimated due to insufficient number of participants with events.	21.9 Months Interval 11.9 to 44.1

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=37 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=22 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Percentage of Participants With Intracranial Objective Response (IC-OR) Based on ICR Assessment	83.8 Percentage of participants Interval 68.0 to 93.8	50.0 Percentage of participants Interval 28.2 to 71.8

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=41 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=24 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Percentage of Participants With Intracranial Objective Response Based on Investigator Assessment	63.4 Percentage of participants Interval 46.9 to 77.9	33.3 Percentage of participants Interval 15.6 to 55.3

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=53 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=20 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Duration of Response (DOR) Based on ICR Assessment	31.7 Months Interval 18.0 to Upper limit of 95% CI could not be estimated due to insufficient number of participants with events.	10.4 Months Interval 2.9 to Upper limit of 95% CI could not be estimated due to insufficient number of participants with events.

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=47 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=17 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
DOR Based on Investigator Assessment	20.9 Months Interval 12.4 to Upper limit of 95% CI could not be estimated due to insufficient number of participants with events.	20.8 Months Interval 5.6 to Upper limit of 95% CI could not be estimated due to insufficient number of participants with events.

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=31 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=11 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Duration of Intracranial Response Based on ICR Assessment	NA Months Interval 30.6 to Median and upper limit of 95% CI were not estimable due to insufficient number of participants with events.	NA Months Interval 5.6 to Median and upper limit of 95% CI were not estimable due to insufficient number of participants with events.

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=26 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Duration of Intracranial Response Based on Investigator Assessment	NA Months Interval 15.1 to Median and upper limit of 95% CI were not estimable due to insufficient number of participants with event.	NA Months Interval 8.3 to Median and upper limit of 95% CI were not estimable due to insufficient number of participants with event.

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=53 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=20 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Time to Tumor Response Based on ICR Assessment	1.4 Months Interval 1.2 to 17.9	1.4 Months Interval 1.2 to 6.9

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=47 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=17 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Time to Tumor Response Based on Investigator Assessment	1.4 Months Interval 1.2 to 27.6	1.4 Months Interval 1.2 to 17.9

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Number of Participants With Adverse Events (AEs) All-causality TEAEs	67 Participants	42 Participants
Number of Participants With Adverse Events (AEs) Treatment-related TEAEs	67 Participants	42 Participants
Number of Participants With Adverse Events (AEs) All-causality serious AEs	23 Participants	16 Participants
Number of Participants With Adverse Events (AEs) Treatment-related serious AEs	11 Participants	5 Participants
Number of Participants With Adverse Events (AEs) All-causalities maximum Grade 3 or 4 AEs	49 Participants	25 Participants
Number of Participants With Adverse Events (AEs) Treatment-related Grade 3 or 4 AEs	46 Participants	19 Participants
Number of Participants With Adverse Events (AEs) All-causality Grade 5 AEs	4 Participants	7 Participants
Number of Participants With Adverse Events (AEs) Treatment-related Grade 5 AEs	0 Participants	0 Participants

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Number of Participants With Central Nervous System-Related Adverse Events Cognitive Effects	2 Participants	1 Participants
Number of Participants With Central Nervous System-Related Adverse Events Mood Effects	1 Participants	2 Participants
Number of Participants With Central Nervous System-Related Adverse Events Speech Effects	0 Participants	1 Participants
Number of Participants With Central Nervous System-Related Adverse Events Psychotic Effects	1 Participants	0 Participants

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Anemia:Grade 1 to Grade 3 or 4	2 Participants	3 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Anemia:Grade 2 to Grade 3 or 4	1 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Anemia: Grade 0 to Grade 3 or 4	3 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Lymphocyte count decreased Grade 0 to Grade 3 or 4	3 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Lymphocyte count decreased:Grade 1 to Grade 3 or 4	1 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Platelet count decreased: Grade 0 to Grade 3 or 4	2 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Alanine aminotransferase increased: Grade 0 to Grade 3 or 4	2 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Alanine aminotransferase increased:Grade 1 to Grade 3 or 4	2 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Alkaline phosphatase increased: Grade 0 to Grade 3 or 4	1 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Aspartate aminotransferase increased: Grade 0 to Grade 3 or 4	2 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Aspartate aminotransferase increased:Grade 1 to Grade 3 or 4	1 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Blood bilirubin increased: Grade 0 to Grade 3 or 4	1 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Blood bilirubin increased:Grade 1 to Grade 3 or 4	0 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities CPK increased: Grade 0 to Grade 3 or 4	0 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities CPK increased:Grade 2 to Grade 3 or 4	1 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Creatinine increased: Grade 0 to Grade 3 or 4	1 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities GGT increased: Grade 0 to Grade 3 or 4	3 Participants	2 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities GGT increased:Grade 1 to Grade 3 or 4	2 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypercalcemia: Grade 0 to Grade 3 or 4	0 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hyperglycemia: Grade 0 to Grade 3 or 4	6 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hyperglycemia:Grade 1 to Grade 3 or 4	1 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypermagnesemia: Grade 0 to Grade 3 or 4	7 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypocalcemia: Grade 0 to Grade 3 or 4	0 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypokalemia: Grade 0 to Grade 3 or 4	2 Participants	2 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypokalemia:Grade 2 to Grade 3 or 4	1 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hyponatremia: Grade 0 to Grade 3 or 4	1 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hyponatremia:Grade 1 to Grade 3 or 4	0 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypophosphatemia: Grade 0 to Grade 3 or 4	4 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypophosphatemia:Grade 1 to Grade 3 or 4	0 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Lipase increased: Grade 0 to Grade 3 or 4	5 Participants	2 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Lipase increased:Grade 1 to Grade 3 or 4	1 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Serum amylase increased: Grade 0 to Grade 3 or 4	1 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Cholesterol high: Grade 0 to Grade 3 or 4	12 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Cholesterol high:Grade 2 to Grade 3 or 4	1 Participants	0 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypertriglyceridemia: Grade 0 to Grade 3 or 4	19 Participants	3 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypertriglyceridemia:Grade 2 to Grade 3 or 4	3 Participants	1 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Cholesterol high:Grade 1 to Grade 3 or 4	6 Participants	3 Participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities Hypertriglyceridemia:Grade 1 to Grade 3 or 4	9 Participants	6 Participants

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting SBP change >=40 mmHg increase	10 Participants	1 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting SBP change >=40 mmHg decrease	2 Participants	0 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting DBP change >=20 mmHg increase	26 Participants	10 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting DBP change >=20 mmHg decrease	12 Participants	7 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting DBP change >=60 mmHg increase	0 Participants	0 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting pulse rate value <50 bpm	0 Participants	0 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting pulse rate value >120 bpm	5 Participants	3 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting pulse rate change >=30 mmHg increase	18 Participants	5 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Sitting pulse rate change >=30 mmHg decrease	5 Participants	7 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria weight 10% <= change <20% kg increase	43 Participants	22 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Weight change >=20% kg increase	14 Participants	6 Participants
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria Weight change >=10% kg decrease	3 Participants	2 Participants

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=42 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria PR interval change >=50% and baseline <200 msec	4 Participants	1 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria PR interval change >=25% and baseline >=200 msec	0 Participants	0 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QRS interval change >=50% and baseline<100 msec	1 Participants	1 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QRS interval change >=25% and baseline >=100 msec	2 Participants	0 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcB value <=450 msec	27 Participants	27 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcB 450 < Value <= 480 msec	26 Participants	9 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcB 480 < Value <= 500 msec	5 Participants	3 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcB value >500 msec	9 Participants	3 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcB change <=30 msec	31 Participants	25 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcB 30 < Change <= 60 msec	24 Participants	14 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcB change >60 msec	12 Participants	3 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcF 450 < Value <= 480 msec	13 Participants	6 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcF 480 < Value <= 500 msec	1 Participants	1 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcF change <=30 msec	39 Participants	29 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcF 30 < Change <= 60 msec	20 Participants	9 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcF change >60 msec	8 Participants	4 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcF value <=450 msec	49 Participants	35 Participants
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria QTcF value >500 msec	4 Participants	0 Participants

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=40 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria LVEF change from baseline normal to post-baseline below LLN	7 Participants	0 Participants
Number of Participants With Left Ventricular Ejection Fraction (LVEF) Meeting Pre-specified Criteria LVEF >=20-point decrease from baseline	3 Participants	0 Participants

SECONDARY outcome

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

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

The loratinib Cmax was estimated using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Cohort 1 n=8 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Cycle 1 Day 1 Maximum Plasma Concentration (Cmax)	1004 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 42	1074 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 58

SECONDARY outcome

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

The loratinib Tmax was estimated using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Cohort 1 n=8 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Cycle 1 Day 1 Time to Cmax (Tmax)	1.02 hour Interval 0.5 to 3.12	1.45 hour Interval 0.483 to 4.0

SECONDARY outcome

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

The loratinib AUCtau was estimated using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Cohort 1 n=8 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau)	7310 nanogram*hour per milliliter (ng.hr/mL) Geometric Coefficient of Variation 17	7778 nanogram*hour per milliliter (ng.hr/mL) Geometric Coefficient of Variation 39

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=8 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Steady-State Cmax	643.9 ng/mL Geometric Coefficient of Variation 50	795.9 ng/mL Geometric Coefficient of Variation 40

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=8 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Steady-State Tmax	1.53 hour Interval 0.533 to 3.03	1.88 hour Interval 0.5 to 8.02

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=8 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Steady-State AUCtau	5388 ng*hr/mL Geometric Coefficient of Variation 37	6801 ng*hr/mL Geometric Coefficient of Variation 40

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=8 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Apparent Clearance (CL/F)	18.55 Liter per hour (L/hr) Geometric Coefficient of Variation 37	14.71 Liter per hour (L/hr) Geometric Coefficient of Variation 40

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=8 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 n=8 Participants Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Observed Accumulation Ratio (Rac)	0.7371 Ratio Geometric Coefficient of Variation 47	0.9578 Ratio Geometric Coefficient of Variation 33

OTHER_PRE_SPECIFIED outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=67 Participants Participants whose disease had progressed after crizotinib as the only ALK inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.	Cohort 2 Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib 100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), participant refusal, participant lost to follow-up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Each cycle duration was 21 days.
Percentage of Participants With Objective Response (Cohort 1)-Final Analysis	79.1 Percentage of participants Interval 67.4 to 88.1	—

Adverse Events

Cohort 1

Serious events: 23 serious events

Other events: 67 other events

Deaths: 28 deaths

Cohort 2

Serious events: 16 serious events

Other events: 42 other events

Deaths: 26 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 disclosure previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER