A Study Of Crizotinib Versus Chemotherapy In Previously Untreated ALK Positive East Asian Non-Small Cell Lung Cancer Patients

• ClinicalTrials.gov Identifier: NCT01639001
• Recruitment Status: Completed
• First Posted: July 12, 2012
• Results First Posted: March 13, 2017
• Last Update Posted: December 8, 2020
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: NSCLC (Non-small Cell Lung Cancer)
• Interventions: Drug: Crizotinib; Drug: Pemetrexed/Cisplatin; Drug: Pemetrexed/Carboplatin
• Enrollment: 207

Participant Flow

Recruitment Details	This phase 3, randomized, open label, multicenter study conducted in 35 centers in 5 countries. A total of 207 actual participants were randomized, 104 in the crizotinib arm and 103 in the chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) arm.
Pre-assignment Details	Participants with histologically or cytologically proven diagnosis of locally advanced, recurrent, or metastatic non squamous non small cell lung cancer and tumors with measurable disease were enrolled. Participants were to be positive for translocation or inversion events involving the ALK gene locus as determined by an ALK break-apart FISH test.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Period Title: Overall Study
Started	104	103
Treated	104	101
Completed [1]	29	26
Not Completed	75	77
Reason Not Completed
Refused further follow-up	9	12
Lost to Follow-up	3	0
Death	62	61
Randomized but not treated	0	2
Long-term follow-up participants who did not respond to the contact from their study sites.	1	2
[1] "Completed" refers to either those patients who switched to commercial supplies of crizotinib or those patients who were in survival follow up, when the Sponsor sent a written End of Study notification to the study sites.

Baseline Characteristics

Arm/Group Title		Crizotinib	Chemotherapy	Total
Arm/Group Description		Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		104	103	207
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	104 participants	103 participants	207 participants
		48.2 (10.6)	48.9 (11.2)	48.5 (10.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	104 participants	103 participants	207 participants
	Female	54 51.9%	60 58.3%	114 55.1%
	Male	50 48.1%	43 41.7%	93 44.9%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Based on IRR by Treatment Arm
Description	PFS was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression (by IRR) or death on study due to any cause, whichever occured first. If tumor progression data included more than 1 date, the first date was used. PFS (in months) was calculated as (first event date - randomization date +1)/30.44. Progression is defined using RECIST v1.1, as at least a 20% increase (including an absolute increase of at least 5 millimeters) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time Frame	Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, assessed up to 33 months)

Outcome Measure Data

Analysis Population Description

The Full Analysis (FA) population included all participants who were randomized with study treatment assignment designated according to the initial randomization.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	103
Median (95% Confidence Interval); Unit of Measure: Months
	11.1; (8.3 to 12.6)	6.8; (5.7 to 7.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	The study was designed to test the null hypothesis H0: λ=1.0 versus the alternative hypothesis HA: λ < 1.0, where λ is the hazard ratio (HR; Crizotinib/Chemotherapy). Evaluation of 160 PFS events in the 2 arms using a 1-sided log-rank test at the 0.025 level of significance was required to detect a HR of 0.64 with 80% power.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The study was to be considered positive if the 1-sided log-rank test for PFS, stratified for baseline stratification factors (ECOG PS, ethnicity, and brain metastases) was significant at the 0.02496level.
	Method	1 sided stratified log-rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.402
	Confidence Interval	(2-Sided) 95%; 0.286 to 0.565
	Estimation Comments	Based on the Cox Proportional hazards model stratified by ECOG PS, ethnicity, and brain metastases. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of crizotinib.

2. Secondary Outcome

Title	Objective Response Rate (ORR) - Percentage of Participants With Objective Response Based on IRR
Description	Percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.
Time Frame	Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (assessed up to 33 months)

Outcome Measure Data

Analysis Population Description

FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	103
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	87.5; (79.6 to 93.2)	45.6; (35.8 to 55.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	The confidence interval for the treatment difference was based on normal distribution.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	If the PFS endpoint was significant, ORR was to be considered significant if 2-sided p-value from Pearson chi-square test was <= 0.04992.
	Method	2-sided pearson chi-square test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	41.869
	Confidence Interval	(2-Sided) 95%; 30.340 to 53.398
	Estimation Comments	Treatment difference in ORR (%)

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to the date of death due to any cause. OS (in months) was calculated as (date of death - date of randomization +1)/30.44. For participants who were lost to follow-up or withdrew consent, the OS was censored on the last date that participants were known to be alive.
Time Frame	From randomization to death or last date known as alive for those who were lost to follow-up or withdrew consent (assessed up to 64 months).

Outcome Measure Data

Analysis Population Description

FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	103
Median (95% Confidence Interval); Unit of Measure: Months
	33.7; (26.5 to 42.5)	32.9; (23.9 to 43.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6172
	Comments	If the PFS and ORR endpoints were significant, OS was to be considered significant if 1-sided, log-rank test stratified for ECOG, ethnicity and metastases was <= 0.02496.
	Method	1 sided stratified log-rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.056
	Confidence Interval	(2-Sided) 95%; 0.734 to 1.521
	Estimation Comments	Based on the Cox Proportional hazards model stratified by ECOG PS, ethnicity, and brain metastases. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of crizotinib.

4. Secondary Outcome

Title	Percentage of Participants With Disease Control at 12 Weeks Based on IRR
Description	Disease Control Rate (DCR) at 12 weeks is defined as the percent of participants with CR, PR or stable disease (SD) at 12 weeks according to RECIST version 1.1 as determined by the IRR. The best response of SD can be assigned if SD criteria were met at least once after randomization at a minimum interval of 6 weeks. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.
Time Frame	From randomization to Week 12

Outcome Measure Data

Analysis Population Description

FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	103
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	82.7; (74.0 to 89.4)	73.8; (64.2 to 82.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	The confidence interval for the treatment difference was based on normal distribution.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1204
	Comments	[Not Specified]
	Method	2-sided pearson chi-square test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	8.906
	Confidence Interval	(2-Sided) 95%; -2.275 to 20.086
	Estimation Comments	Treatment Difference in DCR Rate (%)

5. Secondary Outcome

Title	Estimate of the Percentage of Participants Surviving at 1 Year and at 18 Months
Description	Probability of survival 1 year and 18 month after randomization. The probability of survival at 1 year was estimated using the Kaplan Meier method and a 2-sided 95% CI for the log [-log(1-year survival probability)] was calculated using a normal approximation and then back transformed to give a CI for the 1-year survival probability itself. The probability of survival at 18 months was estimated similarly.
Time Frame	From randomization to 1 year and from randomization to 18 months

Outcome Measure Data

Analysis Population Description

The FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	103
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of paricipants
Up to 1 year	79.3; (70.0 to 86.0)	79.5; (70.0 to 86.3)
Up to 18 months	71.2; (61.2 to 79.0)	72.1; (62.0 to 79.9)

6. Secondary Outcome

Title	Duration of Response (DR) Based on IRR
Description	DR was defined as the time from the first documentation of objective tumor response (CR or PR), as determined by the IRR, to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. DR (in weeks) was calculated as (first date of PD or death - first date of CR or PR +1)/7. DR was only calculated for the subgroup of participants with an objective tumor response.
Time Frame	From objective response to date of progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, up to 33 months)

Outcome Measure Data

Analysis Population Description

FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization. N = Participants with objective tumor response by IRR.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	91	47
Median (95% Confidence Interval); Unit of Measure: Weeks
	44.4; (35.9 to 60.0)	18.1; (16.7 to 19.9)

7. Secondary Outcome

Title	Time to Tumor Response (TTR) Based on IRR
Description	TTR was defined as the time from randomization to first documentation of objective tumor response (CR or PR) as determined by the IRR. For participants proceeding from PR to CR, the onset of PR was taken as the onset of response. TTR was calculated for the subgroup of participants with objective tumor response.
Time Frame	Randomization to first documentation of objective tumor response (up to 33 months).

Outcome Measure Data

Analysis Population Description

FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization. N=Participants who had objective tumor response by IRR.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	91	47
Median (Full Range); Unit of Measure: Weeks
	6.3; (5.1 to 24.9)	12.1; (5.7 to 36.1)

8. Secondary Outcome

Title	Time to Progression (TTP) Based on IRR
Description	TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression, as determined by IRR. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date - randomization date +1)/30.44.
Time Frame	Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, up to 33 months)

Outcome Measure Data

Analysis Population Description

FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	103
Median (95% Confidence Interval); Unit of Measure: Months
	12.0; (8.4 to 15.4)	6.9; (5.7 to 7.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	1 sided unstratified log-rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.348
	Confidence Interval	(2-Sided) 95%; 0.246 to 0.493
	Estimation Comments	Based on the Cox Proportional hazards model.

9. Secondary Outcome

Title	Intracranial Time to Progression (IC-TTP) Based on IRR
Description	IC-TTP was defined similarly to TTP, but only considering intracranial disease (excluding extracranial disease) and the progression was determined based on either new brain metastases or progression of existing brain metastases.
Time Frame	Randomization to objective intracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, up to 33 months)

Outcome Measure Data

Analysis Population Description

FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	103
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (20.8 to NA)	16.0 [2]; (12.6 to NA)

[1]

Median and upper limit for IC-TTP was not reached due to insufficient IC-TTP events.

[2]

Upper limit for IC-TTP was not reached due to insufficient IC-TTP events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1270
	Comments	[Not Specified]
	Method	1 sided unstratified log-rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.669
	Confidence Interval	(2-Sided) 95%; 0.335 to 1.338
	Estimation Comments	Based on the Cox Proportional hazards model.

10. Secondary Outcome

Title	Extracranial Time to Progression (EC-TTP) Based on IRR
Description	EC-TTP was defined similarly to TTP, but only considering extracranial disease (excluding intracranial disease) and the progression was determined based on either new extracranial lesions or progression of existing extracranial lesions.
Time Frame	Randomization to objective extracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, up to 33 months)

Outcome Measure Data

Analysis Population Description

FA population included all participants who were randomized with study treatment assignment designated according to the initial randomization.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	103
Median (95% Confidence Interval); Unit of Measure: Months
	18.0; (12.3 to 20.9)	7.0; (6.0 to 7.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	1 sided unstratified log-rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.277
	Confidence Interval	(2-Sided) 95%; 0.186 to 0.412
	Estimation Comments	Based on the Cox Proportional hazards model.

11. Secondary Outcome

Title	Time to Deterioration (TTD) in Participant Reported Pain, Dyspnea, or Cough Assessed Using Quality of Life Questionnaire Supplement Module for Lung Cancer (QLQ-LC13)
Description	The QLQ-LC13 consisted of 1 multi-item scale and 9 single items that assessed the specific symptoms (dyspnea, cough, hemoptysis, and site specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of lung cancer participants receiving chemotherapy. The QLQ-LC13 Coughing, Dyspnoea and Pain in chest each ranged from 0-100 with higher scores indicating a high level of symptomatology/problems. TTD in pain in chest, dyspnea, or cough from the QLQ-LC13 was a composite endpoint defined as the time from randomization to the earliest time the participant's scale scores showed a 10 point or greater increase after baseline in any of the 3 symptoms.
Time Frame	From Baseline to deterioration while on study treatment. For participants with no deterioration, the data was censored at the last date when QLQ-LC13 assessment for pain, dyspnea, or cough was completed (assessed up to 33 months）

Outcome Measure Data

Analysis Population Description

Participants from the safety analysis population who completed a baseline and at least 1 post-baseline PRO assessment for pain in chest, dyspnea or cough.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	103	98
Median (95% Confidence Interval); Unit of Measure: Months
	2.8; (1.4 to 6.9)	0.3; (0.3 to 0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	2-sided Hochberg adjusted p-values
	Method	2 sided unstratified log rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.432
	Confidence Interval	(2-Sided) 95%; 0.307 to 0.610
	Estimation Comments	Based on the Cox Proportional hazards model.

12. Secondary Outcome

Title	Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)
Description	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). The QLQ-C30 Global QOL, Physical Functioning, Role Functioning, Cognitive Functioning, Emotional Functioning, and Social Functioning each ranged from 0-100 with higher scores indicating a better level of functioning or better quality of life.
Time Frame	From Baseline to deterioration while on study treatment. For participants with no deterioration, the data was censored at the last date when QLQ-LC13 assessment for pain, dyspnea, or cough was completed (assessed up to 33 months）

Outcome Measure Data

Analysis Population Description

Participants from the safety analysis population who completed a baseline and at least 1 post-baseline PRO assessment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	103	98
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
QLQ-C30 Global QoL	5.0891; (2.53 to 7.64)	-2.3619; (-5.00 to 0.28)
QLQ-C30 Cognitive Functioning	-1.1896; (-3.28 to 0.90)	-4.8026; (-6.95 to -2.66)
QLQ-C30 Emotional Functioning	3.7077; (1.76 to 5.66)	2.0557; (0.04 to 4.07)
QLQ-C30 Physical Functioning	3.7705; (1.97 to 5.57)	-2.9562; (-4.82 to -1.10)
QLQ-C30 Role Functioning	1.0538; (-1.56 to 3.66)	-5.7570; (-8.44 to -3.07)
QLQ-C30 Social Functioning	0.8712; (-2.27 to 4.02)	-4.7228; (-7.96 to -1.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 Global QoL. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	7.4510
	Confidence Interval	(2-Sided) 95%; 3.79 to 11.11
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 cognitive functioning. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0140
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.6130
	Confidence Interval	(2-Sided) 95%; 0.73 to 6.49
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 emotional functioning. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2427
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.6520
	Confidence Interval	(2-Sided) 95%; -1.12 to 4.42
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 physical functioning. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6.7267
	Confidence Interval	(2-Sided) 95%; 4.15 to 9.30
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 role functioning. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0003
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6.8109
	Confidence Interval	(2-Sided) 95%; 3.15 to 10.47
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 social functioning. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0140
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.5940
	Confidence Interval	(2-Sided) 95%; 1.13 to 10.06
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the EORTC-QLQ-C30
Description	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). The QLQ-C30 Appetite loss, Constipation, Diarrhea, Dyspnea, Fatigue, Financial difficulties, Insomnia, Nausea/vomiting, and Pain each ranged from 0-100 with higher scores indicating a high level of symptomatology/problems.
Time Frame	From Baseline to deterioration while on study treatment. For participants with no deterioration, the data was censored at the last date when QLQ-LC13 assessment for pain, dyspnea, or cough was completed (assessed up to 33 months）

Outcome Measure Data

Analysis Population Description

Participants from the safety analysis population who completed a baseline and at least 1 post-baseline PRO assessment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	103	98
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
QLQ-C30 Appetite loss	-1.5967; (-4.18 to 0.99)	4.4465; (1.74 to 7.15)
QLQ-C30 Constipation	7.1367; (4.40 to 9.87)	2.6341; (-0.23 to 5.50)
QLQ-C30 Diarrhea	15.3294; (13.35 to 17.31)	-0.4791; (-2.55 to 1.60)
QLQ-C30 Dyspnea	-7.9353; (-10.41 to -5.46)	-0.1903; (-2.75 to 2.37)
QLQ-C30 Fatigue	-3.8888; (-6.20 to -1.58)	2.6028; (0.21 to 5.00)
QLQ-C30 Financial Difficulties	-3.2339; (-7.26 to 0.79)	0.3826; (-3.74 to 4.51)
QLQ-C30 Insomnia	-8.3816; (-10.95 to -5.81)	-1.6060; (-4.29 to 1.07)
QLQ-C30 Nausea and Vomiting	4.0796; (2.06 to 6.09)	6.5986; (4.48 to 8.72)
QLQ-C30 Pain	-9.1305; (-11.27 to -6.99)	-0.6956; (-2.90 to 1.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 appetite loss. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0016
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.0432
	Confidence Interval	(2-Sided) 95%; -9.79 to -2.30
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 constipation. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0263
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.5026
	Confidence Interval	(2-Sided) 95%; 0.53 to 8.47
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 diarrhea. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	15.8085
	Confidence Interval	(2-Sided) 95%; 12.94 to 18.68
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 dyspnea. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.7449
	Confidence Interval	(2-Sided) 95%; -11.30 to -4.19
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 fatigue. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.4915
	Confidence Interval	(2-Sided) 95%; -9.82 to -3.17
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 financial difficulties. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2099
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.6165
	Confidence Interval	(2-Sided) 95%; -9.27 to 2.04
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 insomnia. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.7756
	Confidence Interval	(2-Sided) 95%; -10.49 to -3.06
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 nausea and vomiting. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0902
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.5190
	Confidence Interval	(2-Sided) 95%; -5.43 to 0.40
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-C30 pain. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-8.4349
	Confidence Interval	(2-Sided) 95%; -11.42 to -5.45
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Change From Baseline in Lung Cancer Symptom Scores as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13)
Description	The QLQ-LC13 consisted of 1 multi-item scale and 9 single items that assessed the specific symptoms (dyspnea, cough, hemoptysis, and site specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of lung cancer participants receiving chemotherapy. The QLQ-LC13 Alopecia, Coughing, Dysphagia, Dyspnoea, Haemoptysis, Pain in arm or shoulder, Pain in chest, Pain in other parts, Peripheral neuropathy, and Sore mouth each ranged from 0-100 with higher scores indicating a high level of symptomatology/problems.
Time Frame	From Baseline to deterioration while on study treatment. For participants with no deterioration, the data was censored at the last date when QLQ-LC13 assessment for pain, dyspnea, or cough was completed (assessed up to 33 months）

Outcome Measure Data

Analysis Population Description

Participants from the safety analysis population who completed a baseline and at least 1 post-baseline PRO assessment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	103	98
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
QLQ-LC13 Alopecia	-2.0837; (-4.41 to 0.24)	2.7710; (0.37 to 5.18)
QLQ-LC13 Coughing	-17.2704; (-19.96 to -14.58)	-10.2748; (-13.07 to -7.48)
QLQ-LC13 Dysphagia	0.5354; (-1.34 to 2.41)	1.0535; (-0.90 to 3.01)
QLQ-LC13 Dyspnoea	-9.0842; (-11.34 to -6.83)	-0.4371; (-2.76 to 1.89)
QLQ-LC13 Haemoptysis	-4.3017; (-5.42 to -3.18)	-3.0513; (-4.22 to -1.88)
QLQ-LC13 Pain in Arm or Shoulder	-6.8289; (-9.43 to -4.23)	-2.5927; (-5.29 to 0.11)
QLQ-LC13 Pain in Chest	-8.3565; (-10.81 to -5.90)	-4.1328; (-6.68 to -1.58)
QLQ-LC13 Pain in Other Parts	-4.8475; (-7.22 to -2.48)	-0.2573; (-2.72 to 2.21)
QLQ-LC13 Peripheral Neuropathy	0.1787; (-1.94 to 2.30)	1.8519; (-0.36 to 4.06)
QLQ-LC13 Sore Mouth	1.5134; (-0.01 to 3.03)	3.9114; (2.30 to 5.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 alopecia. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0039
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.8547
	Confidence Interval	(2-Sided) 95%; -8.15 to -1.56
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 coughing. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.9957
	Confidence Interval	(2-Sided) 95%; -10.85 to -3.14
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 dysphagia. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7082
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.5181
	Confidence Interval	(2-Sided) 95%; -3.23 to 2.20
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 dyspnoea. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-8.6471
	Confidence Interval	(2-Sided) 95%; -11.85 to -5.44
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 haemoptysis. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1284
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.2504
	Confidence Interval	(2-Sided) 95%; -2.86 to 0.36
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 pain in arm or shoulder. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0265
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.2363
	Confidence Interval	(2-Sided) 95%; -7.98 to -0.49
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 pain in chest. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0185
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.2237
	Confidence Interval	(2-Sided) 95%; -7.74 to -0.71
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 pain in other parts. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0075
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.5901
	Confidence Interval	(2-Sided) 95%; -7.95 to -1.23
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 peripheral neuropathy. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2848
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.6732
	Confidence Interval	(2-Sided) 95%; -4.74 to 1.39
	Estimation Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis presented for QLQ-LC13 sore mouth. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EORTC QLQ-C30 subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0296
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.3980
	Confidence Interval	(2-Sided) 95%; -4.56 to -0.24
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)-Visual Analog Scale (VAS)
Description	EQ-5D is a standardized, participant-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a visual analog scale (VAS). The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.
Time Frame	From Baseline to deterioration while on study treatment. For participants with no deterioration, the data was censored at the last date when QLQ-LC13 assessment for pain, dyspnea, or cough was completed (assessed up to 33 months）

Outcome Measure Data

Analysis Population Description

Participants from the safety analysis population who completed a baseline and at least 1 post-baseline PRO assessment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	102	98
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
	3.4209; (1.20 to 5.64)	-0.4927; (-2.75 to 1.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	From a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EQ-5D VAS subscale score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0123
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.9136
	Confidence Interval	(2-Sided) 95%; 0.85 to 6.98
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	Change From Baseline in General Health Status as Assessed by EQ-5D-Index
Description	EQ-5D is a standardized, participant-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a visual analog scale (VAS). EQ-5D summary index is obtained with a formula that weights each level of the 5 dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health).
Time Frame	From Baseline to deterioration while on study treatment. For participants with no deterioration, the data was censored at the last date when QLQ-LC13 assessment for pain, dyspnea, or cough was completed (assessed up to 33 months)

Outcome Measure Data

Analysis Population Description

Participants from the safety analysis population who completed a baseline and at least 1 post-baseline PRO assessment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	102	98
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
	0.0502; (0.02 to 0.08)	0.0077; (-0.02 to 0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	From a repeated measures mixed-effects model with an intercept term, treatment, visit day and baseline EQ-5D Index score (intercept and visit day are included as random effects). P-values and confidence intervals are not adjusted for multiplicity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0320
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0425
	Confidence Interval	(2-Sided) 95%; 0.00 to 0.08
	Estimation Comments	[Not Specified]

17. Secondary Outcome

Title	Percentage of Participants With Visual Disturbance as Assessed by Visual Symptom Assessment Questionnaire (VSAQ-ALK)
Description	VSAQ-ALK is a self-report measure that was developed to assess the problems of visual disturbances and symptoms may include the appearance of overlapping shadows and after images; shimmering, flashing or trailing lights; strings, streamers, or floaters; as well as hazy or blurry vision. The participants answered "Yes" to the first question (Q1) of VSAQ-ALK "Have you experienced any visual disturbances?" were considered to have experienced visual disturbance and were instructed to complete the rest of the questionnaire. The percentage of participants who responded to Q1 of VSAQ-ALK as "Yes" and as "No" during each study cycle was calculated as (n/N*)*100 where N* was the number of participants who had completed Q1.
Time Frame	Cycle 1 Day 1 to end of treatment or withdrawal, no later than 4 weeks (+/- 1 week) from last dose of study medication or when the decision was taken to withdraw from the study (whichever was sooner, assessed up to Cycle 86)

Outcome Measure Data

Analysis Population Description

Participants from the safety analysis population who completed a baseline and at least 1 post-baseline PRO assessment.

Arm/Group Title		Crizotinib	Chemotherapy
Arm/Group Description:		Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed		103	98
Measure Type: Number; Unit of Measure: Percentage of participants
Baseline: Cycle 1/Day 1 (Answer to Q1: Yes)	Number Analyzed	103 participants	98 participants
		6.8	7.1
Baseline: Cycle 1/Day 1 (Answer to Q1: No)	Number Analyzed	103 participants	98 participants
		93.2	92.9
Cycle 2/Day 1 (Answer to Q1: Yes)	Number Analyzed	102 participants	97 participants
		51.0	13.4
Cycle 2/Day 1 (Answer to Q1: No)	Number Analyzed	102 participants	97 participants
		49.0	86.6
Cycle 3/Day 1 (Answer to Q1: Yes)	Number Analyzed	102 participants	90 participants
		46.1	11.1
Cycle 3/Day 1 (Answer to Q1: No)	Number Analyzed	102 participants	90 participants
		53.9	88.9
Cycle 4/Day 1 (Answer to Q1: Yes)	Number Analyzed	98 participants	88 participants
		43.9	14.8
Cycle 4/Day 1 (Answer to Q1: No)	Number Analyzed	98 participants	88 participants
		56.1	85.2
Cycle 5/Day 1 (Answer to Q1: Yes)	Number Analyzed	95 participants	74 participants
		35.8	13.5
Cycle 5/Day 1 (Answer to Q1: No)	Number Analyzed	95 participants	74 participants
		64.2	86.5
Cycle 6/Day 1 (Answer to Q1: Yes)	Number Analyzed	91 participants	69 participants
		37.4	10.1
Cycle 6/Day 1 (Answer to Q1: No)	Number Analyzed	91 participants	69 participants
		62.6	89.9
Cycle 7/Day 1 (Answer to Q1: Yes)	Number Analyzed	89 participants	0 participants
		36.0
Cycle 7/Day 1 (Answer to Q1: No)	Number Analyzed	89 participants	0 participants
		64.0
Cycle 8/Day 1 (Answer to Q1: Yes)	Number Analyzed	89 participants	0 participants
		28.1
Cycle 8/Day 1 (Answer to Q1: No)	Number Analyzed	89 participants	0 participants
		71.9
Cycle 9/Day 1 (Answer to Q1: Yes)	Number Analyzed	87 participants	0 participants
		24.1
Cycle 9/Day 1 (Answer to Q1: No)	Number Analyzed	87 participants	0 participants
		75.9
Cycle 10/Day 1 (Answer to Q1: Yes)	Number Analyzed	88 participants	0 participants
		23.9
Cycle 10/Day 1 (Answer to Q1: No)	Number Analyzed	88 participants	0 participants
		76.1
Cycle 11/Day 1 (Answer to Q1: Yes)	Number Analyzed	81 participants	0 participants
		23.5
Cycle 11/Day 1 (Answer to Q1: No)	Number Analyzed	81 participants	0 participants
		76.5
Cycle 12/Day 1 (Answer to Q1: Yes)	Number Analyzed	80 participants	0 participants
		21.3
Cycle 12/Day 1 (Answer to Q1: No)	Number Analyzed	80 participants	0 participants
		78.8
Cycle 13/Day 1 (Answer to Q1: Yes)	Number Analyzed	79 participants	0 participants
		25.3
Cycle 13/Day 1 (Answer to Q1: No)	Number Analyzed	79 participants	0 participants
		74.7
Cycle 14/Day 1 (Answer to Q1: Yes)	Number Analyzed	74 participants	0 participants
		27.0
Cycle 14/Day 1 (Answer to Q1: No)	Number Analyzed	74 participants	0 participants
		73.0
Cycle 15/Day 1 (Answer to Q1: Yes)	Number Analyzed	71 participants	0 participants
		28.2
Cycle 15/Day 1 (Answer to Q1: No)	Number Analyzed	71 participants	0 participants
		71.8
Cycle 16/Day 1 (Answer to Q1: Yes)	Number Analyzed	70 participants	0 participants
		28.6
Cycle 16/Day 1 (Answer to Q1: No)	Number Analyzed	70 participants	0 participants
		71.4
Cycle 17/Day 1 (Answer to Q1: Yes)	Number Analyzed	70 participants	0 participants
		28.6
Cycle 17/Day 1 (Answer to Q1: No)	Number Analyzed	70 participants	0 participants
		71.4
Cycle 18/Day 1 (Answer to Q1: Yes)	Number Analyzed	67 participants	0 participants
		28.4
Cycle 18/Day 1 (Answer to Q1: No)	Number Analyzed	67 participants	0 participants
		71.6
Cycle 19/Day 1 (Answer to Q1: Yes)	Number Analyzed	64 participants	0 participants
		28.1
Cycle 19/Day 1 (Answer to Q1: No)	Number Analyzed	64 participants	0 participants
		71.9
Cycle 20/Day 1 (Answer to Q1: Yes)	Number Analyzed	61 participants	0 participants
		27.9
Cycle 20/Day 1 (Answer to Q1: No)	Number Analyzed	61 participants	0 participants
		72.1
Cycle 21/Day 1 (Answer to Q1: Yes)	Number Analyzed	59 participants	0 participants
		30.5
Cycle 21/Day 1 (Answer to Q1: No)	Number Analyzed	59 participants	0 participants
		69.5
Cycle 22/Day 1 (Answer to Q1: Yes)	Number Analyzed	55 participants	0 participants
		29.1
Cycle 22/Day 1 (Answer to Q1: No)	Number Analyzed	55 participants	0 participants
		70.9
Cycle 23/Day 1 (Answer to Q1: Yes)	Number Analyzed	56 participants	0 participants
		28.6
Cycle 23/Day 1 (Answer to Q1: No)	Number Analyzed	56 participants	0 participants
		71.4
Cycle 24/Day 1 (Answer to Q1: Yes)	Number Analyzed	54 participants	0 participants
		31.5
Cycle 24/Day 1 (Answer to Q1: No)	Number Analyzed	54 participants	0 participants
		68.5
Cycle 25/Day 1 (Answer to Q1: Yes)	Number Analyzed	53 participants	0 participants
		32.1
Cycle 25/Day 1 (Answer to Q1: No)	Number Analyzed	53 participants	0 participants
		67.9
Cycle 26/Day 1 (Answer to Q1: Yes)	Number Analyzed	52 participants	0 participants
		28.8
Cycle 26/Day 1 (Answer to Q1: No)	Number Analyzed	52 participants	0 participants
		71.2
Cycle 27/Day 1 (Answer to Q1: Yes)	Number Analyzed	50 participants	0 participants
		28.0
Cycle 27/Day 1 (Answer to Q1: No)	Number Analyzed	50 participants	0 participants
		72.0
Cycle 28/Day 1 (Answer to Q1: Yes)	Number Analyzed	50 participants	0 participants
		30.0
Cycle 28/Day 1 (Answer to Q1: No)	Number Analyzed	50 participants	0 participants
		70.0
Cycle 29/Day 1 (Answer to Q1: Yes)	Number Analyzed	50 participants	0 participants
		30.0
Cycle 29/Day 1 (Answer to Q1: No)	Number Analyzed	50 participants	0 participants
		70.0
Cycle 30/Day 1 (Answer to Q1: Yes)	Number Analyzed	50 participants	0 participants
		32.0
Cycle 30/Day 1 (Answer to Q1: No)	Number Analyzed	50 participants	0 participants
		68.0
Cycle 31/Day 1 (Answer to Q1: Yes)	Number Analyzed	49 participants	0 participants
		24.5
Cycle 31/Day 1 (Answer to Q1: No)	Number Analyzed	49 participants	0 participants
		75.5
Cycle 32/Day 1 (Answer to Q1: Yes)	Number Analyzed	48 participants	0 participants
		25.0
Cycle 32/Day 1 (Answer to Q1: No)	Number Analyzed	48 participants	0 participants
		75.0
Cycle 33/Day 1 (Answer to Q1: Yes)	Number Analyzed	46 participants	0 participants
		28.3
Cycle 33/Day 1 (Answer to Q1: No)	Number Analyzed	46 participants	0 participants
		71.7
Cycle 34/Day 1 (Answer to Q1: Yes)	Number Analyzed	44 participants	0 participants
		27.3
Cycle 34/Day 1 (Answer to Q1: No)	Number Analyzed	44 participants	0 participants
		72.7
Cycle 35/Day 1 (Answer to Q1: Yes)	Number Analyzed	42 participants	0 participants
		28.6
Cycle 35/Day 1 (Answer to Q1: No)	Number Analyzed	42 participants	0 participants
		71.4
Cycle 36/Day 1 (Answer to Q1: Yes)	Number Analyzed	41 participants	0 participants
		26.8
Cycle 36/Day 1 (Answer to Q1: No)	Number Analyzed	41 participants	0 participants
		73.2
Cycle 37/Day 1 (Answer to Q1: Yes)	Number Analyzed	37 participants	0 participants
		27.0
Cycle 37/Day 1 (Answer to Q1: No)	Number Analyzed	37 participants	0 participants
		73.0
Cycle 38/Day 1 (Answer to Q1: Yes)	Number Analyzed	37 participants	0 participants
		24.3
Cycle 38/Day 1 (Answer to Q1: No)	Number Analyzed	37 participants	0 participants
		75.7
Cycle 39/Day 1 (Answer to Q1: Yes)	Number Analyzed	33 participants	0 participants
		30.3
Cycle 39/Day 1 (Answer to Q1: No)	Number Analyzed	33 participants	0 participants
		69.7
Cycle 40/Day 1 (Answer to Q1: Yes)	Number Analyzed	32 participants	0 participants
		25.0
Cycle 40/Day 1 (Answer to Q1: No)	Number Analyzed	32 participants	0 participants
		75.0
Cycle 41/Day 1 (Answer to Q1: Yes)	Number Analyzed	31 participants	0 participants
		32.3
Cycle 41/Day 1 (Answer to Q1: No)	Number Analyzed	31 participants	0 participants
		67.7
Cycle 42/Day 1 (Answer to Q1: Yes)	Number Analyzed	31 participants	0 participants
		25.8
Cycle 42/Day 1 (Answer to Q1: No)	Number Analyzed	31 participants	0 participants
		74.2
Cycle 43/Day 1 (Answer to Q1: Yes)	Number Analyzed	29 participants	0 participants
		24.1
Cycle 43/Day 1 (Answer to Q1: No)	Number Analyzed	29 participants	0 participants
		75.9
Cycle 44/Day 1 (Answer to Q1: Yes)	Number Analyzed	30 participants	0 participants
		30.0
Cycle 44/Day 1 (Answer to Q1: No)	Number Analyzed	30 participants	0 participants
		70.0
Cycle 45/Day 1 (Answer to Q1: Yes)	Number Analyzed	28 participants	0 participants
		25.0
Cycle 45/Day 1 (Answer to Q1: No)	Number Analyzed	28 participants	0 participants
		75.0
Cycle 46/Day 1 (Answer to Q1: Yes)	Number Analyzed	29 participants	0 participants
		27.6
Cycle 46/Day 1 (Answer to Q1: No)	Number Analyzed	29 participants	0 participants
		72.4
Cycle 47/Day 1 (Answer to Q1: Yes)	Number Analyzed	26 participants	0 participants
		26.9
Cycle 47/Day 1 (Answer to Q1: No)	Number Analyzed	26 participants	0 participants
		73.1
Cycle 48/Day 1 (Answer to Q1: Yes)	Number Analyzed	27 participants	0 participants
		29.6
Cycle 48/Day 1 (Answer to Q1: No)	Number Analyzed	27 participants	0 participants
		70.4
Cycle 49/Day 1 (Answer to Q1: Yes)	Number Analyzed	24 participants	0 participants
		29.2
Cycle 49/Day 1 (Answer to Q1: No)	Number Analyzed	24 participants	0 participants
		70.8
Cycle 50/Day 1 (Answer to Q1: Yes)	Number Analyzed	24 participants	0 participants
		29.2
Cycle 50/Day 1 (Answer to Q1: No)	Number Analyzed	24 participants	0 participants
		70.8
Cycle 51/Day 1 (Answer to Q1: Yes)	Number Analyzed	23 participants	0 participants
		26.1
Cycle 51/Day 1 (Answer to Q1: No)	Number Analyzed	23 participants	0 participants
		73.9
Cycle 52/Day 1 (Answer to Q1: Yes)	Number Analyzed	103 participants	0 participants
		29.2
Cycle 52/Day 1 (Answer to Q1: No)	Number Analyzed	103 participants	0 participants
		70.8
Cycle 53/Day 1 (Answer to Q1: Yes)	Number Analyzed	20 participants	0 participants
		25.0
Cycle 53/Day 1 (Answer to Q1: No)	Number Analyzed	20 participants	0 participants
		75.0
Cycle 54/Day 1 (Answer to Q1: Yes)	Number Analyzed	22 participants	0 participants
		36.4
Cycle 54/Day 1 (Answer to Q1: No)	Number Analyzed	22 participants	0 participants
		63.6
Cycle 55/Day 1 (Answer to Q1: Yes)	Number Analyzed	17 participants	0 participants
		29.4
Cycle 55/Day 1 (Answer to Q1: No)	Number Analyzed	17 participants	0 participants
		70.6
Cycle 56/Day 1 (Answer to Q1: Yes)	Number Analyzed	18 participants	0 participants
		38.9
Cycle 56/Day 1 (Answer to Q1: No)	Number Analyzed	18 participants	0 participants
		61.1
Cycle 57/Day 1 (Answer to Q1: Yes)	Number Analyzed	15 participants	0 participants
		20.0
Cycle 57/Day 1 (Answer to Q1: No)	Number Analyzed	15 participants	0 participants
		80.0
Cycle 58/Day 1 (Answer to Q1: Yes)	Number Analyzed	103 participants	0 participants
		35.3
Cycle 58/Day 1 (Answer to Q1: No)	Number Analyzed	103 participants	0 participants
		64.7
Cycle 59/Day 1 (Answer to Q1: Yes)	Number Analyzed	14 participants	0 participants
		21.4
Cycle 59/Day 1 (Answer to Q1: No)	Number Analyzed	14 participants	0 participants
		78.6
Cycle 60/Day 1 (Answer to Q1: Yes)	Number Analyzed	16 participants	0 participants
		37.5
Cycle 60/Day 1 (Answer to Q1: No)	Number Analyzed	16 participants	0 participants
		62.5
Cycle 61/Day 1 (Answer to Q1: Yes)	Number Analyzed	13 participants	0 participants
		23.1
Cycle 61/Day 1 (Answer to Q1: No)	Number Analyzed	13 participants	0 participants
		76.9
Cycle 62/Day 1 (Answer to Q1: Yes)	Number Analyzed	16 participants	0 participants
		37.5
Cycle 62/Day 1 (Answer to Q1: No)	Number Analyzed	16 participants	0 participants
		62.5
Cycle 63/Day 1 (Answer to Q1: Yes)	Number Analyzed	14 participants	0 participants
		21.4
Cycle 63/Day 1 (Answer to Q1: No)	Number Analyzed	14 participants	0 participants
		78.6
Cycle 64/Day 1 (Answer to Q1: Yes)	Number Analyzed	14 participants	0 participants
		35.7
Cycle 64/Day 1 (Answer to Q1: No)	Number Analyzed	14 participants	0 participants
		64.3
Cycle 65/Day 1 (Answer to Q1: Yes)	Number Analyzed	14 participants	0 participants
		21.4
Cycle 65/Day 1 (Answer to Q1: No)	Number Analyzed	14 participants	0 participants
		78.6
Cycle 66/Day 1 (Answer to Q1: Yes)	Number Analyzed	13 participants	0 participants
		30.8
Cycle 66/Day 1 (Answer to Q1: No)	Number Analyzed	13 participants	0 participants
		69.2
Cycle 67/Day 1 (Answer to Q1: Yes)	Number Analyzed	12 participants	0 participants
		25.0
Cycle 67/Day 1 (Answer to Q1: No)	Number Analyzed	12 participants	0 participants
		75.0
Cycle 68/Day 1 (Answer to Q1: Yes)	Number Analyzed	13 participants	0 participants
		30.8
Cycle 68/Day 1 (Answer to Q1: No)	Number Analyzed	13 participants	0 participants
		69.2
Cycle 69/Day 1 (Answer to Q1: Yes)	Number Analyzed	103 participants	0 participants
		25.0
Cycle 69/Day 1 (Answer to Q1: No)	Number Analyzed	103 participants	0 participants
		75.0
Cycle 70/Day 1 (Answer to Q1: Yes)	Number Analyzed	13 participants	0 participants
		30.8
Cycle 70/Day 1 (Answer to Q1: No)	Number Analyzed	13 participants	0 participants
		69.2
Cycle 71/Day 1 (Answer to Q1: Yes)	Number Analyzed	10 participants	0 participants
		30.0
Cycle 71/Day 1 (Answer to Q1: No)	Number Analyzed	10 participants	0 participants
		70.0
Cycle 72/Day 1 (Answer to Q1: Yes)	Number Analyzed	9 participants	0 participants
		22.2
Cycle 72/Day 1 (Answer to Q1: No)	Number Analyzed	9 participants	0 participants
		77.8
Cycle 73/Day 1 (Answer to Q1: Yes)	Number Analyzed	9 participants	0 participants
		22.2
Cycle 73/Day 1 (No)	Number Analyzed	9 participants	0 participants
		77.8
Cycle 74/Day 1 (Answer to Q1: Yes)	Number Analyzed	8 participants	0 participants
		25.0
Cycle 74/Day 1 (Answer to Q1: No)	Number Analyzed	8 participants	0 participants
		75.0
Cycle 75/Day 1 (Answer to Q1: Yes)	Number Analyzed	9 participants	0 participants
		22.2
Cycle 75/Day 1 (Answer to Q1: No)	Number Analyzed	9 participants	0 participants
		77.8
Cycle 76/Day 1 (Answer to Q1: Yes)	Number Analyzed	6 participants	0 participants
		16.7
Cycle 76/Day 1 (Answer to Q1: No)	Number Analyzed	6 participants	0 participants
		83.3
Cycle 77/Day 1 (Answer to Q1: Yes)	Number Analyzed	8 participants	0 participants
		37.5
Cycle 77/Day 1 (Answer to Q1: No)	Number Analyzed	8 participants	0 participants
		62.5
Cycle 78/Day 1 (Answer to Q1: Yes)	Number Analyzed	5 participants	0 participants
		20.0
Cycle 78/Day 1 (Answer to Q1: No)	Number Analyzed	5 participants	0 participants
		80.0
Cycle 79/Day 1 (Answer to Q1: Yes)	Number Analyzed	5 participants	0 participants
		20.0
Cycle 79/Day 1 (Answer to Q1: No)	Number Analyzed	5 participants	0 participants
		80.0
Cycle 80/Day 1 (Answer to Q1: Yes)	Number Analyzed	4 participants	0 participants
		0.0
Cycle 80/Day 1 (Answer to Q1: No)	Number Analyzed	4 participants	0 participants
		100.0
Cycle 81/Day 1 (Answer to Q1: Yes)	Number Analyzed	1 participants	0 participants
		0.0
Cycle 81/Day 1 (Answer to Q1: No)	Number Analyzed	1 participants	0 participants
		100.0
Cycle 82/Day 1 (Answer to Q1: Yes)	Number Analyzed	2 participants	0 participants
		0.0
Cycle 82/Day 1 Answer to Q1: (No)	Number Analyzed	2 participants	0 participants
		100.0
Cycle 83/Day 1 (Answer to Q1: Yes)	Number Analyzed	1 participants	0 participants
		0.0
Cycle 83/Day 1 (Answer to Q1: No)	Number Analyzed	1 participants	0 participants
		100.0
Cycle 84/Day 1 (Answer to Q1: Yes)	Number Analyzed	2 participants	0 participants
		0.0
Cycle 84/Day 1 (Answer to Q1: No)	Number Analyzed	2 participants	0 participants
		100.0
Cycle 86/Day 1 (Answer to Q1: Yes)	Number Analyzed	1 participants	0 participants
		0.0
Cycle 86/Day 1 (Answer to Q1: No)	Number Analyzed	1 participants	0 participants
		100.0

18. Secondary Outcome

Title	Agreement Between Central Laboratory ALK FISH and ALK IHC Test Results - Molecular Profiling Evaluable
Description	Agreement between central laboratory anaplastic lymphoma kinase (ALK) fluorescence in situ hybridization (FISH) and ALK immunohistochemistry (IHC) test results is based on analysis of participants in the Molecular Profiling (MP) evaluable population that have an ALK IHC result and an ALK FISH result of either positive or negative only. This MP evaluable population included participants who screen failed, which their ALK test results were negative based on FISH test. Tumor tissue samples from these screen failure participants were consented and kept. These samples served as a part of negative sample set for evaluation of IHC test and/or polymerase chain reaction (PCR) to determine ALK fusion events. Participants with FISH results of uninformative and assay not performed and IHC results of valid IHC status not available were excluded from the analysis of agreement between central laboratory ALK FISH and ALK IHC test results.
Time Frame	During the screening (less than or equal to 28 days prior to dosing)

Outcome Measure Data

Analysis Population Description

The MP evaluable population included 812 participants, of which there were 771 participants that had a test result (positive or negative) from both the FISH test and the IHC test.

Arm/Group Title	Participants With Positive ALK FISH Status	Participants With Negative ALK FISH Status
Arm/Group Description:	Participants in the Molecular Profiling Evaluable population that had positive ALK FISH results.	Participants in the Molecular Profiling Evaluable population that had negative ALK FISH results.
Overall Number of Participants Analyzed	238	533
Measure Type: Count of Participants; Unit of Measure: Participants
Participants with Positive ALK IHC Status	218 91.6%	31 5.8%
Participants with Negative ALK IHC Status	20 8.4%	502 94.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Participants With Positive ALK FISH Status, Participants With Negative ALK FISH Status
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Overall percent agreement
	Estimated Value	0.934
	Confidence Interval	(2-Sided) 95%; 0.914 to 0.949
	Estimation Comments	95% CI for agreement rate is calculated by the Wilson (Score) Confidence Limit method with alpha=0.05

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Participants With Positive ALK FISH Status, Participants With Negative ALK FISH Status
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Kappa
	Estimated Value	0.8470
	Confidence Interval	(2-Sided) 95%; 0.8065 to 0.8875
	Estimation Comments	Kappa coefficient is a statistic which measures inter-rater agreement for qualitative (categorical) items.

19. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (AEs; All Causalities)
Description	An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. Grade 3 and 4 AEs in below table indicated severe AE and life-threatening consequences respectively; Grade 5 indicated death due to AE.
Time Frame	From the first dose of study medication up to 28 days after the last dose of study medication or up to the time that a participant died or received subsequent anticancer treatment (maximum duration between first and last dose: 324.4 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	101
Measure Type: Number; Unit of Measure: Percentage of participants
AEs	99.0	99.0
SAEs	44.2	12.9
Grade 3/4 AEs	58.7	52.5
Grade 5 AEs	22.1	2.0
AEs associated with permanent discontinuation	26.9	4.0
AEs associated with dose reduction	14.4	7.9
AEs associated with temporary discontinuation	39.4	37.6

20. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent AEs (Treatment Related)
Description	An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. Grade 3 and 4 AEs in below table indicated severe AE and life-threatening consequences respectively; Grade 5 indicated death due to AE.
Time Frame	From the first dose of study medication up to 28 days after the last dose of study medication or up to the time that a participant died or received subsequent anticancer treatment (maximum duration between first and last dose: 324.4 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Number of Participants Analyzed	104	101
Measure Type: Number; Unit of Measure: Percentage of participants
AEs	98.1	96.0
Serious AEs	8.7	3.0
Grade 3/4 AEs	43.3	40.6
Grade 5 AEs	1.9	0
AEs associated with permanent discontinuation	5.8	1.0
AEs associated with dose reduction	13.5	7.9
AEs associated with temporary discontinuation	28.8	31.7

Adverse Events

Time Frame	From the first dose of study medication up to 28 days after the last dose of study medication or up to the time that a participant died or received subsequent anticancer treatment (maximum duration between first and last dose: 324.4 weeks).
Adverse Event Reporting Description	An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both serious and nonserious event. Participants who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the 1st cycle were analyzed for AEs.
Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description	Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve [AUC] of 5 or 6 mg*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
All-Cause Mortality
	Crizotinib	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	62/104 (59.62%)	61/101 (60.40%)
Serious Adverse Events
	Crizotinib	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	46/104 (44.23%)	13/101 (12.87%)
Blood and lymphatic system disorders
Thrombocytopenia * 1	0/104 (0.00%)	2/101 (1.98%)
Cardiac disorders
Pericardial effusion * 1	0/104 (0.00%)	1/101 (0.99%)
Syncope * 1	0/104 (0.00%)	1/101 (0.99%)
Endocrine disorders
Goitre * 1	1/104 (0.96%)	0/101 (0.00%)
Eye disorders
Ocular hypertension * 1	1/104 (0.96%)	0/101 (0.00%)
Gastrointestinal disorders
Abdominal discomfort * 1	1/104 (0.96%)	0/101 (0.00%)
Dysphagia * 1	2/104 (1.92%)	0/101 (0.00%)
Intestinal obstruction * 1	1/104 (0.96%)	0/101 (0.00%)
Pancreatitis * 1	1/104 (0.96%)	0/101 (0.00%)
Vomiting * 1	1/104 (0.96%)	0/101 (0.00%)
Pancreatitis acute * 1	1/104 (0.96%)	0/101 (0.00%)
General disorders
Death * 1	2/104 (1.92%)	1/101 (0.99%)
Disease progression * 1	15/104 (14.42%)	1/101 (0.99%)
Impaired healing * 1	1/104 (0.96%)	0/101 (0.00%)
Pyrexia * 1	1/104 (0.96%)	1/101 (0.99%)
Hepatobiliary disorders
Drug-induced liver injury * 1	1/104 (0.96%)	0/101 (0.00%)
Hepatic function abnormal * 1	1/104 (0.96%)	0/101 (0.00%)
Immune system disorders
Anaphylactic shock * 1	1/104 (0.96%)	0/101 (0.00%)
Infections and infestations
Lower respiratory tract infection * 1	1/104 (0.96%)	0/101 (0.00%)
Gastrointestinal viral infection * 1	1/104 (0.96%)	0/101 (0.00%)
Pneumonia * 1	5/104 (4.81%)	1/101 (0.99%)
Post procedural infection * 1	1/104 (0.96%)	0/101 (0.00%)
Cellulitis * 1	1/104 (0.96%)	0/101 (0.00%)
Injury, poisoning and procedural complications
Fracture * 1	1/104 (0.96%)	0/101 (0.00%)
Investigations
Transaminases increased * 1	0/104 (0.00%)	1/101 (0.99%)
Alanine aminotransferase increased * 1	1/104 (0.96%)	1/101 (0.99%)
Aspartate aminotransferase increased * 1	1/104 (0.96%)	0/101 (0.00%)
Metabolism and nutrition disorders
Hyperuricaemia * 1	1/104 (0.96%)	0/101 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon adenoma * 1	1/104 (0.96%)	0/101 (0.00%)
Nervous system disorders
Cerebral infarction * 1	0/104 (0.00%)	1/101 (0.99%)
Altered state of consciousness * 1	1/104 (0.96%)	0/101 (0.00%)
Reproductive system and breast disorders
Adenomyosis * 1	1/104 (0.96%)	0/101 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	1/104 (0.96%)	0/101 (0.00%)
Dyspnoea * 1	0/104 (0.00%)	1/101 (0.99%)
Haemoptysis * 1	1/104 (0.96%)	2/101 (1.98%)
Interstitial lung disease * 1	2/104 (1.92%)	0/101 (0.00%)
Pleural effusion * 1	2/104 (1.92%)	1/101 (0.99%)
Pneumothorax * 1	2/104 (1.92%)	0/101 (0.00%)
Pulmonary embolism * 1	3/104 (2.88%)	0/101 (0.00%)
Skin and subcutaneous tissue disorders
Subcutaneous emphysema * 1	1/104 (0.96%)	0/101 (0.00%)
Vascular disorders
Deep vein thrombosis * 1	1/104 (0.96%)	0/101 (0.00%)
Circulatory collapse * 1	1/104 (0.96%)	0/101 (0.00%)
Hypertension * 1	1/104 (0.96%)	0/101 (0.00%)
1 Term from vocabulary, MedDRA 23.0; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Crizotinib	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	103/104 (99.04%)	100/101 (99.01%)
Blood and lymphatic system disorders
Anaemia * 1	20/104 (19.23%)	49/101 (48.51%)
Leukopenia * 1	12/104 (11.54%)	20/101 (19.80%)
Neutropenia * 1	21/104 (20.19%)	37/101 (36.63%)
Thrombocytopenia * 1	4/104 (3.85%)	10/101 (9.90%)
Cardiac disorders
Sinus bradycardia * 1	13/104 (12.50%)	0/101 (0.00%)
Bradycardia * 1	6/104 (5.77%)	0/101 (0.00%)
Eye disorders
Photopsia * 1	7/104 (6.73%)	0/101 (0.00%)
Vision blurred * 1	13/104 (12.50%)	4/101 (3.96%)
Visual impairment * 1	42/104 (40.38%)	8/101 (7.92%)
Gastrointestinal disorders
Abdominal distension * 1	11/104 (10.58%)	6/101 (5.94%)
Abdominal pain * 1	10/104 (9.62%)	3/101 (2.97%)
Abdominal pain upper * 1	8/104 (7.69%)	2/101 (1.98%)
Constipation * 1	37/104 (35.58%)	27/101 (26.73%)
Diarrhoea * 1	63/104 (60.58%)	9/101 (8.91%)
Nausea * 1	56/104 (53.85%)	50/101 (49.50%)
Toothache * 1	7/104 (6.73%)	0/101 (0.00%)
Vomiting * 1	61/104 (58.65%)	46/101 (45.54%)
General disorders
Asthenia * 1	8/104 (7.69%)	10/101 (9.90%)
Chest discomfort * 1	9/104 (8.65%)	4/101 (3.96%)
Chest pain * 1	16/104 (15.38%)	17/101 (16.83%)
Face oedema * 1	7/104 (6.73%)	0/101 (0.00%)
Fatigue * 1	9/104 (8.65%)	17/101 (16.83%)
Oedema * 1	9/104 (8.65%)	1/101 (0.99%)
Oedema peripheral * 1	27/104 (25.96%)	5/101 (4.95%)
Pain * 1	10/104 (9.62%)	6/101 (5.94%)
Pyrexia * 1	19/104 (18.27%)	15/101 (14.85%)
Infections and infestations
Nasopharyngitis * 1	22/104 (21.15%)	8/101 (7.92%)
Upper respiratory tract infection * 1	18/104 (17.31%)	8/101 (7.92%)
Pneumonia * 1	6/104 (5.77%)	0/101 (0.00%)
Investigations
Alanine aminotransferase increased * 1	69/104 (66.35%)	45/101 (44.55%)
Aspartate aminotransferase increased * 1	62/104 (59.62%)	35/101 (34.65%)
Blood albumin decreased * 1	26/104 (25.00%)	16/101 (15.84%)
Blood alkaline phosphatase increased * 1	10/104 (9.62%)	4/101 (3.96%)
Blood bilirubin increased * 1	5/104 (4.81%)	6/101 (5.94%)
Blood creatine phosphokinase increased * 1	14/104 (13.46%)	0/101 (0.00%)
Blood creatinine increased * 1	9/104 (8.65%)	1/101 (0.99%)
Blood lactate dehydrogenase increased * 1	15/104 (14.42%)	1/101 (0.99%)
Gamma-glutamyltransferase increased * 1	14/104 (13.46%)	4/101 (3.96%)
Haemoglobin decreased * 1	7/104 (6.73%)	21/101 (20.79%)
Neutrophil count decreased * 1	40/104 (38.46%)	33/101 (32.67%)
Platelet count decreased * 1	8/104 (7.69%)	27/101 (26.73%)
Protein total decreased * 1	14/104 (13.46%)	3/101 (2.97%)
Red blood cell count decreased * 1	6/104 (5.77%)	9/101 (8.91%)
White blood cell count decreased * 1	43/104 (41.35%)	56/101 (55.45%)
Blood creatine phosphokinase MB increased * 1	6/104 (5.77%)	0/101 (0.00%)
Lymphocyte count decreased * 1	8/104 (7.69%)	6/101 (5.94%)
Metabolism and nutrition disorders
Decreased appetite * 1	27/104 (25.96%)	33/101 (32.67%)
Hypoalbuminaemia * 1	19/104 (18.27%)	8/101 (7.92%)
Hypocalcaemia * 1	13/104 (12.50%)	4/101 (3.96%)
Hypokalaemia * 1	12/104 (11.54%)	7/101 (6.93%)
Hyponatraemia * 1	6/104 (5.77%)	16/101 (15.84%)
Hypoproteinaemia * 1	6/104 (5.77%)	1/101 (0.99%)
Musculoskeletal and connective tissue disorders
Back pain * 1	13/104 (12.50%)	13/101 (12.87%)
Musculoskeletal pain * 1	6/104 (5.77%)	5/101 (4.95%)
Pain in extremity * 1	22/104 (21.15%)	6/101 (5.94%)
Arthralgia * 1	8/104 (7.69%)	4/101 (3.96%)
Muscular weakness * 1	7/104 (6.73%)	0/101 (0.00%)
Nervous system disorders
Dizziness * 1	28/104 (26.92%)	11/101 (10.89%)
Taste disorder * 1	6/104 (5.77%)	0/101 (0.00%)
Headache * 1	29/104 (27.88%)	9/101 (8.91%)
Hypoaesthesia * 1	9/104 (8.65%)	2/101 (1.98%)
Paraesthesia * 1	7/104 (6.73%)	4/101 (3.96%)
Psychiatric disorders
Insomnia * 1	14/104 (13.46%)	9/101 (8.91%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	33/104 (31.73%)	24/101 (23.76%)
Dyspnoea * 1	16/104 (15.38%)	11/101 (10.89%)
Haemoptysis * 1	8/104 (7.69%)	8/101 (7.92%)
Productive cough * 1	6/104 (5.77%)	6/101 (5.94%)
Skin and subcutaneous tissue disorders
Alopecia * 1	10/104 (9.62%)	11/101 (10.89%)
Pruritus * 1	5/104 (4.81%)	8/101 (7.92%)
Rash * 1	12/104 (11.54%)	7/101 (6.93%)
Vascular disorders
Phlebitis * 1	1/104 (0.96%)	8/101 (7.92%)
Hypertension * 1	8/104 (7.69%)	1/101 (0.99%)
1 Term from vocabulary, MedDRA 23.0; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

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

Results Point of Contact

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

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

Wu YL, Lu S, Lu Y, Zhou J, Shi YK, Sriuranpong V, Ho JCM, Ong CK, Tsai CM, Chung CH, Wilner KD, Tang Y, Masters ET, Selaru P, Mok TS. Results of PROFILE 1029, a Phase III Comparison of First-Line Crizotinib versus Chemotherapy in East Asian Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Oct;13(10):1539-1548. doi: 10.1016/j.jtho.2018.06.012. Epub 2018 Aug 14.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01639001
• Other Study ID Numbers: A8081029
• First Submitted: July 10, 2012
• First Posted: July 12, 2012
• Results First Submitted: June 8, 2016
• Results First Posted: March 13, 2017
• Last Update Posted: December 8, 2020