A Clinical Trial Testing The Efficacy Of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin Or Carboplatin In Patients With ALK Positive Non Squamous Cancer Of The Lung (PROFILE 1014)

• ClinicalTrials.gov Identifier: NCT01154140
• Recruitment Status: Completed
• First Posted: June 30, 2010
• Results First Posted: January 5, 2015
• Last Update Posted: November 6, 2017
• 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: Non Squamous Lung Cancer
• Intervention: Drug: treatment
• Enrollment: 343

Participant Flow

Recruitment Details
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 250 mg (milligram) capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of (Response Evaluation Criteria in Solid Tumors) RECIST v1.1 defined PD, as determined by Independent Radiology Review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 intravenous (IV) infusion according to standard of care was administered over 10 minutes (min); either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an area under the concentration time curve (AUC) of 5 or 6 milligram*minute per millilitre (mg*min/mL), approximately 30 min after end of pemetrexed infusion.
Period Title: Overall Study
Started	172	171
Treated	171	169
Completed	81	69
Not Completed	91	102
Reason Not Completed
Death	71	81
Lost to Follow-up	4	5
Withdrawal by Subject	12	13
Other	3	1
Randomized but not treated	1	2

Baseline Characteristics

Arm/Group Title		Crizotinib	Chemotherapy	Total
Arm/Group Description		Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.	Total of all reporting groups
Overall Number of Baseline Participants		172	171	343
Baseline Analysis Population Description		The Full Analysis (FA) population included all participants who were randomized with study treatment assignment designated according to the initial randomization.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	172 participants	171 participants	343 participants
		50.94 (11.9)	52.89 (13.1)	51.92 (12.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	172 participants	171 participants	343 participants
	Female	104 60.5%	108 63.2%	212 61.8%
	Male	68 39.5%	63 36.8%	131 38.2%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Based on IRR
Description	PFS was defined as the time from the date of randomization in study until the date of first documented objective tumor progression (according to RECIST v1.1 as determined by IRR) or death (due to any cause), whichever occurred first. PFS (in months) was calculated as (first event date - randomization date +1)/30.44. Objective progression was defined as a 20 percent (%) increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 millimeter (mm) or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions.
Time Frame	Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Median (95% Confidence Interval); Unit of Measure: months
	10.9; (8.3 to 13.9)	7.0; (6.8 to 8.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was obtained from 1-sided log rank test, stratified by eastern cooperative oncology group performance status (ECOG PS),race,brain metastases. 1-sided log-rank test at 0.0247 level of significance was used to compare PFS between the 2 arms.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.454
	Confidence Interval	(2-Sided) 95%; 0.346 to 0.596
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS (in months) was defined as the duration from start of study treatment to date of death due to any cause. OS = (date of death minus the date of randomization of study medication plus 1) divided by 30.4. For participants who were alive, overall survival was censored on last date the participants were known to be alive.
Time Frame	From randomization to death or last date known alive for those not known to have died (up to 72 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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (45.8 to NA)	47.5 [2]; (32.2 to NA)

[1]

Median and upper limit of 95% CI were not estimable due to the small number of participants who had event.

[2]

Upper limit of 95% CI was not estimable due to the small number of participants who had event.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0489
	Comments	P-value was obtained from 1-sided log rank test, stratified by ECOG PS, race group and brain metastases.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.760
	Confidence Interval	(2-Sided) 95%; 0.548 to 1.053
	Estimation Comments	HR was calculated based on the Cox Proportional hazards model stratified by ECOG PS, race group, and brain metastases. Assuming proportional hazards, a hazard ratio (less than)<1 indicates a reduction in hazard rate in favor of crizotinib.

3. Secondary Outcome

Title	Overall Survival Probability at Month 12 and 18
Description	Overall survival probability at Month 12 and 18 was defined as the probability of overall survival at 12 and 18 months respectively, where the OS was defined as the duration from date of randomization to date of death due to any cause. The survival probability was estimated using the Kaplan-Meier method.
Time Frame	Month 12, 18

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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percent probability
Month 12	83.5; (77.0 to 88.3)	78.4; (71.3 to 83.9)
Month 18	71.5; (64.0 to 77.7)	66.6; (58.8 to 73.2)

4. Secondary Outcome

Title	Objective Response Rate (ORR): Percentage of Participants With Objective Response as Assessed by IRR
Description	ORR was defined as percentage of participants with complete response (CR) or partial response (PR) according to RECIST v1.1 determined by IRR. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as greater than or equal to (>=) 30% decrease taking as reference the baseline sum of lesion dimensions. 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 clear 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 (up to 35 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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	74.4; (67.2 to 80.8)	45.0; (37.4 to 52.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	If the PFS endpoint was significant, ORR was to be considered significant if the 2-sided p-value from Pearson chi-square test was (less than or equal to)<= 0.0494.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was obtained from a Pearson chi-square test.
	Method	Pearson chi-square test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	29.4
	Confidence Interval	(2-Sided) 95%; 19.5 to 39.3
	Estimation Comments	95% CI was calculated based on normal distribution.

5. Secondary Outcome

Title	Duration of Response (DR) Based on IRR
Description	DR: time from first documentation of objective tumor response (CR or PR) to first documentation of PD or death due to any cause, whichever occurred first as per RECIST v1.1 determined by IRR. CR: complete disappearance of all target and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions, disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions. c) PD: 20 % increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions.
Time Frame	From objective response to date of progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 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. Here Overall number of participants analyzed (N) signifies participants with objective tumor response and were evaluable for this outcome measure.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	128	77
Median (95% Confidence Interval); Unit of Measure: weeks
	49.0; (35.1 to 60.0)	22.9; (18.0 to 25.1)

6. 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) according to RECIST v1.1 determined by IRR. CR: complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions.
Time Frame	Randomization to first documentation of objective tumor response (up to 35 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. Here N signifies participants with objective tumor response and were evaluable for this outcome measure.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	128	77
Median (Full Range); Unit of Measure: weeks
	6.1; (2.7 to 41.4)	12.1; (5.1 to 36.7)

7. Secondary Outcome

Title	Percentage of Participants With Disease Control at Week 12 Based on IRR
Description	Disease control rate at week 12 is defined as the percent of participants with CR, PR, or stable disease (SD) at week 12 according to RECIST v1.1 determined by IRR. The best response of SD would be assigned if SD criteria was met at least once after randomization at a minimum interval of 6 weeks. CR: complete disappearance of all target lesions and non-target disease, with 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: >=30% decrease taking as reference the baseline sum of lesion dimensions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions.
Time Frame	Week 12

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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	78.5; (71.6 to 84.4)	68.4; (60.9 to 75.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	The confidence interval for the difference in percentage was based on normal distribution.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0381
	Comments	[Not Specified]
	Method	Pearson chi-square test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	10.067
	Confidence Interval	(2-Sided) 95%; 0.8 to 19.4
	Estimation Comments	[Not Specified]

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 according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions. 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 or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Median (95% Confidence Interval); Unit of Measure: months
	13.6; (8.5 to 15.0)	7.0; (6.8 to 8.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR <1 indicated a reduction in hazard rate in favor of Crizotinib.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was obtained from 1-sided unstratified log-rank test.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.441
	Confidence Interval	(2-Sided) 95%; 0.335 to 0.582
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Time to Intracranial 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. TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions.
Time Frame	Randomization to objective intracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	17.8 [2]; (13.9 to NA)

[1]

Median and CI were not reached due to immaturity of data and low number of events.

[2]

Upper limit of 95% CI was not estimable due to the small number of participants who had event.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of Crizotinib.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0347
	Comments	P-value was obtained from 1-sided unstratified log-rank test.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.595
	Confidence Interval	(2-Sided) 95%; 0.338 to 1.048
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Time to Extracranial 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. TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions.
Time Frame	Randomization to objective extracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Median (95% Confidence Interval); Unit of Measure: months
	15.2; (12.6 to 21.9)	7.2; (6.9 to 8.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of Crizotinib.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was obtained from 1-sided unstratified log-rank test.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.387
	Confidence Interval	(2-Sided) 95%; 0.286 to 0.524
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs.
Time Frame	Baseline up to follow up period (up to 72 months)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all randomized participants who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	171	169
Measure Type: Number; Unit of Measure: percentage of participants
AEs	99.4	99.4
SAEs	41.5	29.0

12. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator.
Time Frame	Baseline up to follow up period (up to 72 months)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	171	169
Measure Type: Number; Unit of Measure: percentage of participants
AEs	98.2	92.3
SAEs	12.9	8.9

13. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs) According to Maximum Severity
Description	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Grade 1 =mild; Grade 2 =moderate; within normal limits, Grade 3 =severe or medically significant but not immediately life-threatening; Grade 4 =life-threatening or disabling; urgent intervention indicated; Grade 5 =death.
Time Frame	Baseline up to follow up period (up to 72 months)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	171	169
Measure Type: Number; Unit of Measure: percentage of participants
Grade 1	7.0	9.5
Grade 2	28.7	34.3
Grade 3	41.5	44.4
Grade 4	8.8	8.9
Grade 5	13.5	2.4

14. Secondary Outcome

Title	Plasma Predose Concentration (Ctrough) of Crizotinib and Its Metabolite PF-06260182
Description	Ctrough is the concentration prior to study drug administration on Day 1 of Cycle 2 onwards. PF-06260182 is the metabolite of Crizotinib.
Time Frame	Predose at Day 1 of Cycle 2, 3 and 5

Outcome Measure Data

Analysis Population Description

Pharmacokinetic concentration population included all participants in the safety analysis population who had at least 1 plasma concentration of crizotinib or its metabolite.N=participants evaluable for this measure.Number of participants analyzed(n)=participants evaluable at specified time points.This analysis was performed in crizotinib arm only.

Arm/Group Title		Crizotinib
Arm/Group Description:		Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.
Overall Number of Participants Analyzed		162
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
Crizotinib Ctrough: Cycle 2 Day 1	Number Analyzed	91 participants
		324.2; (39%)
Crizotinib Ctrough: Cycle 3 Day 1	Number Analyzed	85 participants
		320.9; (40%)
Crizotinib Ctrough: Cycle 5 Day 1	Number Analyzed	82 participants
		308.2; (39%)
PF-06260182 Ctrough: Cycle 2 Day 1	Number Analyzed	100 participants
		98.4; (46%)
PF-06260182 Ctrough: Cycle 3 Day 1	Number Analyzed	94 participants
		99.0; (49%)
PF-06260182 Ctrough: Cycle 5 Day 1	Number Analyzed	86 participants
		92.9; (55%)

15. Secondary Outcome

Title	Percentage of Participants For Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants
Description	The Response Genetics, Inc. Echinoderm Microtubule Associated Protein Like 4 (EML4) ALK reverse transcriptase polymerase chain reaction (RT PCR) gene fusion test was used for the analysis of tissue samples for the ALK gene fusion variants (either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements [V1, V2, V3a, V3b,V3a/b, V4, V5a, V6, V7]). Percentage of participants who tested positive for ALK gene fusion variants were reported in this outcome measure.
Time Frame	28 days prior to day 1 of study treatment

Outcome Measure Data

Analysis Population Description

The ALK variant evaluable population included participants from the FA population who had a result from ALK gene fusion variant testing of either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements (V1, V2, V3a, V3b, V3a/b, V4, V5a, V6, and V7).

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	70	78
Measure Type: Number; Unit of Measure: percentage of participants
V1	27.1	25.6
V2	7.1	7.7
V3a	1.4	1.3
V3a/b	4.3	6.4
No rearrangement	60.0	59.0

16. Secondary Outcome

Title	Objective Response Rate (ORR) of Anaplastic Lymphoma Kinase (ALK) Variant Groups Based on IRR
Description	The Response Genetics, Inc. EML4 ALK reverse transcriptase polymerase chain reaction (RT PCR) gene fusion test was used for the analysis of tissue samples for the ALK gene fusion variants (either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements [V1, V2, V3a, V3b,V3a/b, V4, V5a, V6, V7]). Percentage of participants with confirmed CR or PR according to RECIST v1.1 determined by IRR, by type of ALK gene fusion variant were reported in this outcome measure. CR: complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear 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 (up to 35 months)

Outcome Measure Data

Analysis Population Description

The ALK variant evaluable population included participants from the FA population who had a result from ALK gene fusion variant testing of either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements (V1, V2, V3a, V3b, V3a/b, V4, V5a, V6, and V7). Here, n signifies participants who were evaluable at specified time points.

Arm/Group Title		Crizotinib	Chemotherapy
Arm/Group Description:		Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed		70	78
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
V1	Number Analyzed	19 participants	20 participants
		84.2; (60.4 to 96.6)	45.0; (23.1 to 68.5)
V2	Number Analyzed	5 participants	6 participants
		100; (47.8 to 100)	33.3; (4.3 to 77.7)
V3a	Number Analyzed	1 participants	1 participants
		0.0 [1]; (NA to NA)	100; (2.5 to 100)
V3a/b	Number Analyzed	3 participants	5 participants
		100; (29.2 to 100)	60.0; (14.7 to 94.7)
No rearrangement	Number Analyzed	42 participants	46 participants
		71.4; (55.4 to 84.3)	43.5; (28.9 to 58.9)

[1]

Upper and lower limit of 95% CI was not estimable as the percentage of participants were 0.0 for this specific strain.

17. Secondary Outcome

Title	Time to Deterioration (TTD) in Chest Pain, Dyspnea or Cough
Description	TTD in pain in chest, dyspnea, or cough from the Quality of Life Questionnaire Core 30 (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. For those who had not shown deterioration, the data was censored at the last date when the participants completed an assessment (QLQ-LC13) for pain, dyspnea, or cough or at last visit date prior to crossover for participants randomized to chemotherapy who subsequently crossed over to crizotinib. A 10-point or higher change in the score was perceived by participants as clinically significant. The transformed score of pain, dyspnea, and cough symptom scales of EORTC QLQ-LC13 (European Organization for the Research and Treatment of Cancer) range from 0 to 100, where higher scores indicate greater symptom severity.
Time Frame	From randomization of treatment up to deterioration while on study treatment (up to 35 months)

Outcome Measure Data

Analysis Population Description

The patient reported outcome (PRO) evaluable population included all participants from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	166	163
Median (95% Confidence Interval); Unit of Measure: months
	2.1; (0.8 to 4.2)	0.5; (0.4 to 0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	HR was calculated based on the Cox Proportional hazards model. Assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of crizotinib.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Two-sided p-value from the unstratified log rank test was used.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.591
	Confidence Interval	(2-Sided) 95%; 0.452 to 0.773
	Estimation Comments	[Not Specified]

18. 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 5 functional scales (physical, role, cognitive, emotional and social), global health status/global quality of life scale, 3 symptom scales (fatigue, pain, nausea and vomiting), 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea) and financial difficulties. All scales and single-item measures range from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning, for the global health status/QoL represents a high QoL (better participant state), and for a symptom scale/item represents a high level of symptoms/problems (worse participant state).
Time Frame	Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)

Outcome Measure Data

Analysis Population Description

The PRO evaluable population included all participants from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	166	163
Mean (95% Confidence Interval); Unit of Measure: units on a scale
QLQ-C30 Global QoL	5.9815; (3.92 to 8.05)	-7.8488; (-10.15 to -5.55)
QLQ-C30 Cognitive Functioning	1.1836; (-0.66 to 3.03)	-2.1696; (-4.21 to -0.13)
QLQ-C30 Emotional Functioning	8.7431; (6.77 to 10.72)	1.2266; (-0.95 to 3.40)
QLQ-C30 Physical Functioning	5.9370; (3.94 to 7.93)	-4.4664; (-6.59 to -2.34)
QLQ-C30 Role Functioning	4.8122; (1.92 to 7.71)	-10.7391; (-13.87 to -7.61)
QLQ-C30 Social Functioning	4.3790; (1.60 to 7.15)	-4.3851; (-7.37 to -1.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 Global QoL: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	13.8303
	Confidence Interval	(2-Sided) 95%; 10.74 to 16.92
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 cognitive functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0170
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.3532
	Confidence Interval	(2-Sided) 95%; 0.60 to 6.11
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 emotional functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	7.5165
	Confidence Interval	(2-Sided) 95%; 4.57 to 10.46
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 physical functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	10.4035
	Confidence Interval	(2-Sided) 95%; 7.48 to 13.32
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 role functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	15.5513
	Confidence Interval	(2-Sided) 95%; 11.29 to 19.81
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 social functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	8.7641
	Confidence Interval	(2-Sided) 95%; 4.69 to 12.84
	Estimation Comments	[Not Specified]

19. Secondary Outcome

Title	Change From Baseline Scores in QLQ-C30 Symptoms 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 5 functional scales (physical, role, cognitive, emotional and social), global health status/global quality of life scale, 3 symptom scales (fatigue, pain, nausea and vomiting), 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea) and financial difficulties. All scales and single-item measures range from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning, for the global health status/QoL represents a high QoL (better participant state), and for a symptom scale/item represents a high level of symptoms/problems (worse participant state).
Time Frame	Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)

Outcome Measure Data

Analysis Population Description

The PRO evaluable population included all participants from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	166	163
Mean (95% Confidence Interval); Unit of Measure: units on a scale
QLQ-C30 Appetite loss	-5.4906; (-8.52 to -2.47)	8.0070; (4.63 to 11.38)
QLQ-C30 Constipation	6.4858; (3.46 to 9.51)	10.9194; (7.50 to 14.34)
QLQ-C30 Diarrhea	12.9558; (10.67 to 15.24)	0.4652; (-2.20 to 3.13)
QLQ-C30 Dysponea	-14.9019; (-17.40 to -12.40)	-1.4398; (-4.21 to 1.33)
QLQ-C30 Fatigue	-7.3476; (-9.72 to -4.98)	7.6511; (5.05 to 10.25)
QLQ-C30 Financial Difficulties	-0.5984; (-3.13 to 1.93)	0.2203; (-2.54 to 2.98)
QLQ-C30 Insomnia	-10.3095; (-13.10 to -7.52)	-0.2665; (-3.38 to 2.84)
QLQ-C30 Nausea and Vomiting	3.7742; (1.54 to 6.01)	7.2188; (4.66 to 9.78)
QLQ-C30 Pain	-11.0993; (-13.27 to -8.92)	-1.1716; (-3.66 to 1.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 appetite loss: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	-13.4976
	Confidence Interval	(2-Sided) 95%; -18.03 to -8.97
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 constipation: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0570
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.4336
	Confidence Interval	(2-Sided) 95%; -9.00 to 0.13
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 diarrhea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	12.4906
	Confidence Interval	(2-Sided) 95%; 8.98 to 16.00
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 dysponea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	Median Difference (Net)
	Estimated Value	-13.4622
	Confidence Interval	(2-Sided) 95%; -17.20 to -9.73
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 fatigue: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	-14.9987
	Confidence Interval	(2-Sided) 95%; -18.52 to -11.48
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 financial difficulties: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6681
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.8186
	Confidence Interval	(2-Sided) 95%; -4.56 to 2.92
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 insomnia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	-10.0430
	Confidence Interval	(2-Sided) 95%; -14.22 to -5.87
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 nausea and vomiting: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0468
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.4446
	Confidence Interval	(2-Sided) 95%; -6.84 to -0.05
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-C30 pain: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.9277
	Confidence Interval	(2-Sided) 95%; -13.23 to -6.62
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Change From Baseline in Lung Cancer Symptom Scores as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13)
Description	QLQ-LC13 consists of 1 multi-item scale and 9 single items that assess the specific symptoms (dyspnea, cough, hemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of patients with lung cancer receiving chemotherapy. All multi-item scales and single-item measures range from 0 to 100, where higher score indicates greater degree of symptom severity.
Time Frame	Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)

Outcome Measure Data

Analysis Population Description

The PRO evaluable population included all participants from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	166	163
Mean (95% Confidence Interval); Unit of Measure: units on a scale
QLQ-LC13 Alopecia	-4.4879; (-6.99 to -1.99)	0.3271; (-2.40 to 3.06)
QLQ-LC13 Coughing	-16.4819; (-18.92 to -14.05)	-8.0893; (-10.83 to -5.35)
QLQ-LC13 Dysphagia	0.7618; (-0.82 to 2.35)	0.09660; (-1.76 to 1.95)
QLQ-LC13 Dyspnoea	-9.2029; (-11.20 to -7.20)	-0.1948; (-2.36 to 1.97)
QLQ-LC13 Haemoptysis	-3.2197; (-3.83 to -2.61)	-2.3369; (-3.05 to -1.62)
QLQ-LC13 Pain in Arm or Shoulder	-10.1693; (-12.26 to -8.08)	-4.1218; (-6.51 to -1.74)
QLQ-LC13 Pain in Chest	-8.1437; (-10.31 to -5.98)	-0.04790; (-2.48 to 2.38)
QLQ-LC13 Pain in Other Parts	-8.0757; (-10.28 to -5.87)	-1.3040; (-3.97 to 1.36)
QLQ-LC13 Peripheral Neuropathy	3.1779; (1.04 to 5.31)	-0.1742; (-2.60 to 2.25)
QLQ-LC13 Sore Mouth	2.2472; (0.36 to 4.13)	4.3993; (2.27 to 6.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 alopecia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0108
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.8149
	Confidence Interval	(2-Sided) 95%; -8.52 to -1.11
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 coughing: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	-8.3926
	Confidence Interval	(2-Sided) 95%; -12.06 to -4.72
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 dysphagia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5938
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.6651
	Confidence Interval	(2-Sided) 95%; -1.78 to 3.11
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 dyspnoea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.0080
	Confidence Interval	(2-Sided) 95%; -11.96 to -6.06
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 haemoptysis: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0656
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.8828
	Confidence Interval	(2-Sided) 95%; -1.82 to 0.06
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 pain in arm or shoulder: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.0475
	Confidence Interval	(2-Sided) 95%; -9.22 to -2.88
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 pain in chest: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	-8.0959
	Confidence Interval	(2-Sided) 95%; -11.35 to -4.84
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 pain in other parts: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	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	-6.7717
	Confidence Interval	(2-Sided) 95%; -10.24 to -3.31
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 peripheral neuropathy: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0427
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.3521
	Confidence Interval	(2-Sided) 95%; 0.11 to 6.59
	Estimation Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	QLQ-LC13 sore mouth: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1382
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.1521
	Confidence Interval	(2-Sided) 95%; -5.00 to 0.69
	Estimation Comments	[Not Specified]

21. Secondary Outcome

Title	Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS)
Description	EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. VAS component: participants rated their current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health.
Time Frame	Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)

Outcome Measure Data

Analysis Population Description

The patient reported outcome (PRO) evaluable population included all participants from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment. Here, "N" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	160	160
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	4.5323; (2.44 to 6.62)	0.5415; (-1.85 to 2.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib, Chemotherapy
	Comments	Analysis was based on a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EQ-5D VAS subscale baseline score (intercept and time from first dose were included as random effects).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0139
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.9908
	Confidence Interval	(2-Sided) 95%; 0.81 to 7.17
	Estimation Comments	[Not Specified]

22. Secondary Outcome

Title	Percentage of Participants With Hospital Admissions-Healthcare Resource Utilization (HCRU)
Description	Healthcare resource utilization was to be evaluated using the assessment of the following: date and duration of index admission, duration of hospitalization and date of discharge.
Time Frame	Baseline up to follow up period (up to 72 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 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	172	171
Measure Type: Number; Unit of Measure: percentage of participants
	40.12	36.26

23. Secondary Outcome

Title	Percentage of Participants With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities
Description	Anemia(grade[g]1:Less than[<] Lower limit of normal[LLN] to 10gram per[/] deciliter[g/dL],g2:<10 to 8g/dL,g3:<8g/dL,g4:lifethreatening);platelet (g1:<LLN to 75*10^3/millimeter[mm]^3,g2:<75*10^3/mm^3 to 50*10^3/mm^3,g3:<50*10^3/mm^3 to 25*10^3/mm^3,g4:<25*10^3/mm^3);lymphopenia(g1:<LLN to 8*10^2/mm^3,g2:<8*10^2 to 5*10^2/mm^3,g3:<5*10^2 to 2*10^2/mm^3,g4:<2*10^2/mm^3);neutrophil (Absolute)(g1:<LLN to 15*10^2/mm^3,g2:<15*10^2 to 10*10^2/mm^3,g3:<10*10^2 to 5*10^2/mm^3,g4:<5*10^2/mm^3);white blood cell count(g1:<LLN to 3*10^3/mm^3,g2:<3*10^3 to 2*10^3/mm^3,g3:<2*10^3 to 1*10^3/mm^3,g4:<1*10^3/mm^3);hemoglobin(g1:increase in hemoglobin level>0 to 2 g/dL above ULN or above baseline if baseline is above ULN,g2:increase in hemoglobin level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3:increase in hemoglobin level>4 g/dL above ULN or above baseline if baseline is above ULN). Only categories with atleast 1 participant with abnormality are reported in this outcome measure.
Time Frame	Baseline up to follow up period (up to 72 months)

Outcome Measure Data

Analysis Population Description

Safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle. Here, N=participants who were evaluable for this outcome measure.

Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description:	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed	170	165
Measure Type: Number; Unit of Measure: percentage of participants
Anemia: Grade 1	47.1	46.7
Anemia: Grade 2	13.5	27.9
Anemia: Grade 3	0.6	10.9
Hemoglobin increased: Grade 1	6.5	3.0
Hemoglobin increased: Grade 2	0.6	0.0
Lymphocyte count increased: Grade 2	3.5	1.2
Lymphopenia: Grade 1	34.1	26.1
Lymphopenia: Grade 2	24.7	33.9
Lymphopenia: Grade 3	10.6	13.9
Lymphopenia: Grade 4	2.4	1.8
Neutrophils (Absolute): Grade 1	20.6	14.5
Neutrophils (Absolute): Grade 2	20.0	26.7
Neutrophils (Absolute): Grade 3	14.1	13.9
Neutrophils (Absolute): Grade 4	0.6	3.6
Platelets: Grade 1	9.4	21.8
Platelets: Grade 2	2.4	7.9
Platelets: Grade 3	0.6	7.9
Platelets: Grade 4	0.0	0.6
White blood cells: Grade 1	23.5	34.5
White blood cells: Grade 2	22.9	24.2
White blood cells: Grade 3	2.9	9.1
White blood cells: Grade 4	0.0	0.6

24. Secondary Outcome

Title	Percentage of Participants With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities
Description	ALT/AST (Grade[g]1:>ULN-3*ULN,g2:>3-5*ULN,g3:>5-20*ULN,g4:>20*ULN);Alkaline Phosphatase (g1:>ULN-2.5*ULN,g2:>2.5-5*ULN,g3:>5-20*ULN,g4:>20*ULN);Creatinine (g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-6*ULN,g4:>6*ULN);hyperglycemia (g1:>ULN-160,g2:>160-250,g3:>250-500,g4:>500mg/dL);bilirubin(total) (g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-10*ULN,g4:>10*ULN);hypoglycaemia (g1:<LLN-55,g2:<55-40,g3:<40-30,g4:<30mg/dL);hyperkalemia (g1:>ULN-5.5,g2:>5.5-6,g3:>6-7,g4:>7mmol/L);hypokalemia (g1:<LLN-3,g2:<LLN-3,g3:<3-2.5,g4:<2.5mmol/L);hypermagnesemia (g1:>ULN-3,g3:>3-8,g4:>8mg/dL);hypocalcemia (g1:<LLN-8,g2:<8-7,g3:<7-6,g4:<6mg/dL); hypercalcemia (g1:>ULN-11.5,g2:>11.5-12.5,g3:>12.5-13.5,g4:>13.5mg/dL);hypomagnesemia (g1:<LLN-1.2,g2:<1.2-0.9,g3:<0.9-0.7,g4:<0.7mg/dL);hyponatremia (g1:<LLN-130,g3:<130-120,g4:<120mmol/L);hypoalbuminemia (g1:<LLN-3,g2:<3-2,g3:<2,g4:lifethreatening);hypophosphatemia (g1:<LLN-2.5,g2:<2.5-2,g3:<2-1,g4:<1mg/dL). Participant>=1 abnormality given.
Time Frame	Baseline up to follow up period (up to 72 months)

Outcome Measure Data

Analysis Population Description

Safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle. Here, N=participants who were evaluable for this outcome measure. Here, "n"=participants who were evaluable at specified time points.

Arm/Group Title		Crizotinib	Chemotherapy
Arm/Group Description:		Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
Overall Number of Participants Analyzed		171	165
Measure Type: Number; Unit of Measure: percentage of participants
Alanine aminotransferase: Grade 1	Number Analyzed	171 participants	165 participants
		64.3	34.5
Alanine aminotransferase: Grade 2	Number Analyzed	171 participants	165 participants
		10.5	7.3
Alanine aminotransferase: Grade 3	Number Analyzed	171 participants	165 participants
		12.3	1.8
Alanine aminotransferase: Grade 4	Number Analyzed	171 participants	165 participants
		2.3	0.0
Alkaline phosphatase: Grade 1	Number Analyzed	171 participants	165 participants
		55.6	33.9
Alkaline phosphatase: Grade 2	Number Analyzed	171 participants	165 participants
		8.8	4.8
Alkaline phosphatase: Grade 3	Number Analyzed	171 participants	165 participants
		0.6	1.2
Aspartate Aminotransferase: Grade 1	Number Analyzed	171 participants	165 participants
		57.9	32.1
Aspartate Aminotransferase: Grade 2	Number Analyzed	171 participants	165 participants
		6.4	1.8
Aspartate Aminotransferase: Grade 3	Number Analyzed	171 participants	165 participants
		7.6	1.2
Aspartate Aminotransferase: Grade 4	Number Analyzed	171 participants	165 participants
		0.6	0.0
Bilirubin: Grade 1	Number Analyzed	171 participants	165 participants
		10.5	7.3
Bilirubin: Grade 2	Number Analyzed	171 participants	165 participants
		5.8	1.2
Bilirubin: Grade 3	Number Analyzed	171 participants	165 participants
		0.0	0.6
Creatinine: Grade 1	Number Analyzed	171 participants	165 participants
		50.3	78.8
Creatinine: Grade 2	Number Analyzed	171 participants	165 participants
		47.4	15.8
Creatinine: Grade 3	Number Analyzed	171 participants	165 participants
		1.2	0.0
Hypercalcemia: Grade 1	Number Analyzed	171 participants	165 participants
		0.6	9.1
Hypercalcemia: Grade 4	Number Analyzed	171 participants	165 participants
		0.6	0.0
Hyperglycemia: Grade 1	Number Analyzed	171 participants	165 participants
		50.3	42.4
Hyperglycemia: Grade 2	Number Analyzed	171 participants	165 participants
		15.8	23.6
Hyperglycemia: Grade 3	Number Analyzed	171 participants	165 participants
		4.1	3.6
Hyperkalemia: Grade 1	Number Analyzed	171 participants	165 participants
		17.5	12.1
Hyperkalemia: Grade 2	Number Analyzed	171 participants	165 participants
		5.8	3.0
Hyperkalemia: Grade 3	Number Analyzed	171 participants	165 participants
		2.3	1.8
Hyperkalemia: Grade 4	Number Analyzed	171 participants	165 participants
		0.6	0.0
Hypermagnesemia: Grade 1	Number Analyzed	171 participants	162 participants
		17.6	8.0
Hypermagnesemia: Grade 3	Number Analyzed	171 participants	162 participants
		1.8	0.0
Hypernatremia: Grade 1	Number Analyzed	171 participants	165 participants
		21.1	5.5
Hypernatremia: Grade 2	Number Analyzed	171 participants	165 participants
		0.6	0.0
Hypernatremia: Grade 4	Number Analyzed	171 participants	165 participants
		0.6	0.0
Hypoalbuminemia: Grade 1	Number Analyzed	171 participants	164 participants
		35.1	22.6
Hypoalbuminemia: Grade 2	Number Analyzed	171 participants	164 participants
		44.4	14.6
Hypoalbuminemia: Grade 3	Number Analyzed	171 participants	164 participants
		1.2	0.6
Hypocalcemia: Grade 1	Number Analyzed	171 participants	165 participants
		39.8	24.8
Hypocalcemia: Grade 2	Number Analyzed	171 participants	165 participants
		38.0	4.8
Hypocalcemia: Grade 3	Number Analyzed	171 participants	165 participants
		2.3	0.6
Hypoglycemia: Grade 1	Number Analyzed	171 participants	165 participants
		19.9	3.6
Hypoglycemia: Grade 2	Number Analyzed	171 participants	165 participants
		4.7	1.8
Hypoglycemia: Grade 4	Number Analyzed	171 participants	165 participants
		0.0	0.6
Hypokalemia: Grade 1	Number Analyzed	171 participants	165 participants
		14.6	9.1
Hypokalemia: Grade 3	Number Analyzed	171 participants	165 participants
		2.3	3.0
Hypokalemia: Grade 4	Number Analyzed	171 participants	165 participants
		0.0	0.6
Hypomagnesemia: Grade 1 (n =170, 162)	Number Analyzed	170 participants	162 participants
		12.4	26.5
Hypomagnesemia: Grade 2	Number Analyzed	170 participants	162 participants
		0.0	1.9
Hyponatremia: Grade 1	Number Analyzed	171 participants	165 participants
		25.7	22.4
Hyponatremia: Grade 3	Number Analyzed	171 participants	165 participants
		4.1	5.5
Hyponatremia: Grade 4	Number Analyzed	171 participants	165 participants
		0.6	1.2
Hypophosphatemia: Grade 1	Number Analyzed	169 participants	161 participants
		5.3	3.1
Hypophosphatemia: Grade 2	Number Analyzed	169 participants	161 participants
		27.2	13.0
Hypophosphatemia: Grade 3	Number Analyzed	169 participants	161 participants
		13.0	6.8
Hypophosphatemia: Grade 4	Number Analyzed	169 participants	161 participants
		1.2	0.0

Adverse Events

Time Frame	Baseline up to follow up period (up to 72 months)
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Crizotinib	Chemotherapy
Arm/Group Description	Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days. Participants could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit.	Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 IV infusion according to standard of care was administered over 10 min; either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 min after end of pemetrexed infusion.
All-Cause Mortality
	Crizotinib	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Crizotinib	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	71/171 (41.52%)	49/169 (28.99%)
Blood and lymphatic system disorders
Lymphadenopathy mediastinal * 1	1/171 (0.58%)	0/169 (0.00%)
Anaemia * 1	0/171 (0.00%)	1/169 (0.59%)
Febrile neutropenia * 1	0/171 (0.00%)	2/169 (1.18%)
Cardiac disorders
Atrial fibrillation * 1	1/171 (0.58%)	1/169 (0.59%)
Atrioventricular block * 1	1/171 (0.58%)	0/169 (0.00%)
Pericardial effusion * 1	0/171 (0.00%)	1/169 (0.59%)
Pericarditis * 1	0/171 (0.00%)	1/169 (0.59%)
Syncope * 1	0/171 (0.00%)	2/169 (1.18%)
Cardiac arrest * 1	0/171 (0.00%)	1/169 (0.59%)
Myocardial ischaemia * 1	0/171 (0.00%)	1/169 (0.59%)
Bradycardia * 1	1/171 (0.58%)	0/169 (0.00%)
Cardiac tamponade * 1	2/171 (1.17%)	0/169 (0.00%)
Gastrointestinal disorders
Abdominal pain * 1	1/171 (0.58%)	0/169 (0.00%)
Constipation * 1	0/171 (0.00%)	1/169 (0.59%)
Diarrhoea * 1	2/171 (1.17%)	1/169 (0.59%)
Dysphagia * 1	0/171 (0.00%)	1/169 (0.59%)
Haemorrhoids * 1	1/171 (0.58%)	0/169 (0.00%)
Intestinal obstruction * 1	2/171 (1.17%)	0/169 (0.00%)
Nausea * 1	4/171 (2.34%)	1/169 (0.59%)
Oesophageal ulcer * 1	1/171 (0.58%)	0/169 (0.00%)
Oesophagitis * 1	3/171 (1.75%)	0/169 (0.00%)
Vomiting * 1	3/171 (1.75%)	4/169 (2.37%)
Colitis * 1	1/171 (0.58%)	0/169 (0.00%)
General disorders
Chest pain * 1	1/171 (0.58%)	1/169 (0.59%)
Disease progression * 1	18/171 (10.53%)	1/169 (0.59%)
Fatigue * 1	1/171 (0.58%)	0/169 (0.00%)
General physical health deterioration * 1	0/171 (0.00%)	2/169 (1.18%)
Oedema peripheral * 1	1/171 (0.58%)	0/169 (0.00%)
Pyrexia * 1	1/171 (0.58%)	2/169 (1.18%)
Asthenia * 1	2/171 (1.17%)	0/169 (0.00%)
Death * 1	1/171 (0.58%)	0/169 (0.00%)
Hepatobiliary disorders
Drug-induced liver injury * 1	1/171 (0.58%)	0/169 (0.00%)
Cholecystitis * 1	2/171 (1.17%)	0/169 (0.00%)
Cholecystitis acute * 1	0/171 (0.00%)	1/169 (0.59%)
Bile duct obstruction * 1	0/171 (0.00%)	1/169 (0.59%)
Infections and infestations
Abdominal abscess * 1	1/171 (0.58%)	0/169 (0.00%)
Cellulitis * 1	2/171 (1.17%)	0/169 (0.00%)
Hepatitis B * 1	1/171 (0.58%)	0/169 (0.00%)
Lower respiratory tract infection * 1	2/171 (1.17%)	0/169 (0.00%)
Periodontitis * 1	1/171 (0.58%)	0/169 (0.00%)
Pneumonia * 1	3/171 (1.75%)	1/169 (0.59%)
Pulmonary sepsis * 1	1/171 (0.58%)	0/169 (0.00%)
Respiratory tract infection * 1	2/171 (1.17%)	1/169 (0.59%)
Septic shock * 1	2/171 (1.17%)	0/169 (0.00%)
Upper respiratory tract infection * 1	1/171 (0.58%)	0/169 (0.00%)
Urinary tract infection * 1	2/171 (1.17%)	0/169 (0.00%)
Bronchitis * 1	0/171 (0.00%)	1/169 (0.59%)
Lung infection * 1	1/171 (0.58%)	0/169 (0.00%)
Sepsis * 1	2/171 (1.17%)	0/169 (0.00%)
Arthritis bacterial * 1	1/171 (0.58%)	0/169 (0.00%)
Influenza * 1	1/171 (0.58%)	0/169 (0.00%)
Neutropenic sepsis * 1	1/171 (0.58%)	0/169 (0.00%)
Peritonitis * 1	1/171 (0.58%)	0/169 (0.00%)
Pyelonephritis * 1	1/171 (0.58%)	0/169 (0.00%)
Respiratory tract infection viral * 1	1/171 (0.58%)	0/169 (0.00%)
Skin infection * 1	1/171 (0.58%)	0/169 (0.00%)
Atypical pneumonia * 1	1/171 (0.58%)	0/169 (0.00%)
Injury, poisoning and procedural complications
Overdose * 1	0/171 (0.00%)	1/169 (0.59%)
Rib fracture * 1	0/171 (0.00%)	1/169 (0.59%)
Investigations
Alanine aminotransferase increased * 1	1/171 (0.58%)	0/169 (0.00%)
Aspartate aminotransferase increased * 1	1/171 (0.58%)	0/169 (0.00%)
Metabolism and nutrition disorders
Decreased appetite * 1	2/171 (1.17%)	0/169 (0.00%)
Dehydration * 1	0/171 (0.00%)	2/169 (1.18%)
Diabetic ketoacidosis * 1	1/171 (0.58%)	0/169 (0.00%)
Hypokalaemia * 1	1/171 (0.58%)	0/169 (0.00%)
Hyponatraemia * 1	1/171 (0.58%)	1/169 (0.59%)
Hypoproteinaemia * 1	1/171 (0.58%)	0/169 (0.00%)
Musculoskeletal and connective tissue disorders
Arthritis * 1	2/171 (1.17%)	0/169 (0.00%)
Bone pain * 1	1/171 (0.58%)	0/169 (0.00%)
Muscle spasms * 1	0/171 (0.00%)	1/169 (0.59%)
Muscular weakness * 1	2/171 (1.17%)	0/169 (0.00%)
Osteonecrosis * 1	1/171 (0.58%)	0/169 (0.00%)
Rotator cuff syndrome * 1	0/171 (0.00%)	1/169 (0.59%)
Spinal column stenosis * 1	1/171 (0.58%)	0/169 (0.00%)
Flank pain * 1	1/171 (0.58%)	0/169 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Thyroid adenoma * 1	0/171 (0.00%)	1/169 (0.59%)
Nervous system disorders
Altered state of consciousness * 1	1/171 (0.58%)	0/169 (0.00%)
Central nervous system lesion * 1	1/171 (0.58%)	0/169 (0.00%)
Headache * 1	3/171 (1.75%)	0/169 (0.00%)
Loss of consciousness * 1	1/171 (0.58%)	0/169 (0.00%)
Multiple sclerosis * 1	1/171 (0.58%)	0/169 (0.00%)
Partial seizures * 1	0/171 (0.00%)	1/169 (0.59%)
Transient ischaemic attack * 1	0/171 (0.00%)	1/169 (0.59%)
Cervicobrachial syndrome * 1	1/171 (0.58%)	0/169 (0.00%)
Dizziness * 1	1/171 (0.58%)	0/169 (0.00%)
Paraesthesia * 1	1/171 (0.58%)	0/169 (0.00%)
Seizure * 1	1/171 (0.58%)	5/169 (2.96%)
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy * 1 [1]	1/104 (0.96%)	0/108 (0.00%)
Psychiatric disorders
Completed suicide * 1	0/171 (0.00%)	1/169 (0.59%)
Hypomania * 1	1/171 (0.58%)	0/169 (0.00%)
Renal and urinary disorders
Haematuria * 1	0/171 (0.00%)	1/169 (0.59%)
Renal cyst * 1	3/171 (1.75%)	0/169 (0.00%)
Urinary retention * 1	1/171 (0.58%)	0/169 (0.00%)
Dysuria * 1	1/171 (0.58%)	0/169 (0.00%)
Acute kidney injury * 1	0/171 (0.00%)	1/169 (0.59%)
Reproductive system and breast disorders
Uterine prolapse * 1 [1]	1/104 (0.96%)	0/108 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure * 1	1/171 (0.58%)	0/169 (0.00%)
Asthma * 1	0/171 (0.00%)	1/169 (0.59%)
Dyspnoea * 1	7/171 (4.09%)	4/169 (2.37%)
Haemoptysis * 1	0/171 (0.00%)	2/169 (1.18%)
Pneumothorax * 1	0/171 (0.00%)	1/169 (0.59%)
Interstitial lung disease * 1	1/171 (0.58%)	1/169 (0.59%)
Lung infiltration * 1	0/171 (0.00%)	1/169 (0.59%)
Pleural effusion * 1	2/171 (1.17%)	5/169 (2.96%)
Pleurisy * 1	0/171 (0.00%)	1/169 (0.59%)
Pneumonitis * 1	1/171 (0.58%)	0/169 (0.00%)
Pulmonary embolism * 1	5/171 (2.92%)	7/169 (4.14%)
Pulmonary oedema * 1	0/171 (0.00%)	1/169 (0.59%)
Acute respiratory distress syndrome * 1	1/171 (0.58%)	0/169 (0.00%)
Vascular disorders
Deep vein thrombosis * 1	1/171 (0.58%)	1/169 (0.59%)
Orthostatic hypotension * 1	1/171 (0.58%)	0/169 (0.00%)
Aortic dissection * 1	1/171 (0.58%)	0/169 (0.00%)
Embolism * 1	1/171 (0.58%)	0/169 (0.00%)
Phlebitis * 1	1/171 (0.58%)	0/169 (0.00%)
Superior vena cava syndrome * 1	1/171 (0.58%)	0/169 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 19.1; [1] This adverse event is gender specific.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Crizotinib	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	169/171 (98.83%)	164/169 (97.04%)
Blood and lymphatic system disorders
Anaemia * 1	18/171 (10.53%)	53/169 (31.36%)
Leukopenia * 1	8/171 (4.68%)	16/169 (9.47%)
Thrombocytopenia * 1	1/171 (0.58%)	14/169 (8.28%)
Neutropenia * 1	32/171 (18.71%)	36/169 (21.30%)
Cardiac disorders
Bradycardia * 1	22/171 (12.87%)	0/169 (0.00%)
Sinus bradycardia * 1	10/171 (5.85%)	1/169 (0.59%)
Ear and labyrinth disorders
Tinnitus * 1	4/171 (2.34%)	10/169 (5.92%)
Eye disorders
Photopsia * 1	18/171 (10.53%)	2/169 (1.18%)
Vision blurred * 1	13/171 (7.60%)	5/169 (2.96%)
Visual impairment * 1	98/171 (57.31%)	5/169 (2.96%)
Vitreous floaters * 1	11/171 (6.43%)	1/169 (0.59%)
Gastrointestinal disorders
Abdominal pain * 1	25/171 (14.62%)	8/169 (4.73%)
Abdominal pain upper * 1	27/171 (15.79%)	10/169 (5.92%)
Constipation * 1	78/171 (45.61%)	51/169 (30.18%)
Diarrhoea * 1	111/171 (64.91%)	22/169 (13.02%)
Dyspepsia * 1	27/171 (15.79%)	5/169 (2.96%)
Dysphagia * 1	19/171 (11.11%)	3/169 (1.78%)
Gastrooesophageal reflux disease * 1	14/171 (8.19%)	6/169 (3.55%)
Nausea * 1	100/171 (58.48%)	98/169 (57.99%)
Stomatitis * 1	13/171 (7.60%)	17/169 (10.06%)
Vomiting * 1	87/171 (50.88%)	57/169 (33.73%)
Abdominal distension * 1	11/171 (6.43%)	1/169 (0.59%)
General disorders
Asthenia * 1	28/171 (16.37%)	40/169 (23.67%)
Chest pain * 1	21/171 (12.28%)	14/169 (8.28%)
Fatigue * 1	54/171 (31.58%)	66/169 (39.05%)
Mucosal inflammation * 1	2/171 (1.17%)	9/169 (5.33%)
Oedema peripheral * 1	89/171 (52.05%)	12/169 (7.10%)
Pyrexia * 1	40/171 (23.39%)	17/169 (10.06%)
Influenza like illness * 1	10/171 (5.85%)	1/169 (0.59%)
Pain * 1	9/171 (5.26%)	5/169 (2.96%)
Infections and infestations
Nasopharyngitis * 1	30/171 (17.54%)	5/169 (2.96%)
Upper respiratory tract infection * 1	41/171 (23.98%)	13/169 (7.69%)
Bronchitis * 1	11/171 (6.43%)	2/169 (1.18%)
Conjunctivitis * 1	3/171 (1.75%)	10/169 (5.92%)
Rhinitis * 1	9/171 (5.26%)	2/169 (1.18%)
Urinary tract infection * 1	10/171 (5.85%)	2/169 (1.18%)
Investigations
Alanine aminotransferase increased * 1	59/171 (34.50%)	21/169 (12.43%)
Aspartate aminotransferase increased * 1	47/171 (27.49%)	16/169 (9.47%)
Electrocardiogram QT prolonged * 1	11/171 (6.43%)	2/169 (1.18%)
Neutrophil count decreased * 1	14/171 (8.19%)	17/169 (10.06%)
Platelet count decreased * 1	1/171 (0.58%)	19/169 (11.24%)
Weight decreased * 1	12/171 (7.02%)	5/169 (2.96%)
Weight increased * 1	16/171 (9.36%)	4/169 (2.37%)
White blood cell count decreased * 1	11/171 (6.43%)	12/169 (7.10%)
Blood bilirubin increased * 1	9/171 (5.26%)	2/169 (1.18%)
Blood creatinine increased * 1	9/171 (5.26%)	5/169 (2.96%)
Metabolism and nutrition disorders
Decreased appetite * 1	59/171 (34.50%)	58/169 (34.32%)
Hypoalbuminaemia * 1	19/171 (11.11%)	2/169 (1.18%)
Hypomagnesaemia * 1	3/171 (1.75%)	13/169 (7.69%)
Hypocalcaemia * 1	10/171 (5.85%)	1/169 (0.59%)
Hypophosphataemia * 1	10/171 (5.85%)	2/169 (1.18%)
Hypoproteinaemia * 1	10/171 (5.85%)	0/169 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	25/171 (14.62%)	11/169 (6.51%)
Back pain * 1	35/171 (20.47%)	20/169 (11.83%)
Bone pain * 1	12/171 (7.02%)	4/169 (2.37%)
Muscle spasms * 1	17/171 (9.94%)	2/169 (1.18%)
Musculoskeletal pain * 1	21/171 (12.28%)	8/169 (4.73%)
Pain in extremity * 1	44/171 (25.73%)	14/169 (8.28%)
Flank pain * 1	9/171 (5.26%)	2/169 (1.18%)
Muscular weakness * 1	9/171 (5.26%)	4/169 (2.37%)
Musculoskeletal chest pain * 1	10/171 (5.85%)	5/169 (2.96%)
Myalgia * 1	14/171 (8.19%)	6/169 (3.55%)
Neck pain * 1	11/171 (6.43%)	2/169 (1.18%)
Nervous system disorders
Dizziness * 1	35/171 (20.47%)	15/169 (8.88%)
Dysgeusia * 1	45/171 (26.32%)	9/169 (5.33%)
Headache * 1	48/171 (28.07%)	25/169 (14.79%)
Neuropathy peripheral * 1	4/171 (2.34%)	12/169 (7.10%)
Paraesthesia * 1	29/171 (16.96%)	8/169 (4.73%)
Peripheral sensory neuropathy * 1	6/171 (3.51%)	10/169 (5.92%)
Psychiatric disorders
Anxiety * 1	10/171 (5.85%)	9/169 (5.33%)
Insomnia * 1	23/171 (13.45%)	15/169 (8.88%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	44/171 (25.73%)	28/169 (16.57%)
Dyspnoea * 1	31/171 (18.13%)	23/169 (13.61%)
Haemoptysis * 1	11/171 (6.43%)	6/169 (3.55%)
Oropharyngeal pain * 1	14/171 (8.19%)	8/169 (4.73%)
Productive cough * 1	15/171 (8.77%)	8/169 (4.73%)
Skin and subcutaneous tissue disorders
Alopecia * 1	16/171 (9.36%)	17/169 (10.06%)
Pruritus * 1	9/171 (5.26%)	10/169 (5.92%)
Rash * 1	22/171 (12.87%)	20/169 (11.83%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 19.1

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):

Camidge DR, Kim EE, Usari T, Polli A, Lewis I, Wilner KD. Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC. J Thorac Oncol. 2019 Jun;14(6):1077-1085. doi: 10.1016/j.jtho.2019.02.015. Epub 2019 Feb 26.

Wilner KD, Usari T, Polli A, Kim EE. Comparison of cardiovascular effects of crizotinib and chemotherapy in ALK-positive advanced non-small-cell lung cancer. Future Oncol. 2019 Apr;15(10):1097-1103. doi: 10.2217/fon-2018-0869. Epub 2019 Jan 17.

Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Tang Y, Wilner KD, Blackhall F, Mok TS. Final Overall Survival Analysis From a Study Comparing First-Line Crizotinib Versus Chemotherapy in ALK-Mutation-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2018 Aug 1;36(22):2251-2258. doi: 10.1200/JCO.2017.77.4794. Epub 2018 May 16.

Yoneda KY, Scranton JR, Cadogan MA, Tassell V, Nadanaciva S, Wilner KD, Stollenwerk NS. Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials. Clin Lung Cancer. 2017 Sep;18(5):472-479. doi: 10.1016/j.cllc.2017.03.004. Epub 2017 Mar 14.

Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, Nakagawa K, Wu YL, Mekhail T, Paolini J, Tursi J, Usari T, Wilner KD, Selaru P, Mok TS. Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non-Small-Cell Lung Cancer: Results From PROFILE 1014. J Clin Oncol. 2016 Aug 20;34(24):2858-65. doi: 10.1200/JCO.2015.63.5888. Epub 2016 Mar 28.

Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. doi: 10.1056/NEJMoa1408440. Erratum In: N Engl J Med. 2015 Oct 15;373(16):1582.

Ou SH. Crizotinib: a drug that crystallizes a unique molecular subset of non-small-cell lung cancer. Expert Rev Anticancer Ther. 2012 Feb;12(2):151-62. doi: 10.1586/era.11.186.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01154140
• Other Study ID Numbers: A8081014; 2010-021336-33 ( EudraCT Number ); XALCORI ( Other Identifier: Alias Study Number )
• First Submitted: June 29, 2010
• First Posted: June 30, 2010
• Results First Submitted: November 26, 2014
• Results First Posted: January 5, 2015
• Last Update Posted: November 6, 2017