Trial Outcomes & Findings for A Study Of Crizotinib Versus Chemotherapy In Previously Untreated ALK Positive East Asian Non-Small Cell Lung Cancer Patients (NCT NCT01639001)

Last Updated: 2020-12-08

Results Overview

PFS was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression (by IRR) or death on study due to any cause, whichever occured first. If tumor progression data included more than 1 date, the first date was used. PFS (in months) was calculated as (first event date - randomization date +1)/30.44. Progression is defined using RECIST v1.1, as at least a 20% increase (including an absolute increase of at least 5 millimeters) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

207 participants

Primary outcome timeframe

Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, assessed up to 33 months)

Results posted on

2020-12-08

Participant Flow

This phase 3, randomized, open label, multicenter study conducted in 35 centers in 5 countries. A total of 207 actual participants were randomized, 104 in the crizotinib arm and 103 in the chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) arm.

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.

Participant milestones

Participant milestones
Measure	Crizotinib Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Chemotherapy Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve \[AUC\] of 5 or 6 mg\*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Overall Study STARTED	104	103
Overall Study Treated	104	101
Overall Study COMPLETED	29	26
Overall Study NOT COMPLETED	75	77

Reasons for withdrawal

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

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Crizotinib n=104 Participants Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Chemotherapy n=103 Participants Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve \[AUC\] of 5 or 6 mg\*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.	Total n=207 Participants Total of all reporting groups
Age, Continuous	48.2 Years STANDARD_DEVIATION 10.6 • n=5 Participants	48.9 Years STANDARD_DEVIATION 11.2 • n=7 Participants	48.5 Years STANDARD_DEVIATION 10.9 • n=5 Participants
Sex: Female, Male Female	54 Participants n=5 Participants	60 Participants n=7 Participants	114 Participants n=5 Participants
Sex: Female, Male Male	50 Participants n=5 Participants	43 Participants n=7 Participants	93 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, assessed up to 33 months)

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

Outcome measures

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

SECONDARY outcome

Timeframe: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (assessed up to 33 months)

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

Percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

Outcome measures

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

SECONDARY outcome

Timeframe: From randomization to death or last date known as alive for those who were lost to follow-up or withdrew consent (assessed up to 64 months).

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

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

Outcome measures

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

SECONDARY outcome

Timeframe: From randomization to Week 12

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

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

Outcome measures

Outcome measures
Measure	Crizotinib n=104 Participants Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Chemotherapy n=103 Participants Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve \[AUC\] of 5 or 6 mg\*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Percentage of Participants With Disease Control at 12 Weeks Based on IRR	82.7 Percentage of participants Interval 74.0 to 89.4	73.8 Percentage of participants Interval 64.2 to 82.0

SECONDARY outcome

Timeframe: From randomization to 1 year and from randomization to 18 months

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

Probability of survival 1 year and 18 month after randomization. The probability of survival at 1 year was estimated using the Kaplan Meier method and a 2-sided 95% CI for the log \[-log(1-year survival probability)\] was calculated using a normal approximation and then back transformed to give a CI for the 1-year survival probability itself. The probability of survival at 18 months was estimated similarly.

Outcome measures

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

SECONDARY outcome

Timeframe: From objective response to date of progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, up to 33 months)

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

DR was defined as the time from the first documentation of objective tumor response (CR or PR), as determined by the IRR, to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. DR (in weeks) was calculated as (first date of PD or death - first date of CR or PR +1)/7. DR was only calculated for the subgroup of participants with an objective tumor response.

Outcome measures

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

SECONDARY outcome

Timeframe: Randomization to first documentation of objective tumor response (up to 33 months).

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

TTR was defined as the time from randomization to first documentation of objective tumor response (CR or PR) as determined by the IRR. For participants proceeding from PR to CR, the onset of PR was taken as the onset of response. TTR was calculated for the subgroup of participants with objective tumor response.

Outcome measures

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

SECONDARY outcome

Timeframe: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, up to 33 months)

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

TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression, as determined by IRR. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date - randomization date +1)/30.44.

Outcome measures

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

SECONDARY outcome

Timeframe: Randomization to objective intracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, up to 33 months)

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

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.

Outcome measures

Outcome measures
Measure	Crizotinib n=104 Participants Crizotinib capsules, 250 mg twice daily (BID), were administered orally at approximately the same time each day on a continuous daily dosing schedule. Each treatment cycle was defined as 21 days. Participants could continue crizotinib treatment beyond the time of RECIST defined Progressive Disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the participant was perceived to be experiencing clinical benefit. The maximum duration of crizotinib treatment was 324.4 weeks.	Chemotherapy n=103 Participants Standard doses of chemotherapy were administered by intravenous (IV) infusion every 3 weeks for a maximum of 6 cycles. Pemetrexed (500 mg/m2) was administered over 10 minutes or according to institutional administration timing; cisplatin (75 mg/m2) was administered after adequate hydration beginning approximately 30 minutes after the end of the pemetrexed infusion and carboplatin was administered on Day 1 of a 21-day cycle at a dose calculated to produce an area under the concentration time curve \[AUC\] of 5 or 6 mg\*min/mL, beginning approximately 30 minutes after end of pemetrexed infusion. The maximum duration of chemotherapy treatment was 24.1 weeks.
Intracranial Time to Progression (IC-TTP) Based on IRR	NA Months Interval 20.8 to Median and upper limit for IC-TTP was not reached due to insufficient IC-TTP events.	16.0 Months Interval 12.6 to Upper limit for IC-TTP was not reached due to insufficient IC-TTP events.

SECONDARY outcome

Timeframe: Randomization to objective extracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, up to 33 months)

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

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.

Outcome measures

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

SECONDARY outcome

Timeframe: From Baseline to deterioration while on study treatment. For participants with no deterioration, the data was censored at the last date when QLQ-LC13 assessment for pain, dyspnea, or cough was completed (assessed up to 33 months）

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

The QLQ-LC13 consisted of 1 multi-item scale and 9 single items that assessed the specific symptoms (dyspnea, cough, hemoptysis, and site specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of lung cancer participants receiving chemotherapy. The QLQ-LC13 Coughing, Dyspnoea and Pain in chest each ranged from 0-100 with higher scores indicating a high level of symptomatology/problems. TTD in pain in chest, dyspnea, or cough from the QLQ-LC13 was a composite endpoint defined as the time from randomization to the earliest time the participant's scale scores showed a 10 point or greater increase after baseline in any of the 3 symptoms.