A Study of Tarceva (Erlotinib) or Placebo in Combination With Platinum-Based Therapy as First Line Treatment in Patients With Advanced or Recurrent Non-Small Cell Lung Cancer

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00883779
• Collaborator: (none)
• Enrollment: 451
• Locations: 26
• Arms: 2
• Duration (Months): 68
• Patients Per Site: 17.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This 2 arm study will compare the efficacy and safety of sequential treatment with Tarceva or placebo, plus platinum-based therapy, as first line treatment in patients with advanced or recurrent non-small cell lung cancer. Patients will be randomized to receive gemcitabine (1250mg/m2 iv) on days 1 and 8, and cisplatin (75mg/m2) or carboplatin (5xAUC)on day 1, followed by Tarceva 150mg/day or placebo from day 15 to day 28 of each 4 week cycle for a total of 6 cycles,then followed by Tarceva or placebo monotherapy.The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.

Condition or Disease	Intervention/Treatment	Phase
Non-Squamous Non-Small Cell Lung Cancer	Drug: Placebo; Drug: Platinum chemotherapy (cisplatin or carboplatin); Drug: erlotinib [Tarceva]; Drug: gemcitabine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 451 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-controlled, Double-blind Phase III Study of the Effect of First-line Treatment With Intercalated Tarceva Versus Placebo in Combination With Gemcitabine/Platinum on Progression-free Survival in Patients With Stage IIIB/IV Non-small Cell Lung Cancer
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: Platinum chemotherapy (cisplatin or carboplatin); cisplatin --75mg/m2 oon day 1 of each 4 week cycle for 6 cycles or carboplatin--5xAUC on day 1 of each 4 week cycle for 6 cycles; Drug: erlotinib [Tarceva]; 150mg po on days 15-28 of each 4 week cycle until disease progression; Drug: gemcitabine; 1250mg/m2 iv on days 1 and 8 of each 4 week cycle for 6 cycles
Placebo Comparator: 2	Drug: Placebo; po on days 15-28 of each 4 week cycle until disease progression; Drug: Platinum chemotherapy (cisplatin or carboplatin); cisplatin --75mg/m2 oon day 1 of each 4 week cycle for 6 cycles or carboplatin--5xAUC on day 1 of each 4 week cycle for 6 cycles; Drug: gemcitabine; 1250mg/m2 iv on days 1 and 8 of each 4 week cycle for 6 cycles

Outcome Measures

Primary Outcome Measures

1. Median Progression Free Survival (PFS) Time [Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])]

   Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. PFS is the time (in months) between the date of randomization and the date of first documented disease progression or death from any cause, whichever comes first. Participants who had neither progressed nor died at the time of data cut-off or who were lost to follow-up were censored at the date of the last tumor assessment where non-progression was documented or last date of follow up for progression of disease, whichever was last. Participants without post baseline tumor assessments who were known to be alive were censored at the time of randomization. Analysis was performed using Kaplan-Meier method.

Secondary Outcome Measures

1. Percentage of Participants Alive and Free From Disease Progression [Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])]

   Tumor response was evaluated according to RECIST (version 1.0). PD was defined as at least a 20% increase in the sum of LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions.

2. Median PFS Time Based on Different Subgroups [Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])]

   Tumor response was evaluated according to RECIST (version 1.0). PD was defined in outcome measure 1. PFS is the time (in months) between the date of randomization and the date of first documented disease progression or death from any cause, whichever comes first. Participants who had neither progressed nor died at the time of data cut-off or who were lost to follow-up were censored at the date of the last tumor assessment where non-progression was documented or last date of follow up for progression of disease, whichever was last. Participants without post baseline tumor assessments who were known to be alive were censored at the time of randomization. PFS among different subgroups of type of carcinoma, smoking habit, epidermal growth factor receptor (EGFR) mutation type, KRAS mutation type, EGFR immunohistochemistry (IHC) test result type, and EGFR fluorescent in situ hybridization (FISH) result type.

3. Median Overall Survival (OS) Time-Overall and Among Different Subgroups [Randomization until death (assessed at baseline and every 8 weeks thereafter until death or end of study [up to approximately 5.5 years])]

   OS was defined as the time between the date of randomization and the date of death from any cause. Participants for whom no death was captured on the clinical database were censored at the most recent date they were known to be alive. Participants with no post baseline information were censored at the time of randomization. OS among different subgroups of type of carcinoma, smoking habit, EGFR mutation type, KRAS mutation type, EGFR IHC test result type, and EGFR FISH result type. Analysis was performed using Kaplan-Meier method.

4. Percentage of Participants Alive at the End of Study-Overall and Among Different Subgroups [Randomization until death (assessed at baseline and every 8 weeks thereafter until death or end of study [up to approximately 5.5 years])]

5. Non-Progression Rate: Percentage of Participants With a Confirmed Best Overall Response of Either Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) for At Least 16 Weeks [Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])]

   Tumor response was evaluated according to RECIST (version 1.0). CR is defined as the disappearance of all target and non-target lesions and normalization of tumor marker level; PR is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the screening sum LD; SD for target lesions is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started and SD for non-target lesions defined as persistence of 1 or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. Responses were confirmed with repeated assessment 4 weeks after initial response was observed.

6. Objective Response Rate: Percentage of Participants With a Confirmed Best Overall Response of CR or PR [Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])]

   Tumor response was evaluated according to RECIST (version 1.0). CR is defined as the disappearance of all target and non-target lesions and normalization of tumor marker level; PR is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the screening sum LD. Responses were confirmed with repeated assessment 4 weeks after initial response was observed.

7. Duration of Response [Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])]

   Duration of response is defined as the time between the date of first documented response (CR or PR, as determined by the RECIST criteria) and the date of first documented PD or death. Participants who did not progress or die after they had a confirmed response (CR or PR) were censored at the date of their last tumor assessment where non-progression was documented or last date of follow-up for progression of disease, whichever was last. CR and PR are defined in Outcome Measure 7.

8. Time to Progression [Randomization until PD (assessed at baseline and every 8 weeks thereafter until PD or end of study [up to approximately 1.5 years])]

   Time to progression is defined as the time between the date of randomization and the date of the first documented disease progression. Participants who have not progressed at the time of study completion (or data cut off) or who were lost to follow up were censored at the date of the last tumor assessment where non-progression was documented or last date of follow-up for progression of disease, whichever was latest. PD was defined as at least a 20% increase in the sum of LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. Participants with no post baseline tumor assessments were censored at the time of randomization. Analysis was performed using Kaplan-Meier method.

9. Percentage of Participants With Symptomatic Progression Assessed Using the Lung Cancer Subscale (LCS) [Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)]

   LCS scores were obtained from a 7-item questionnaire from the Functional Assessment of Cancer Therapy - Lung (FACT-L) (version 4.0). Participants responded to questions such as shortness of breath, cough, tightness in chest, breathing difficulty, appetite loss, weight loss and unclear thinking; on a 5-point scale from 0-4, where 0 equaled (=) "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 (most symptomatic) to 28 (asymptomatic); higher score indicates fewer symptoms. A clinically meaningful decline used to determine symptomatic progression in this study was at least a three point decline in LCS score from baseline. Participants without symptomatic progression at the time of analysis were censored at the time of the last FACT-L assessment.

10. Time to Symptomatic Progression [Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)]

    Time to symptomatic progression was the time from randomization until the earlier of a clinically meaningful decline from baseline in LCS score, or death on study. LCS scores were obtained from a 7-item questionnaire from the FACT-L (version 4.0). Participants responded to questions such as shortness of breath, cough, tightness in chest, breathing difficulty, appetite loss, weight loss and unclear thinking; on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 (most symptomatic) to 28 (asymptomatic); higher score indicates fewer symptoms. A clinically meaningful decline used to determine symptomatic progression in this study was at least a three point decline in LCS score from baseline. Participants without symptomatic progression at the time of analysis were censored at the time of the last FACT-L assessment. Analysis was performed using Kaplan-Meier method.

11. Percentage of Participants With Deterioration in Trial Outcome Index (TOI) Using FACT-L Version 4.0 [Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)]

    TOI was defined as the sum of the scores of the Physical Well-Being (PWB), Functional Well-Being (FWB), and LCS. PWB, FWB, and LCS scores were obtained from 7-item questionnaires from the FACT-L (Version 4.0). Participants responded to questions on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 to 84; higher score indicates better physical aspects of quality of life (QoL). A clinically meaningful decline used to determine deterioration in TOI was greater than or equal to (≥) 6-point decline from baseline. Participants without deterioration in TOI at the time of analysis were censored at the time of the last FACT-L assessment.

12. Time to Deterioration in TOI Using FACT-L Version 4.0 [Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)]

    Time to deterioration in TOI is defined as time from randomization until the earlier of a clinically meaningful decline from baseline in TOI or death on study. TOI is defined as the sum of the scores of the PWB, FWB, and LCS. PWB, FWB, and LCS scores were obtained from 7-item questionnaires from the FACT-L (Version 4.0). Participants responded to questions on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 to 84; higher score indicates better physical aspects of QoL. A clinically meaningful decline used to determine deterioration in TOI was ≥6-point decline from baseline. Participants without deterioration in TOI at the time of analysis were censored at the time of the last FACT-L assessment. Analysis was performed using Kaplan-Meier method.

13. Percentage of Participants With Deterioration in Quality of Life (QOL) Using FACT-L Version 4.0 [Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)]

    Total FACT-L score was defined as the sum of the TOI, Social Well Being (SWB) and EWB of the FACT-L questionnaires. TOI (PWB + FWB + LCS), SWB and EWB scores were obtained from 7-item (6-item in the case of EWB) questionnaires from the FACT-L (Version 4.0). Participants responded to questions on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 to 136; higher score indicates better QoL. A clinically meaningful decline used to determine deterioration in QoL was ≥6-point decline from baseline. Participants without deterioration in QoL at the time of analysis were censored at the time of the last FACT-L assessment.

14. Time to Deterioration in QOL Using FACT-L Version 4.0 [Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)]

    Time to deterioration in QoL is defined as time from randomization until the earlier of a clinically meaningful decline from baseline in Total FACT-L or death on study. Total FACT-L score was defined as the sum of the TOI, SWB and EWB of the FACT-L questionnaires. TOI (PWB + FWB + LCS), SWB and EWB scores were obtained from 7-item (6-item in the case of EWB) questionnaires from the FACT-L (Version 4.0). Participants responded to questions on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 to 136; higher score indicates better QoL. A clinically meaningful decline used to determine deterioration in QoL was ≥6-point decline from baseline. Participants without deterioration in QoL at the time of analysis were censored at the time of the last FACT-L assessment. Analysis was performed using Kaplan-Meier method.

15. Median Follow-up Time During the Study [Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 5.5 years])]

    Median follow-up was calculated using 'Reverse Kaplan-Meier' analysis for Overall survival.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• adult patients, >=18 years of age;

• advanced (stage IIIB/IV)non-small cell lung cancer;

• measurable disease;

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.

Exclusion Criteria:

• prior exposure to agents directed at the HER axis;

• prior chemotherapy or systemic anti-tumor therapy after advanced disease;

• unstable systemic disease;

• any other malignancy within last 5 years, except cured basal cell cancer of skin or cured cancer in situ of cervix;

• brain metastasis or spinal cord compression.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Beijing		China	100021
2		Beijing		China	100142
3		Beijing		China	101149
4		Guangzhou		China	510060
5		Guangzhou		China
6		Hangzhou		China
7		Nanjing		China	210029
8		Shanghai		China	200030
9		Shanghai		China	200433
10		Hong Kong		Hong Kong	852
11		Hong Kong		Hong Kong
12		Shatin		Hong Kong
13		Jakarta		Indonesia	13230
14		Jogjakarta		Indonesia	55284
15		Surabaya		Indonesia	60286
16		Gyeonggi-do		Korea, Republic of	410-769
17		Manila		Philippines	1000
18		Pasig City		Philippines	1605
19		Quezon City		Philippines	1104
20		Taichung		Taiwan	407
21		Taipei		Taiwan	100
22		Taipei		Taiwan	116
23		Taipei		Taiwan
24		Bangkok		Thailand	10400
25		Bangkok		Thailand	10700
26		Chiang Mai		Thailand	50200

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00883779
• Other Study ID Numbers: MO22201
• First Posted: Apr 20, 2009
• Last Update Posted: Dec 14, 2015
• Last Verified: Nov 1, 2015

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Gemcitabine; Carboplatin; Erlotinib Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 milligrams per squared meter (mg/m^2) of gemcitabine intravenous (IV) infusion on Day 1 and 8, carboplatin 5 times (5x) area under concentration versus time curve (AUC) or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day Cycle) until disease progression (PD), unacceptable toxicity or death in primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 milligrams per day (mg/day) from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Period Title: Primary Study Treatment Phase
STARTED	225	226
COMPLETED	120	140
NOT COMPLETED	105	86
Period Title: Primary Study Treatment Phase
STARTED	112	135
COMPLETED	0	0
NOT COMPLETED	112	135
Period Title: Primary Study Treatment Phase
STARTED	209	202
COMPLETED	0	0
NOT COMPLETED	209	202

Baseline Characteristics

Arm/Group Title	Placebo	Erlotinib	Total
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).	Total of all reporting groups
Overall Participants	225	226	451
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.4 (11.08)	57.2 (9.71)	56.8 (10.41)
Sex: Female, Male (Count of Participants)
Female	85 37.8%	94 41.6%	179 39.7%
Male	140 62.2%	132 58.4%	272 60.3%

Outcome Measures

1. Primary Outcome

Title	Median Progression Free Survival (PFS) Time
Description	Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. PFS is the time (in months) between the date of randomization and the date of first documented disease progression or death from any cause, whichever comes first. Participants who had neither progressed nor died at the time of data cut-off or who were lost to follow-up were censored at the date of the last tumor assessment where non-progression was documented or last date of follow up for progression of disease, whichever was last. Participants without post baseline tumor assessments who were known to be alive were censored at the time of randomization. Analysis was performed using Kaplan-Meier method.
Time Frame	Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Median (95% Confidence Interval) [months]	6.0	7.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.46 to 0.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants Alive and Free From Disease Progression
Description	Tumor response was evaluated according to RECIST (version 1.0). PD was defined as at least a 20% increase in the sum of LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions.
Time Frame	Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Number [percentage of participants]	6.2 2.8%	22.6 10%

3. Secondary Outcome

Title	Median PFS Time Based on Different Subgroups
Description	Tumor response was evaluated according to RECIST (version 1.0). PD was defined in outcome measure 1. PFS is the time (in months) between the date of randomization and the date of first documented disease progression or death from any cause, whichever comes first. Participants who had neither progressed nor died at the time of data cut-off or who were lost to follow-up were censored at the date of the last tumor assessment where non-progression was documented or last date of follow up for progression of disease, whichever was last. Participants without post baseline tumor assessments who were known to be alive were censored at the time of randomization. PFS among different subgroups of type of carcinoma, smoking habit, epidermal growth factor receptor (EGFR) mutation type, KRAS mutation type, EGFR immunohistochemistry (IHC) test result type, and EGFR fluorescent in situ hybridization (FISH) result type.
Time Frame	Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])

Outcome Measure Data

Analysis Population Description

FAS population. "n" is the number of participants evaluable under the specified category.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Adenocarcinoma (n=168,174)	6.5	8.2
Non-adenocarcinoma (n=57,52)	5.8	5.7
Never smoked (n=107,112)	6.6	10.9
Former/current smoker (n=118,114)	5.9	5.7
EGFR mutation (n=48,49)	6.9	15.6
EGFR wild-type (n=67,69)	5.9	7.1
KRAS mutation (n=11,10)	4.5	6.0
KRAS wild-type (n=101,101)	6.8	8.0
EGFR IHC positive (n=36,40)	6.0	8.1
EGFR IHC negative (n=25,12)	6.7	10.1
EGFR FISH positive (n=20,14)	5.9	12.9
EGFR FISH negative (n=23,25)	6.0	7.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in adenocarcinoma subgroup
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in non-adenocarcinoma subgroup
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.579
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.60 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in never smoked subgroup
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in former/current smoker subgroup
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.2067
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in subgroup EGFR mutation
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; 0.12 to 0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in subgroup EGFR wild-type
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.7511
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in subgroup KRAS mutation
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3169
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.25 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in subgroup KRAS wild-type
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.37 to 0.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in subgroup EGFR IHC positive
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0091
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in subgroup EGFR IHC negative
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0179
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.18 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in subgroup EGFR FISH positive
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0017
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; 0.11 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	PFS in subgroup EGFR FISH negative
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1880
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.37 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Median Overall Survival (OS) Time-Overall and Among Different Subgroups
Description	OS was defined as the time between the date of randomization and the date of death from any cause. Participants for whom no death was captured on the clinical database were censored at the most recent date they were known to be alive. Participants with no post baseline information were censored at the time of randomization. OS among different subgroups of type of carcinoma, smoking habit, EGFR mutation type, KRAS mutation type, EGFR IHC test result type, and EGFR FISH result type. Analysis was performed using Kaplan-Meier method.
Time Frame	Randomization until death (assessed at baseline and every 8 weeks thereafter until death or end of study [up to approximately 5.5 years])

Outcome Measure Data

Analysis Population Description

FAS population. "n" is the number of participants evaluable under the specified category.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Overall participants (n=225,226)	15.2	18.2
Adenocarcinoma (n=168,174)	15.8	20.9
Non-adenocarcinoma (n=57,52)	12.4	10.3
Never smoked (n=107,112)	17.5	25.9
Current/former smoker (n=118,114)	13.0	13.0
EGFR mutation (n=48,49)	20.6	30.3
EGFR wild-type (n=67,69)	12.2	14.9
KRAS mutation (n=11,10)	11.2	17.5
KRAS wild-type (n=101,101)	14.1	18.1
EGFR IHC positive (n=36,40)	15.2	18.6
EGFR IHC negative (n=25,12)	12.5	21.9
EGFR FISH positive (n=20,14)	17.7	43.1
EGFR FISH negative (n=23,25)	12.5	16.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in overall participants (FAS population)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1213
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup adenocarcinoma
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0356
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup non-adenocarcinoma
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1157
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.92 to 2.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup never smoked
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0056
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup current/former smoker
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3473
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup EGFR mutation
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1614
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup EGFR wild-type
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1691
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup KRAS mutation
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1415
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.19 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup KRAS wild-type
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1447
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in EGFR IHC positive
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0310
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.35 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS in subgroup EGFR IHC negative
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0581
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.21 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS of subgroup EGFR FISH positive
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0063
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95%; 0.14 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	OS of subgroup EGFR FISH negative
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3268
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.40 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants Alive at the End of Study-Overall and Among Different Subgroups
Time Frame	Randomization until death (assessed at baseline and every 8 weeks thereafter until death or end of study [up to approximately 5.5 years])

Outcome Measure Data

Analysis Population Description

FAS population. "n" is the number of participants evaluable under the specified category.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Overall participants (n=225,226)	13.3 5.9%	15.9 7%
Adenocarcinoma (n=168,174)	14.9 6.6%	19.5 8.6%
Non-adenocarcinoma (n=57,52)	8.8 3.9%	3.8 1.7%
Never smoked (n=107,112)	13.1 5.8%	23.2 10.3%
Current/former smoker (n=118,114)	13.6 6%	8.8 3.9%
EGFR mutation (n=48,49)	22.9 10.2%	30.6 13.5%
EGFR wild-type (n=67,69)	7.5 3.3%	10.1 4.5%
KRAS mutation (n=11,10)	0.0 0%	20.0 8.8%
KRAS wild-type (n=101,101)	14.9 6.6%	17.8 7.9%
EGFR IHC positive (n=36,40)	11.1 4.9%	25.0 11.1%
EGFR IHC negative (n=25,12)	8.0 3.6%	33.3 14.7%
EGFR FISH positive (n=20,14)	10.0 4.4%	42.9 19%
EGFR FISH negative (n=23,25)	13.0 5.8%	16.0 7.1%

6. Secondary Outcome

Title	Non-Progression Rate: Percentage of Participants With a Confirmed Best Overall Response of Either Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) for At Least 16 Weeks
Description	Tumor response was evaluated according to RECIST (version 1.0). CR is defined as the disappearance of all target and non-target lesions and normalization of tumor marker level; PR is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the screening sum LD; SD for target lesions is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started and SD for non-target lesions defined as persistence of 1 or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. Responses were confirmed with repeated assessment 4 weeks after initial response was observed.
Time Frame	Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Number (95% Confidence Interval) [percentage of participants]	64.4 28.6%	67.3 29.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	Difference in non-progression response rates
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.5289
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.81
	Confidence Interval	(2-Sided) 95%; -6.2 to 11.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Objective Response Rate: Percentage of Participants With a Confirmed Best Overall Response of CR or PR
Description	Tumor response was evaluated according to RECIST (version 1.0). CR is defined as the disappearance of all target and non-target lesions and normalization of tumor marker level; PR is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the screening sum LD. Responses were confirmed with repeated assessment 4 weeks after initial response was observed.
Time Frame	Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Number (95% Confidence Interval) [percentage of participants]	17.8 7.9%	42.9 19%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments	Difference in objective response rates
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	25.14
	Confidence Interval	(2-Sided) 95%; 16.7 to 33.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined as the time between the date of first documented response (CR or PR, as determined by the RECIST criteria) and the date of first documented PD or death. Participants who did not progress or die after they had a confirmed response (CR or PR) were censored at the date of their last tumor assessment where non-progression was documented or last date of follow-up for progression of disease, whichever was last. CR and PR are defined in Outcome Measure 7.
Time Frame	Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 1.5 years])

Outcome Measure Data

Analysis Population Description

FAS population participants who were responders (CR or PR).

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	40	97
Median (95% Confidence Interval) [months]	5.6	10.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95%; 0.21 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Time to Progression
Description	Time to progression is defined as the time between the date of randomization and the date of the first documented disease progression. Participants who have not progressed at the time of study completion (or data cut off) or who were lost to follow up were censored at the date of the last tumor assessment where non-progression was documented or last date of follow-up for progression of disease, whichever was latest. PD was defined as at least a 20% increase in the sum of LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. Participants with no post baseline tumor assessments were censored at the time of randomization. Analysis was performed using Kaplan-Meier method.
Time Frame	Randomization until PD (assessed at baseline and every 8 weeks thereafter until PD or end of study [up to approximately 1.5 years])

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Median (95% Confidence Interval) [months]	6.5	7.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Participants With Symptomatic Progression Assessed Using the Lung Cancer Subscale (LCS)
Description	LCS scores were obtained from a 7-item questionnaire from the Functional Assessment of Cancer Therapy - Lung (FACT-L) (version 4.0). Participants responded to questions such as shortness of breath, cough, tightness in chest, breathing difficulty, appetite loss, weight loss and unclear thinking; on a 5-point scale from 0-4, where 0 equaled (=) "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 (most symptomatic) to 28 (asymptomatic); higher score indicates fewer symptoms. A clinically meaningful decline used to determine symptomatic progression in this study was at least a three point decline in LCS score from baseline. Participants without symptomatic progression at the time of analysis were censored at the time of the last FACT-L assessment.
Time Frame	Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Number [percentage of participants]	72.4 32.2%	66.4 29.4%

11. Secondary Outcome

Title	Time to Symptomatic Progression
Description	Time to symptomatic progression was the time from randomization until the earlier of a clinically meaningful decline from baseline in LCS score, or death on study. LCS scores were obtained from a 7-item questionnaire from the FACT-L (version 4.0). Participants responded to questions such as shortness of breath, cough, tightness in chest, breathing difficulty, appetite loss, weight loss and unclear thinking; on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 (most symptomatic) to 28 (asymptomatic); higher score indicates fewer symptoms. A clinically meaningful decline used to determine symptomatic progression in this study was at least a three point decline in LCS score from baseline. Participants without symptomatic progression at the time of analysis were censored at the time of the last FACT-L assessment. Analysis was performed using Kaplan-Meier method.
Time Frame	Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Mean (95% Confidence Interval) [months]	6.6	7.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0364
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.63 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Percentage of Participants With Deterioration in Trial Outcome Index (TOI) Using FACT-L Version 4.0
Description	TOI was defined as the sum of the scores of the Physical Well-Being (PWB), Functional Well-Being (FWB), and LCS. PWB, FWB, and LCS scores were obtained from 7-item questionnaires from the FACT-L (Version 4.0). Participants responded to questions on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 to 84; higher score indicates better physical aspects of quality of life (QoL). A clinically meaningful decline used to determine deterioration in TOI was greater than or equal to (≥) 6-point decline from baseline. Participants without deterioration in TOI at the time of analysis were censored at the time of the last FACT-L assessment.
Time Frame	Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Number [percentage of participants]	75.6 33.6%	65.9 29.2%

13. Secondary Outcome

Title	Time to Deterioration in TOI Using FACT-L Version 4.0
Description	Time to deterioration in TOI is defined as time from randomization until the earlier of a clinically meaningful decline from baseline in TOI or death on study. TOI is defined as the sum of the scores of the PWB, FWB, and LCS. PWB, FWB, and LCS scores were obtained from 7-item questionnaires from the FACT-L (Version 4.0). Participants responded to questions on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 to 84; higher score indicates better physical aspects of QoL. A clinically meaningful decline used to determine deterioration in TOI was ≥6-point decline from baseline. Participants without deterioration in TOI at the time of analysis were censored at the time of the last FACT-L assessment. Analysis was performed using Kaplan-Meier method.
Time Frame	Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Median (95% Confidence Interval) [months]	5.6	6.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0181
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Percentage of Participants With Deterioration in Quality of Life (QOL) Using FACT-L Version 4.0
Description	Total FACT-L score was defined as the sum of the TOI, Social Well Being (SWB) and EWB of the FACT-L questionnaires. TOI (PWB + FWB + LCS), SWB and EWB scores were obtained from 7-item (6-item in the case of EWB) questionnaires from the FACT-L (Version 4.0). Participants responded to questions on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 to 136; higher score indicates better QoL. A clinically meaningful decline used to determine deterioration in QoL was ≥6-point decline from baseline. Participants without deterioration in QoL at the time of analysis were censored at the time of the last FACT-L assessment.
Time Frame	Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Number [percentage of participants]	79.6 35.4%	70.4 31.2%

15. Secondary Outcome

Title	Time to Deterioration in QOL Using FACT-L Version 4.0
Description	Time to deterioration in QoL is defined as time from randomization until the earlier of a clinically meaningful decline from baseline in Total FACT-L or death on study. Total FACT-L score was defined as the sum of the TOI, SWB and EWB of the FACT-L questionnaires. TOI (PWB + FWB + LCS), SWB and EWB scores were obtained from 7-item (6-item in the case of EWB) questionnaires from the FACT-L (Version 4.0). Participants responded to questions on a 5-point scale from 0-4, where 0 = "not at all" and 4 = "very much." The participants' responses were summed to result in an overall score, scores range on a scale of 0 to 136; higher score indicates better QoL. A clinically meaningful decline used to determine deterioration in QoL was ≥6-point decline from baseline. Participants without deterioration in QoL at the time of analysis were censored at the time of the last FACT-L assessment. Analysis was performed using Kaplan-Meier method.
Time Frame	Baseline, Day 1 of Cycles 3 and 5, Day 1 of post-study Visits 1 and 2 until end of study medication administration or PD (up to approximately 1.5 years)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Median (95% Confidence Interval) [months]	4.5	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0035
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Median Follow-up Time During the Study
Description	Median follow-up was calculated using 'Reverse Kaplan-Meier' analysis for Overall survival.
Time Frame	Randomization until PD or death (assessed at baseline and every 8 weeks thereafter until PD, death or end of study [up to approximately 5.5 years])

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Placebo	Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
Measure Participants	225	226
Median (95% Confidence Interval) [months]	50.3	50.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erlotinib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9130
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.60 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 28 days after the last dose in the primary and post study treatment phases of the study (up to approximately 5.5 years)
Arm/Group Title	Placebo		Erlotinib
Arm/Group Description	Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral placebo daily from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from placebo could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants had the option to be crossed over to open-label erlotinib 150 mg/day outside the study (Off-study phase).		Participants received 1250 mg/m^2 of gemcitabine IV infusion on Day 1 and 8, carboplatin 5x AUC or cisplatin 75 mg/m^2 IV infusion on Day 1 and oral erlotinib 150 mg/day from Day 15 to 28 every 4 weeks, continued for 6 cycles (28-day cycle) until PD, unacceptable toxicity or death in the primary study treatment phase. Participants who completed 6 cycles of treatment without PD or unacceptable toxicity, or if they withdrew early because of toxicity from the platinum-doublet chemotherapy, entered the post-study treatment phase and continued same treatment until PD, unacceptable toxicity or death. Participants who withdrew due to PD or toxicity from erlotinib could not enter the post-study treatment phase. Upon PD (during either the primary or post-study treatment phase), participants were treated at the discretion of the investigators' discretion (Off-study phase).
All Cause Mortality
	Placebo		Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/222 (34.2%)		70/226 (31%)
Blood and lymphatic system disorders
Anaemia	26/222 (11.7%)		22/226 (9.7%)
Thrombocytopenia	16/222 (7.2%)		10/226 (4.4%)
Neutropenia	2/222 (0.9%)		4/226 (1.8%)
Febrile neutropenia	3/222 (1.4%)		2/226 (0.9%)
Bone marrow failure	2/222 (0.9%)		1/226 (0.4%)
Leukopenia	1/222 (0.5%)		1/226 (0.4%)
Cardiac disorders
Acute myocardial infarction	1/222 (0.5%)		0/226 (0%)
Myocardial infarction	0/222 (0%)		1/226 (0.4%)
Palpitations	0/222 (0%)		1/226 (0.4%)
Pericardial effusion	0/222 (0%)		1/226 (0.4%)
Ventricular extrasystoles	1/222 (0.5%)		0/226 (0%)
Ear and labyrinth disorders
Vertigo	0/222 (0%)		3/226 (1.3%)
Gastrointestinal disorders
Vomiting	3/222 (1.4%)		2/226 (0.9%)
Diarrhoea	2/222 (0.9%)		1/226 (0.4%)
Abdominal pain	2/222 (0.9%)		0/226 (0%)
Ileus	1/222 (0.5%)		1/226 (0.4%)
Abdominal pain lower	1/222 (0.5%)		0/226 (0%)
Constipation	0/222 (0%)		1/226 (0.4%)
Lower gastrointestinal haemorrhage	0/222 (0%)		1/226 (0.4%)
Melaena	0/222 (0%)		1/226 (0.4%)
Oesophageal compression	1/222 (0.5%)		0/226 (0%)
Rectal haemorrhage	1/222 (0.5%)		0/226 (0%)
General disorders
Pyrexia	2/222 (0.9%)		3/226 (1.3%)
Asthenia	1/222 (0.5%)		1/226 (0.4%)
Chest pain	0/222 (0%)		1/226 (0.4%)
Fatigue	1/222 (0.5%)		0/226 (0%)
Pain	1/222 (0.5%)		0/226 (0%)
Thrombosis in device	0/222 (0%)		1/226 (0.4%)
Hepatobiliary disorders
Cholecystitis	1/222 (0.5%)		0/226 (0%)
Liver injury	1/222 (0.5%)		0/226 (0%)
Infections and infestations
Pneumonia	9/222 (4.1%)		7/226 (3.1%)
Cellulitis	1/222 (0.5%)		2/226 (0.9%)
Lower respiratory tract infection	1/222 (0.5%)		2/226 (0.9%)
Pneumonia bacterial	2/222 (0.9%)		1/226 (0.4%)
Sepsis	1/222 (0.5%)		2/226 (0.9%)
Appendicitis	0/222 (0%)		1/226 (0.4%)
Bronchitis	2/222 (0.9%)		0/226 (0%)
Gastroenteritis	2/222 (0.9%)		0/226 (0%)
Pneumonia viral	1/222 (0.5%)		1/226 (0.4%)
Device related infection	0/222 (0%)		1/226 (0.4%)
Gastroenteritis bacterial	0/222 (0%)		1/226 (0.4%)
Infection	1/222 (0.5%)		0/226 (0%)
Lung abscess	1/222 (0.5%)		0/226 (0%)
Lung infection	0/222 (0%)		1/226 (0.4%)
Ophthalmic herpes zoster	1/222 (0.5%)		0/226 (0%)
Pulmonary sepsis	1/222 (0.5%)		0/226 (0%)
Urinary tract infection	1/222 (0.5%)		0/226 (0%)
Injury, poisoning and procedural complications
Multiple injuries	0/222 (0%)		1/226 (0.4%)
Investigations
Blood creatinine increased	0/222 (0%)		2/226 (0.9%)
White blood cell count decreased	1/222 (0.5%)		0/226 (0%)
Metabolism and nutrition disorders
Cachexia	0/222 (0%)		1/226 (0.4%)
Dehydration	0/222 (0%)		1/226 (0.4%)
Hypokalaemia	0/222 (0%)		1/226 (0.4%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/222 (0.5%)		1/226 (0.4%)
Bone pain	1/222 (0.5%)		0/226 (0%)
Musculoskeletal chest pain	0/222 (0%)		1/226 (0.4%)
Osteoarthritis	0/222 (0%)		1/226 (0.4%)
Pathological fracture	1/222 (0.5%)		0/226 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hodgkin's disease	0/222 (0%)		1/226 (0.4%)
Lymphangiosis carcinomatosa	1/222 (0.5%)		0/226 (0%)
Non-small cell lung cancer metastatic	0/222 (0%)		1/226 (0.4%)
Nervous system disorders
Altered state of consciousness	0/222 (0%)		1/226 (0.4%)
Ataxia	1/222 (0.5%)		0/226 (0%)
Cerebrovascular accident	0/222 (0%)		1/226 (0.4%)
Paraparesis	0/222 (0%)		1/226 (0.4%)
Pyramidal tract syndrome	0/222 (0%)		1/226 (0.4%)
Vocal cord paralysis	1/222 (0.5%)		0/226 (0%)
Psychiatric disorders
Agitation	1/222 (0.5%)		0/226 (0%)
Confusional state	0/222 (0%)		1/226 (0.4%)
Transient psychosis	0/222 (0%)		1/226 (0.4%)
Renal and urinary disorders
Renal failure	1/222 (0.5%)		0/226 (0%)
Renal ischaemia	0/222 (0%)		1/226 (0.4%)
Tubulointerstitial nephritis	0/222 (0%)		1/226 (0.4%)
Urinary incontinence	0/222 (0%)		1/226 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	6/222 (2.7%)		4/226 (1.8%)
Pleural effusion	1/222 (0.5%)		3/226 (1.3%)
Haemoptysis	0/222 (0%)		3/226 (1.3%)
Pneumonia aspiration	2/222 (0.9%)		0/226 (0%)
Pulmonary embolism	0/222 (0%)		2/226 (0.9%)
Acute respiratory distress syndrome	0/222 (0%)		1/226 (0.4%)
Acute respiratory failure	1/222 (0.5%)		0/226 (0%)
Dyspnoea exertional	0/222 (0%)		1/226 (0.4%)
Orthopnoea	0/222 (0%)		1/226 (0.4%)
Respiratory failure	1/222 (0.5%)		0/226 (0%)
Skin and subcutaneous tissue disorders
Rash	0/222 (0%)		1/226 (0.4%)
Vascular disorders
Superior vena cava occlusion	0/222 (0%)		1/226 (0.4%)
Other (Not Including Serious) Adverse Events
	Placebo		Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	217/222 (97.7%)		223/226 (98.7%)
Blood and lymphatic system disorders
Neutropenia	110/222 (49.5%)		114/226 (50.4%)
Leukopenia	51/222 (23%)		42/226 (18.6%)
Anaemia	96/222 (43.2%)		87/226 (38.5%)
Thrombocytopenia	46/222 (20.7%)		45/226 (19.9%)
Gastrointestinal disorders
Nausea	92/222 (41.4%)		90/226 (39.8%)
Vomiting	68/222 (30.6%)		69/226 (30.5%)
Diarrhoea	34/222 (15.3%)		69/226 (30.5%)
Constipation	46/222 (20.7%)		47/226 (20.8%)
Stomatitis	8/222 (3.6%)		27/226 (11.9%)
Mouth ulceration	2/222 (0.9%)		15/226 (6.6%)
Dyspepsia	14/222 (6.3%)		4/226 (1.8%)
Abdominal distension	5/222 (2.3%)		13/226 (5.8%)
General disorders
Fatigue	60/222 (27%)		55/226 (24.3%)
Pyrexia	25/222 (11.3%)		37/226 (16.4%)
Asthenia	16/222 (7.2%)		16/226 (7.1%)
Mucosal inflammation	13/222 (5.9%)		24/226 (10.6%)
Chest pain	21/222 (9.5%)		24/226 (10.6%)
Malaise	10/222 (4.5%)		12/226 (5.3%)
Infections and infestations
Upper respiratory tract infection	9/222 (4.1%)		16/226 (7.1%)
Nasopharyngitis	12/222 (5.4%)		10/226 (4.4%)
Paronychia	0/222 (0%)		15/226 (6.6%)
Investigations
Alanine aminotransferase increased	19/222 (8.6%)		16/226 (7.1%)
White blood cell count decreased	13/222 (5.9%)		10/226 (4.4%)
Aspartate aminotransferase increased	12/222 (5.4%)		11/226 (4.9%)
Weight decreased	7/222 (3.2%)		13/226 (5.8%)
Metabolism and nutrition disorders
Decreased appetite	92/222 (41.4%)		79/226 (35%)
Hypokalaemia	12/222 (5.4%)		17/226 (7.5%)
Musculoskeletal and connective tissue disorders
Back pain	22/222 (9.9%)		22/226 (9.7%)
Musculoskeletal pain	11/222 (5%)		20/226 (8.8%)
Myalgia	12/222 (5.4%)		8/226 (3.5%)
Nervous system disorders
Dizziness	20/222 (9%)		23/226 (10.2%)
Headache	18/222 (8.1%)		14/226 (6.2%)
Psychiatric disorders
Insomnia	37/222 (16.7%)		46/226 (20.4%)
Respiratory, thoracic and mediastinal disorders
Cough	35/222 (15.8%)		37/226 (16.4%)
Dyspnoea	26/222 (11.7%)		25/226 (11.1%)
Haemoptysis	19/222 (8.6%)		18/226 (8%)
Hiccups	14/222 (6.3%)		8/226 (3.5%)
Oropharyngeal pain	7/222 (3.2%)		13/226 (5.8%)
Rhinorrhoea	6/222 (2.7%)		13/226 (5.8%)
Productive cough	5/222 (2.3%)		12/226 (5.3%)
Skin and subcutaneous tissue disorders
Rash	72/222 (32.4%)		142/226 (62.8%)
Alopecia	51/222 (23%)		41/226 (18.1%)
Pruritus	21/222 (9.5%)		27/226 (11.9%)
Dermatitis acneiform	12/222 (5.4%)		33/226 (14.6%)
Dry skin	9/222 (4.1%)		34/226 (15%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.