BIBW 2992 (Afatinib) vs Gemcitabine-cisplatin in 1st Line Non-small Cell Lung Cancer (NSCLC)

• ClinicalTrials.gov Identifier: NCT01121393
• Recruitment Status: Completed
• First Posted: May 12, 2010
• Results First Posted: January 26, 2015
• Last Update Posted: December 14, 2018
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Carcinoma, Non-Small-Cell Lung; Adenocarcinoma
• Interventions: Drug: Gemcitabine+Cisplatin; Drug: BIBW 2992
• Enrollment: 364

Participant Flow

Recruitment Details	Two-arm, randomised (2:1 ratio), open-label, active-controlled, parallel-group comparison of afatinib versus gemcitabine / cisplatin chemotherapy.
Pre-assignment Details	All patients were screened for eligibility to participate in the trial. Patients attended a specialist sites which ensured that they met all strictly implemented inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria was violated.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Period Title: Overall Study
Started	242 [1]	122 [1]
Treated	239 [2]	113 [2]
Completed	0 [3]	38 [4]
Not Completed	242	84
Reason Not Completed
Progressive disease	201	20
Other Adverse events	24	45
Non-compliant with protocol	0	3
Lost to Follow-up	1	0
Refused cont. medication	7	7
Not treated	3	9
Other than listed	6	0
[1] Randomised; [2] Treated; [3] At the time of data cut-off for last-patient out (07 December 2017); [4] Completed 6 courses of chemotherapy

Baseline Characteristics

Arm/Group Title		Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy	Total
Arm/Group Description		Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.	Total of all reporting groups
Overall Number of Baseline Participants		242	122	364
Baseline Analysis Population Description		The randomised set (RS) included all patients randomised to receive treatment, whether treated or not.
Age, Continuous [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	242 participants	122 participants	364 participants
		56.7 (11.2)	55.6 (10.1)	56.4 (10.9)
		[1] Measure Analysis Population Description: Treated Set
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	242 participants	122 participants	364 participants
	Female	155 64.0%	83 68.0%	238 65.4%
	Male	87 36.0%	39 32.0%	126 34.6%
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants	0 participants	0 participants
				0
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Epidermal growth factor receptor (EGFR) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	242 participants	122 participants	364 participants
	L858R (L858R alone and L858R + Deletion Exon 19)	92 38.0%	46 37.7%	138 37.9%
	Deletion Exon 19 (alone)	124 51.2%	62 50.8%	186 51.1%
	Other	26 10.7%	14 11.5%	40 11.0%
		[1] Measure Description: EGFR mutation group (L858R / Deletion Exon 19 / other) was a stratification factor.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	242 participants	122 participants	364 participants
	ECOG PS 0 (baseline)	48 19.8%	41 33.6%	89 24.5%
	ECOG PS 1 (baseline)	194 80.2%	81 66.4%	275 75.5%
		[1] Measure Description: ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work; 2=Ambulatory (>50 percent of waking hours), capable of all selfcare, unable to carry out any work activities; 3=Capable of only limited self care, confined to bed or chair more then 50 percent of waking hours; 4=Completely disabled, cannot carry on any selfcare, totally confined to bed or chair; 5=Dead

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	The primary endpoint was progression-free survival (PFS) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Progression-free survival was defined as the time from randomisation to disease progression or death whichever occurs earlier. A pre-defined set of censoring rules were used for patients who did not have a PFS. Only data collected up until the analysis cut-off date (27 December 2013) were considered. Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 168

Outcome Measure Data

Analysis Population Description

The randomised set (RS) included all patients randomised to receive treatment, whether treated or not.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	242	122
Median (95% Confidence Interval); Unit of Measure: months
	11.01; (9.66 to 13.73)	5.59; (4.67 to 6.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	A stratified log-rank test (by the epidermal growth factor receptor (EGFR) mutation category stratification factor used at randomisation) was used to test for the effect of afatinib on PFS compared with gemcitabine / cisplatin chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	A Cox proportional-hazards model, stratified by EGFR mutation category was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) between the 2 treatment arms.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.281
	Confidence Interval	(2-Sided) 95%; 0.203 to 0.389
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Objective Response (OR)
Description	OR is defined as a best overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1 and will be presented as the percentage of patients with OR. CR is defined as the disappearance of all target lesions and non-target lesions and no new lesions. PR is defined as at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD, non-Progressive Disease or non evaluation of all non-target lesions and no new lesions. (Exact 95% Confidence interval by Clopper and Pearson.)
Time Frame	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374

Outcome Measure Data

Analysis Population Description

The randomised set.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	242	122
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	67.8; (61.5 to 73.6)	23.0; (15.8 to 31.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	A logistic regression model, stratified by EGFR mutation category was used to compare the objective response rate between the 2 treatment arms.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	7.572
	Confidence Interval	(2-Sided) 95%; 4.522 to 12.679
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Disease Control (DC)
Description	DC is defined as a patient with objective response (OR) or stable disease (SD) assessed by central independent review according to RECIST version 1.1 and will be presented as the percentage of patients with DC.
Time Frame	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374

Outcome Measure Data

Analysis Population Description

The randomised set.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	242	122
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	92.6; (88.5 to 95.5)	76.2; (67.7 to 83.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	stratified for EGFR mutation group
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.843
	Confidence Interval	(2-Sided) 95%; 2.039 to 7.240
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from randomisation to death. For patients who had not died until 7 December 2017, the date they were last known to be alive was derived from patient status records, the trial completion record, radiological imaging assessments, the study treatment termination record, and the randomisation date. Median time results from unstratified Kaplan-Meier estimates.
Time Frame	From randomisation up to 374 weeks

Outcome Measure Data

Analysis Population Description

The randomised set.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	242	122
Median (95% Confidence Interval); Unit of Measure: months
	23.10; (20.40 to 27.33)	23.46; (17.94 to 25.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	A stratified log-rank test (by the epidermal growth factor receptor (EGFR) mutation category stratification factor used at randomisation) was used to test for the effect of afatinib on OS compared with gemcitabine / cisplatin chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4013
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	A Cox proportional hazard model stratified (by EGFR mutation category stratification factor used at randomisation) was used to test the effect of afatinib on OS compared with gemcitabine / cisplatin chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.904
	Confidence Interval	(2-Sided) 95%; 0.715 to 1.144
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Time to Objective Response (OR)
Description	OR is defined as a best of overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1. For patients with an objective response, time to objective response was defined as the time from randomisation to the first objective response. Outcome data are the percentage of patients with OR by each scheduled tumour assessment.
Time Frame	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374

Outcome Measure Data

Analysis Population Description

The RS included all patients randomised to receive treatment, whether treated or not.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	242	122
Measure Type: Number; Unit of Measure: percentage of participants
By Week 6	49.2	13.1
By Week 12	59.9	19.7
By Week 18	64.0	23.0
By Week 24	64.9	23.0
By Week 30	65.7	23.0
By Week 36	66.1	23.0
By Week 42	66.5	23.0
By Week 48	66.5	23.0
By Week 60	66.9	23.0
By Week 72	66.9	23.0
By Week 84	66.9	23.0
By Week 96	67.4	23.0
By Week 108	67.4	23.0
By Week 120	67.8	23.0

6. Secondary Outcome

Title	Duration of Objective Response
Description	OR is defined as a best of overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1. For patients with an objective response, duration of objective response was defined as the time from the first objective response to disease progression or death whichever occurs earlier. A pre-defined set of censoring rules were used for patients who did not progress/die. The Median values are Kaplan-Meier estimates.
Time Frame	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374

Outcome Measure Data

Analysis Population Description

The Randomised set with an objective response.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	164	28
Median (95% Confidence Interval); Unit of Measure: months
	9.72; (8.34 to 12.45)	4.27; (2.76 to 5.75)

7. Secondary Outcome

Title	Duration of Disease Control
Description	For patients with disease control, duration of disease control was defined as the time from randomisation to progression or death whichever occurs first. A pre-defined set of censoring rules were used for patients who did not progress/die. The Median values are Kaplan-Meier estimates.
Time Frame	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374

Outcome Measure Data

Analysis Population Description

The randomised set with disease control.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	224	93
Median (95% Confidence Interval); Unit of Measure: months
	11.07; (9.69 to 13.80)	5.65; (5.49 to 6.93)

8. Secondary Outcome

Title	Tumour Shrinkage
Description	Tumour shrinkage is calculated as the minimum post-baseline sum of longest diameters of target lesions (longest for non-nodal lesions, short axis for nodal lesions) (SLD), as assessed by central independent review. The mean of these minimum values are presented after adjusting for baseline sum of longest diameters and EGFR mutation category. Only data collected up until the analysis cut-off date (27 Dec 2013) were considered. A negative value means the smallest post-baseline SLD was smaller than baseline (decreased since baseline); a positive value means tumor size increased since baseline. The means are adjusted for baseline sum of lesions and EGFR mutation category.
Time Frame	Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374

Outcome Measure Data

Analysis Population Description

The randomised set. There were ony 220 patients in the Afatinib arm and 101 patients in the Gemcitabine / Cisplatin arm with baseline and post-baseline target lesion measurements.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	220	101
Mean (Standard Error); Unit of Measure: millimetre (mm)
	33.41 (0.99)	47.06 (1.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	adjusted for baseline sum of diameters and EGFR mutation group
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.64
	Confidence Interval	(2-Sided) 95%; -17.10 to -10.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.76
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	The change from baseline to the lowest and the last body weight recorded or during the the study.
Time Frame	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.

Outcome Measure Data

Analysis Population Description

The randomised set. Data only presented for a patient with a baseline and at least on post-baseline assessment of weight.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	237	109
Mean (Standard Deviation); Unit of Measure: kilogram (kg)
Change from baseline at lowest value	-3.03 (3.99)	-1.52 (3.65)
Change from baseline at last value	-0.76 (4.79)	0.00 (4.52)

10. Secondary Outcome

Title	Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
Description	The last ECOG performance score category recorded during the study. Outcome data are the percentage of patients with an shift of ECOG performance status from baseline to the last ECOG performance status. ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work;; Ambulatory (>50 percent of waking hours), capable of all selfcare, unable to carry out any work activities;; Capable of only limited self care, confined to bed or chair more then 50 percent of waking hours;; Completely disabled, cannot carry on any selfcare, totally confined to bed or chair;; Dead
Time Frame	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.

Outcome Measure Data

Analysis Population Description

The randomised set. Data only presented for patients with a baseline and at least one post-baseline assessment of ECOG status.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	237	110
Measure Type: Number; Unit of Measure: percentage of participants
ECOG PS 0 (baseline) 0 (last value)	11.4	21.8
ECOG PS 1 (baseline) 0 (last value)	6.8	3.6
ECOG PS 0 (baseline) 1 (last value)	8.0	14.5
ECOG PS 1 (baseline) 1 (last value)	67.5	51.8
ECOG PS 0 (baseline) 2 (last value)	0.4	0.0
ECOG PS 1 (baseline) 2 (last value)	2.1	1.8
ECOG PS 0 (baseline) 3 (last value)	0.0	0.0
ECOG PS 1 (baseline) 3 (last value)	2.1	4.5
ECOG PS 0 (baseline) 4 (last value)	0.4	0.0
ECOG PS 1 (baseline) 4 (last value)	1.3	1.8

11. Secondary Outcome

Title	Health Related Quality of Life (HRQOL): Time of Deterioration in Coughing
Description	HRQOL as measured by standardised questionnaires (EuropeanOrganisation for Research and Treatment of Cancer (EORTC)) quality of life questionaires (OLQ-C30) and its lung cancer module (QLQ-LC13). Analysis for cough: QLQ-LC13, question 1. Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.
Time Frame	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.

Outcome Measure Data

Analysis Population Description

The randomised set.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	242	122
Median (95% Confidence Interval); Unit of Measure: months
	31.05 [1]; (17.45 to NA)	10.28 [2]; (4.63 to NA)

[1]

As only 84 patients (34.7 percent) in Afatinib 40mg deteriorated, the upper limit of the confidence interval was not estimable.

[2]

As only 39 patients (32.0 percent) in Gemcitabine / Cisplatin deteriorated, the upper limit of the confidence interval was not estimable.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	A stratified log-rank test (by the epidermal growth factor receptor (EGFR) mutation category stratification factor used at randomisation) was used to test for the effect of afatinib on HRQOL compared with gemcitabine / cisplatin chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	Cox proportional hazard model stratified by EGFR mutation group
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.458
	Confidence Interval	(2-Sided) 95%; 0.303 to 0.692
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Health Related Quality of Life (HRQOL): Time of Deterioration in Dyspnoea
Description	HRQOL as measured by OLQ-C30 and its lung cancer module (QLQ-LC13). Analysis for dyspnoea: composite of QLQ-LC13, questions 3 to 5; individual item from QLQ-C30, question 8. Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.
Time Frame	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.

Outcome Measure Data

Analysis Population Description

The randomised set.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	242	122
Median (95% Confidence Interval); Unit of Measure: months
	7.66; (4.76 to 11.17)	1.68; (1.38 to 3.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	A stratified log-rank test (by the epidermal growth factor receptor (EGFR) mutation category stratification factor used at randomisation) was used to test for the effect of afatinib on HRQOL compared with gemcitabine / cisplatin chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	Cox proportional hazard model stratified by EGFR mutation group
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.534
	Confidence Interval	(2-Sided) 95%; 0.394 to 0.724
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Health Related Quality of Life (HRQOL): Time of Deterioration in Pain
Description	HRQOL as measured by OLQ-C30 and its lung cancer module QLQ-LC13. Analysis for pain: composite of QLQ-C30, questions 9 and 19; individual items from QLQ-LC13, questions 10, 11 and 12. Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.
Time Frame	Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks.

Outcome Measure Data

Analysis Population Description

The randomised set.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	242	122
Median (95% Confidence Interval); Unit of Measure: months
	6.93; (4.21 to 10.38)	3.38; (1.77 to 5.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	A stratified log-rank test (by the epidermal growth factor receptor (EGFR) mutation category stratification factor used at randomisation) was used to test for the effect of afatinib on HRQOL compared with gemcitabine / cisplatin chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0220
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 Milligram (mg), Gemcitabine / Cisplatin Chemotherapy
	Comments	Cox proportional hazard model stratified by EGFR mutation group
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.699
	Confidence Interval	(2-Sided) 95%; 0.511 to 0.956
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Pharmacokinetics of Afatinib at Day 22
Description	Outcome data are the trough plasma concentrations of afatinib at day 22 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the Pharmacokinetics (PK) assessment period).
Time Frame	Day 22 (course 2, visit 1)

Outcome Measure Data

Analysis Population Description

All patients who had at least 1 afatinib dose and who had at least 1 valid afatinib plasma concentration available.

Arm/Group Title	Afatinib 30mg q.d.	Afatinib 40mg q.d.	Afatinib 50mg q.d.
Arm/Group Description:	Patients receiving Afatinib 30mg once daily (q.d.) orally after a dose reduction.	Patients receiving Afatinib 40mg once daily (q.d.) orally	Patients receiving Afatinib 50mg once daily (q.d.) orally after a dose escalation.
Overall Number of Participants Analyzed	3	210	0
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram/millilitre (ng/mL)
	17.7; (109%)	23.1; (65.1%)

15. Secondary Outcome

Title	Pharmacokinetics of Afatinib at Day 29
Description	Outcome data are the trough plasma concentrations of afatinib at day 29 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the PK assessment period).
Time Frame	Day 29 (course 2, visit 2)

Outcome Measure Data

Analysis Population Description

All patients who had at least 1 afatinib dose and who had at least 1 valid afatinib plasma concentration available.

Arm/Group Title	Afatinib 30mg q.d.	Afatinib 40mg q.d.	Afatinib 50mg q.d.
Arm/Group Description:	Patients receiving Afatinib 30mg once daily (q.d.) after a dose reduction.	Patients receiving Afatinib 40mg once daily (q.d.)	Patients receiving Afatinib 50mg once daily (q.d.) after a dose escalation.
Overall Number of Participants Analyzed	6	161	34
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
	19.5; (90.3%)	23.8; (70.6%)	22.8; (60.8%)

16. Secondary Outcome

Title	Pharmacokinetics of Afatinib at Day 43
Description	Outcome data are the trough plasma concentrations of afatinib at day 43 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the PK assessment period).
Time Frame	Day 43 (course 3, visit 1)

Outcome Measure Data

Analysis Population Description

All patients who had at least 1 afatinib dose and who had at least 1 valid afatinib plasma concentration available.

Arm/Group Title	Afatinib 30mg q.d.	Afatinib 40mg q.d.	Afatinib 50mg q.d.
Arm/Group Description:	Patients receiving Afatinib 30mg once daily (q.d.) after a dose reduction.	Patients receiving Afatinib 40mg once daily (q.d.)	Patients receiving Afatinib 50mg once daily (q.d.) after a dose escalation.
Overall Number of Participants Analyzed	21	158	35
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
	21.5; (52.9%)	22.1; (67.4%)	22.9; (62.5%)

17. Secondary Outcome

Title	Safety of Afatinib as Indicated by Intensity and Incidence of Adverse Events
Description	Safety of Afatinib as indicated by intensity and incidence of adverse events graded according to the US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Presented as the percentage of patients with an Adverse Events during the on-treatment period by highest CTCAE grade.
Time Frame	From first administration of study medication up to 28 days after the last administration of study medication up to 374 weeks.

Outcome Measure Data

Analysis Population Description

The treated set (TS) included all randomised patients who were documented to have taken at least 1 dose of study medication (i.e. afatinib or gemcitabine / cisplatin). Patients were allocated according to the treatment actually received.

Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed	239	113
Measure Type: Number; Unit of Measure: percentage of participants
CTCAE Grade 1	13.8	8.0
CTCAE Grade 2	36.0	29.2
CTCAE Grade 3	39.3	38.1
CTCAE Grade 4	4.2	21.2
CTCAE Grade 5	6.7	2.7

18. Secondary Outcome

Title	Changes in Safety Laboratory Parameters
Description	Outcome data presented are the percentage of patients by worst CTCAE grade (only Grades 2 to 4 presented) on treatment for the following laboratory parameters: Potassium, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Creatine and Creatine Kinase. For Potassium; only CTCAE grades resulting from hypokalemia (low values) are presented.
Time Frame	From first administration of study medication up to 28 days after the last administration of study medication up to 374 weeks.

Outcome Measure Data

Analysis Population Description

Treated set (TS) included all randomised patients who were documented to have taken at least 1 dose of study medication. Patients were allocated according to the treatment actually received. Patients with a baseline and at least one on-treatment assessment of the parameter are of interest.

Arm/Group Title		Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description:		Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
Overall Number of Participants Analyzed		239	113
Measure Type: Number; Unit of Measure: percentage of participants
Potassium CTCAE grade 2	Number Analyzed	235 participants	109 participants
		NA [1]	NA [1]
Potassium CTCAE grade 3	Number Analyzed	235 participants	109 participants
		5.1	15.6
Potassium CTCAE grade 4	Number Analyzed	235 participants	109 participants
		2.6	0.9
AST CTCAE grade 2	Number Analyzed	235 participants	107 participants
		5.1	1.9
AST CTCAE grade 3	Number Analyzed	235 participants	107 participants
		1.3	1.9
AST CTCAE grade 4	Number Analyzed	235 participants	107 participants
		0.0	0.0
ALT CTCAE grade 2	Number Analyzed	235 participants	108 participants
		8.1	5.6
ALT CTCAE grade 3	Number Analyzed	235 participants	108 participants
		3.4	1.9
ALT CTCAE grade 4	Number Analyzed	235 participants	108 participants
		0.0	0.0
Creatinine CTCAE grade 2	Number Analyzed	235 participants	109 participants
		2.1	2.8
Creatinine CTCAE grade 3	Number Analyzed	235 participants	109 participants
		0.0	0.0
Creatinine CTCAE grade 4	Number Analyzed	235 participants	109 participants
		0.0	0.0
Creatinine Kinase CTCAE grade 2	Number Analyzed	216 participants	104 participants
		3.7	1.0
Creatinine Kinase CTCAE grade 3	Number Analyzed	216 participants	104 participants
		1.9	0.0
Creatinine Kinase CTCAE grade 4	Number Analyzed	216 participants	104 participants
		0.0	0.0

[1]

no corresponding rules defined

Adverse Events

Time Frame	From first administration of study medication until 28 days after the last administration of study medication up to 374 weeks
Adverse Event Reporting Description	The treated set (TS) included all randomised patients documented to have taken at least 1 dose of study medication. Analysis of Adverse Events (AEs) was based on the concept of treatment-emergent AEs. AEs with onset after the first administration of study drug and within 28 days after the last administration were considered to be on-treatment.
Arm/Group Title	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib film-coated tablets 40 mg once daily (q.d.) orally with possible dose escalation to 50 mg q.d. and dose reduction to 40 mg q.d. (if applicable), 30 mg q.d., or 20 mg q.d. (according to the protocol-defined dose-escalation and dose-reduction scheme), if required. No dose increase was allowed after dose reduction. Each treatment course was planned to be 21 days. For afatinib, patients received continuous daily dosing until disease progression, unacceptable adverse events (AEs) occurred, or withdrawal of consent for any reason.	Patients received Gemcitabine (lyophilised powder) 1000 milligram per square metre (mg/m²) as an intravenous infusion over 30 minutes on day 1 and day 8, cisplatin (solution for infusion) 75 mg/m² as an intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles; Chemotherapy could be delayed or the dose could be reduced in accordance with the guidance in the current summary of product characteristics. For gemcitabine / cisplatin, patients were to receive a maximum of 6 treatment courses unless they developed disease progression, experienced unacceptable AEs, or withdrawal of consent for any reason.
All-Cause Mortality
	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	16/239 (6.69%)	3/113 (2.65%)
Serious Adverse Events
	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	40/239 (16.74%)	12/113 (10.62%)
Blood and lymphatic system disorders
Anaemia † 1	0/239 (0.00%)	1/113 (0.88%)
Febrile neutropenia † 1	0/239 (0.00%)	1/113 (0.88%)
Thrombocytopenia † 1	0/239 (0.00%)	2/113 (1.77%)
Cardiac disorders
Cardiac failure † 1	0/239 (0.00%)	1/113 (0.88%)
Ear and labyrinth disorders
Vertigo positional † 1	1/239 (0.42%)	0/113 (0.00%)
Gastrointestinal disorders
Abdominal distension † 1	1/239 (0.42%)	0/113 (0.00%)
Constipation † 1	1/239 (0.42%)	0/113 (0.00%)
Diarrhoea † 1	2/239 (0.84%)	0/113 (0.00%)
Dysphagia † 1	1/239 (0.42%)	0/113 (0.00%)
Intestinal obstruction † 1	1/239 (0.42%)	0/113 (0.00%)
Nausea † 1	1/239 (0.42%)	0/113 (0.00%)
Upper gastrointestinal haemorrhage † 1	1/239 (0.42%)	0/113 (0.00%)
Vomiting † 1	2/239 (0.84%)	0/113 (0.00%)
General disorders
Death † 1	0/239 (0.00%)	1/113 (0.88%)
Fatigue † 1	0/239 (0.00%)	1/113 (0.88%)
Multiple organ dysfunction syndrome † 1	1/239 (0.42%)	0/113 (0.00%)
Pyrexia † 1	1/239 (0.42%)	0/113 (0.00%)
Sudden death † 1	1/239 (0.42%)	0/113 (0.00%)
Immune system disorders
Hypersensitivity † 1	1/239 (0.42%)	0/113 (0.00%)
Infections and infestations
Appendicitis † 1	1/239 (0.42%)	0/113 (0.00%)
Central nervous system infection † 1	1/239 (0.42%)	0/113 (0.00%)
Device related infection † 1	1/239 (0.42%)	0/113 (0.00%)
Meningitis viral † 1	1/239 (0.42%)	0/113 (0.00%)
Paronychia † 1	1/239 (0.42%)	0/113 (0.00%)
Pneumonia † 1	2/239 (0.84%)	0/113 (0.00%)
Urinary tract infection † 1	1/239 (0.42%)	0/113 (0.00%)
Injury, poisoning and procedural complications
Toxicity to various agents † 1	1/239 (0.42%)	0/113 (0.00%)
Investigations
Alanine aminotransferase increased † 1	0/239 (0.00%)	1/113 (0.88%)
Aspartate aminotransferase increased † 1	0/239 (0.00%)	1/113 (0.88%)
Blood creatinine increased † 1	0/239 (0.00%)	1/113 (0.88%)
Hepatic enzyme increased † 1	1/239 (0.42%)	0/113 (0.00%)
Platelet count decreased † 1	0/239 (0.00%)	1/113 (0.88%)
Metabolism and nutrition disorders
Cachexia † 1	1/239 (0.42%)	0/113 (0.00%)
Decreased appetite † 1	2/239 (0.84%)	1/113 (0.88%)
Diabetes mellitus † 1	1/239 (0.42%)	0/113 (0.00%)
Musculoskeletal and connective tissue disorders
Muscular weakness † 1	1/239 (0.42%)	0/113 (0.00%)
Pathological fracture † 1	1/239 (0.42%)	0/113 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic † 1	1/239 (0.42%)	0/113 (0.00%)
Malignant neoplasm progression † 1	2/239 (0.84%)	1/113 (0.88%)
Metastases to central nervous system † 1	1/239 (0.42%)	0/113 (0.00%)
Metastases to meninges † 1	1/239 (0.42%)	0/113 (0.00%)
Nervous system disorders
Cerebral infarction † 1	1/239 (0.42%)	1/113 (0.88%)
Cerebral ischaemia † 1	1/239 (0.42%)	0/113 (0.00%)
Dizziness † 1	1/239 (0.42%)	0/113 (0.00%)
Dysarthria † 1	1/239 (0.42%)	0/113 (0.00%)
Epilepsy † 1	0/239 (0.00%)	1/113 (0.88%)
Headache † 1	3/239 (1.26%)	1/113 (0.88%)
Hypoaesthesia † 1	1/239 (0.42%)	0/113 (0.00%)
Loss of consciousness † 1	1/239 (0.42%)	0/113 (0.00%)
Somnolence † 1	1/239 (0.42%)	0/113 (0.00%)
Transient ischaemic attack † 1	1/239 (0.42%)	0/113 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	0/239 (0.00%)	1/113 (0.88%)
Renal failure † 1	0/239 (0.00%)	1/113 (0.88%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	4/239 (1.67%)	0/113 (0.00%)
Interstitial lung disease † 1	1/239 (0.42%)	0/113 (0.00%)
Pleural effusion † 1	1/239 (0.42%)	1/113 (0.88%)
Pneumothorax † 1	1/239 (0.42%)	0/113 (0.00%)
Respiratory failure † 1	5/239 (2.09%)	1/113 (0.88%)
Skin and subcutaneous tissue disorders
Rash † 1	2/239 (0.84%)	0/113 (0.00%)
Skin disorder † 1	1/239 (0.42%)	0/113 (0.00%)
Vascular disorders
Embolism † 1	0/239 (0.00%)	1/113 (0.88%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Afatinib 40 Milligram (mg)	Gemcitabine / Cisplatin Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	236/239 (98.74%)	112/113 (99.12%)
Blood and lymphatic system disorders
Anaemia † 1	23/239 (9.62%)	31/113 (27.43%)
Leukopenia † 1	17/239 (7.11%)	58/113 (51.33%)
Neutropenia † 1	13/239 (5.44%)	61/113 (53.98%)
Thrombocytopenia † 1	6/239 (2.51%)	20/113 (17.70%)
Gastrointestinal disorders
Abdominal discomfort † 1	3/239 (1.26%)	7/113 (6.19%)
Constipation † 1	9/239 (3.77%)	31/113 (27.43%)
Diarrhoea † 1	212/239 (88.70%)	17/113 (15.04%)
Mouth ulceration † 1	58/239 (24.27%)	2/113 (1.77%)
Nausea † 1	28/239 (11.72%)	85/113 (75.22%)
Stomatitis † 1	52/239 (21.76%)	1/113 (0.88%)
Vomiting † 1	33/239 (13.81%)	91/113 (80.53%)
General disorders
Asthenia † 1	17/239 (7.11%)	10/113 (8.85%)
Chest pain † 1	27/239 (11.30%)	8/113 (7.08%)
Fatigue † 1	32/239 (13.39%)	35/113 (30.97%)
Mucosal inflammation † 1	18/239 (7.53%)	1/113 (0.88%)
Pain † 1	12/239 (5.02%)	1/113 (0.88%)
Pyrexia † 1	25/239 (10.46%)	12/113 (10.62%)
Infections and infestations
Nasopharyngitis † 1	21/239 (8.79%)	2/113 (1.77%)
Paronychia † 1	80/239 (33.47%)	0/113 (0.00%)
Upper respiratory tract infection † 1	17/239 (7.11%)	2/113 (1.77%)
Urinary tract infection † 1	12/239 (5.02%)	2/113 (1.77%)
Investigations
Alanine aminotransferase increased † 1	58/239 (24.27%)	18/113 (15.93%)
Aspartate aminotransferase increased † 1	47/239 (19.67%)	12/113 (10.62%)
Blood creatine phosphokinase increased † 1	13/239 (5.44%)	0/113 (0.00%)
Blood creatinine increased † 1	11/239 (4.60%)	9/113 (7.96%)
Haemoglobin decreased † 1	6/239 (2.51%)	22/113 (19.47%)
Neutrophil count decreased † 1	2/239 (0.84%)	29/113 (25.66%)
Platelet count decreased † 1	4/239 (1.67%)	11/113 (9.73%)
Weight decreased † 1	33/239 (13.81%)	6/113 (5.31%)
White blood cell count decreased † 1	5/239 (2.09%)	27/113 (23.89%)
Metabolism and nutrition disorders
Decreased appetite † 1	38/239 (15.90%)	47/113 (41.59%)
Hypocalcaemia † 1	5/239 (2.09%)	7/113 (6.19%)
Hypokalaemia † 1	28/239 (11.72%)	26/113 (23.01%)
Hyponatraemia † 1	7/239 (2.93%)	14/113 (12.39%)
Hypoproteinaemia † 1	14/239 (5.86%)	6/113 (5.31%)
Musculoskeletal and connective tissue disorders
Back pain † 1	31/239 (12.97%)	9/113 (7.96%)
Musculoskeletal pain † 1	18/239 (7.53%)	1/113 (0.88%)
Pain in extremity † 1	26/239 (10.88%)	4/113 (3.54%)
Nervous system disorders
Dizziness † 1	22/239 (9.21%)	9/113 (7.96%)
Headache † 1	30/239 (12.55%)	8/113 (7.08%)
Psychiatric disorders
Insomnia † 1	13/239 (5.44%)	15/113 (13.27%)
Renal and urinary disorders
Proteinuria † 1	10/239 (4.18%)	8/113 (7.08%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	47/239 (19.67%)	8/113 (7.08%)
Dyspnoea † 1	14/239 (5.86%)	4/113 (3.54%)
Epistaxis † 1	38/239 (15.90%)	2/113 (1.77%)
Oropharyngeal pain † 1	18/239 (7.53%)	1/113 (0.88%)
Rhinorrhoea † 1	17/239 (7.11%)	1/113 (0.88%)
Skin and subcutaneous tissue disorders
Alopecia † 1	7/239 (2.93%)	11/113 (9.73%)
Dry skin † 1	14/239 (5.86%)	1/113 (0.88%)
Palmar-plantar erythrodysaesthesia syndrome † 1	16/239 (6.69%)	0/113 (0.00%)
Pruritus † 1	27/239 (11.30%)	0/113 (0.00%)
Rash † 1	175/239 (73.22%)	10/113 (8.85%)
Skin fissures † 1	18/239 (7.53%)	0/113 (0.00%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

Results Point of Contact

• Name/Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim
• Phone: 1-800-243-0127
• EMail: clintriage.rdg@boehringer-ingelheim.com

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

Wu YL, Xu CR, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Marten A, Fan J, Peil B, Zhou C. Afatinib versus gemcitabine/cisplatin for first-line treatment of Chinese patients with advanced non-small-cell lung cancer harboring EGFR mutations: subgroup analysis of the LUX-Lung 6 trial. Onco Targets Ther. 2018 Nov 30;11:8575-8587. doi: 10.2147/OTT.S160358. eCollection 2018.

Wu YL, Sequist LV, Tan EH, Geater SL, Orlov S, Zhang L, Lee KH, Tsai CM, Kato T, Barrios CH, Schuler M, Hirsh V, Yamamoto N, O'Byrne K, Boyer M, Mok T, Peil B, Marten A, Chih-Hsin Yang J, Paz-Ares L, Park K. Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 Trials. Clin Lung Cancer. 2018 Jul;19(4):e465-e479. doi: 10.1016/j.cllc.2018.03.009. Epub 2018 Mar 17.

Yang JC, Sequist LV, Zhou C, Schuler M, Geater SL, Mok T, Hu CP, Yamamoto N, Feng J, O'Byrne K, Lu S, Hirsh V, Huang Y, Sebastian M, Okamoto I, Dickgreber N, Shah R, Marten A, Massey D, Wind S, Wu YL. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol. 2016 Nov;27(11):2103-2110. doi: 10.1093/annonc/mdw322. Epub 2016 Sep 6.

Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. doi: 10.1016/j.jtho.2015.11.014. Epub 2016 Jan 25.

Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. doi: 10.1016/S1470-2045(15)00026-1. Epub 2015 Jun 4.

Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. doi: 10.1016/S1470-2045(14)71173-8. Epub 2015 Jan 12.

Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. doi: 10.1016/S1470-2045(13)70604-1. Epub 2014 Jan 15.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01121393
• Other Study ID Numbers: 1200.34
• First Submitted: April 21, 2010
• First Posted: May 12, 2010
• Results First Submitted: December 27, 2014
• Results First Posted: January 26, 2015
• Last Update Posted: December 14, 2018