Docetaxel or Pemetrexed With or Without Cetuximab in Patients With Recurrent or Progressive Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT00095199
• Recruitment Status: Completed
• First Posted: November 2, 2004
• Results First Posted: October 15, 2012
• Last Update Posted: October 15, 2012
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non Small Cell Lung Cancer
• Interventions: Drug: Pemetrexed; Biological: Cetuximab; Drug: Docetaxel
• Enrollment: 939

Participant Flow

Recruitment Details
Pre-assignment Details	Although 939 participants were initially randomized, 1 participant's data was inadvertently lost by a site prior to being entered into the database. As a result, we are reporting 938 as randomized.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab and Docetaxel	Docetaxel
Arm/Group Description	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles, until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 week cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.
Period Title: Overall Study
Started	302 [1]	304	167	166
Completed	6	62	7	23
Not Completed	296	242	160	143
Reason Not Completed
Adverse Event	40	22	26	11
Progressive disease	213	179	105	98
Death	10	6	11	9
Withdrawal by Subject	21	16	13	22
Protocol Violation	4	4	2	0
Liver function test results elevated	0	0	1	1
Surgery needed could not start in 7 days	0	0	1	0
Physician Decision	5	6	1	1
Not eligible	1	7	0	1
Started Palliative Radiotherapy	1	0	0	0
Started radiotherapy regimen	0	1	0	0
Primary tumor removed in other surgery	0	1	0	0
Data inadvertently lost by site	1	0	0	0
[1] 1 participant has no data in database; not included in analyses. Data was lost/destroyed at site.

Baseline Characteristics

Arm/Group Title		Cetuximab & Pemetrexed	Pemetrexed	Cetuximab & Docetaxel	Docetaxel	Total
Arm/Group Description		Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Total of all reporting groups
Overall Number of Baseline Participants		301	304	167	166	938
Baseline Analysis Population Description		[Not Specified]
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	301 participants	304 participants	167 participants	166 participants	938 participants
		62.8 (10.0)	64.0 (9.4)	63.6 (9.4)	63.9 (9.2)	63.5 (9.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	301 participants	304 participants	167 participants	166 participants	938 participants
	Female	128 42.5%	116 38.2%	75 44.9%	73 44.0%	392 41.8%
	Male	173 57.5%	188 61.8%	92 55.1%	93 56.0%	546 58.2%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	301 participants	304 participants	167 participants	166 participants	938 participants
White		268	265	146	141	820
Black or African American		25	24	13	20	82
Asian		3	6	5	2	16
Hispanic		4	8	2	2	16
Unknown or Not Reported		1	1	1	1	4
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	301 participants	304 participants	167 participants	166 participants	938 participants
United States		265	270	152	151	838
Canada		36	34	15	15	100
Epidermal growth factor receptor (EGFR) by immunohistochemistry [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	301 participants	304 participants	167 participants	166 participants	938 participants
+1		36	35	13	19	103
+2		46	53	26	34	159
+3		118	108	72	58	356
0		21	32	12	10	75
Missing		80	76	44	45	245
		[1] Measure Description: Immunohistochemical staining intensity of anti-EGFR antibody: Score 0=No staining is observed in membrane; Score +1=Staining in membrane is partial, weak and barely perceptible; Score +2=Staining is weak but is completely observed in membrane; Score +3=Strong complete membrane staining is observed. EGFR positive staining is a potential prognostic factor in non-small cell lung cancer. Presence of EGFR staining was not, however, an inclusion criteria or used to stratify participants in the trial.
Karnofsky Performance Status [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	301 participants	304 participants	167 participants	166 participants	938 participants
60		12	14	2	11	39
70		35	35	21	14	105
80		103	91	55	57	306
90		101	116	74	64	355
100		48	47	14	18	127
Missing/unknown		2	1	1	2	6
		[1] Measure Description: Karnofsky performance status was part of eligibility criteria and classifies participants according to their functional impairment. Scores range from 0-100, the lower the score, the worse the survival for most serious illnesses. 100=Normal. No complaints. No evidence of disease; 90=Able to carry on normal activity. Minor signs of disease; 80=Activity with effort. Some signs of disease; 70=Unable to carry on normal activity or to do active work; 60=Requires occasional assistance, but is able to care for most needs; <60=Needs increasing assistance, up to a score of 0=death.
Pathological Diagnosis; Measure Type: Number; Unit of measure: Participants	Number Analyzed	301 participants	304 participants	167 participants	166 participants	938 participants
Adenocarcinoma		161	185	99	83	528
Large cell carcinoma		19	7	7	3	36
All other non-squamous diagnoses		45	41	20	29	135
Squamous cell carcinoma		76	71	41	51	239

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from randomization until the date of progressive disease (PD) or death from any cause. Participants who were alive and without progression were censored at the date of their last tumor assessment. PFS was assessed by the independent review committee (IRC) in the Pemetrexed group (Cetuximab & Pemetrexed versus Pemetrexed) and by the investigator in the Docetaxel group (Cetuximab & Docetaxel versus Docetaxel).
Time Frame	Randomization to progression of disease or death due to any cause up to 59.6 months

Outcome Measure Data

Analysis Population Description

The intent-to-treat population (ITT) included all participants classified according to the treatment arms into which they were randomized, regardless of the actual treatment received. Censored participants: 10 in Cetuximab + Pemetrexed arm; 25 in Pemetrexed arm; 6 in Cetuximab + Docetaxel arm; 16 in Docetaxel arm.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab & Docetaxel	Docetaxel
Arm/Group Description:	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week cycles).	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously every 3 weeks cycle for up to six (3-week) cycles, after 6 cycles participants on the chemotherapy/cetuximab combination may continue cetuximab alone. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.
Overall Number of Participants Analyzed	301	304	167	166
Median (95% Confidence Interval); Unit of Measure: months
	2.89; (2.69 to 3.22)	2.76; (2.53 to 3.29)	2.37; (1.61 to 2.89)	1.54; (1.45 to 2.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Pemetrexed, Pemetrexed
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.756
	Comments	The 2-sided unstratified log-rank test was employed at the 5% significance level.
	Method	Log Rank
	Comments	Kaplan-Meier method estimated median PFS time. HR was calculated with unstratified Cox proportional hazards model. HR<1 favours Cetuximab arm
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.21
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Docetaxel, Docetaxel
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.391
	Comments	The 2-sided unstratified log-rank test was employed at the 5% significance level.
	Method	Log Rank
	Comments	Kaplan-Meier method estimated median PFS time. HR was calculated with unstratified Cox proportional hazards model. HR<1 favours Cetuximab arm
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.13
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to death. Participants without a date of death were censored on the last date participants were known to be alive, or lost to follow-up.
Time Frame	Randomization to the date of death from any cause up to 72.8 months

Outcome Measure Data

Analysis Population Description

The intent-to-treat population (ITT) included all participants classified according to the treatment arms into which they were randomized, regardless of the actual treatment received. Censored participants: 24 in Cetuximab + Pemetrexed arm; 43 in Pemetrexed arm; 12 in Cetuximab + Docetaxel arm; 22 in Docetaxel arm.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab & Docetaxel	Docetaxel
Arm/Group Description:	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously every 3 weeks cycle for up to six (3-week) cycles, after 6 cycles participants on the chemotherapy/cetuximab combination may continue cetuximab alone. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.
Overall Number of Participants Analyzed	301	304	167	166
Median (95% Confidence Interval); Unit of Measure: months
	6.93; (6.28 to 7.85)	7.79; (6.77 to 8.41)	5.75; (4.73 to 8.31)	8.15; (6.11 to 9.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Pemetrexed, Pemetrexed
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.864
	Comments	The 2-sided unstratified log-rank test was employed at the 5% significance level
	Method	Log Rank
	Comments	Kaplan-Meier method estimated median OS time. HR was calculated with unstratified Cox proportional hazards model. HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.20
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Docetaxel, Docetaxel
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.307
	Comments	The 2-sided unstratified log-rank test was employed at the 5% significance level.
	Method	Log Rank
	Comments	Kaplan-Meier method estimated median OS time. HR was calculated with unstratified Cox proportional hazards model. HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.41
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Proportion of Randomized Participants With the Best Overall Response (OR) of Partial Response (PR) or Complete Response (CR) (Overall Response Rate [ORR])
Description	The best overall response rate (ORR) was the proportion of randomized participants with a best OR of CR or PR, according to modified World Health Organization (WHO) guidelines. It was calculated as the total number of participants with CR or PR divided by the total number of participants treated in that arm. Participants with no post-baseline evaluation were considered as non-responders. The tumor response was assessed by the independent review committee (IRC) in the Pemetrexed group and by the investigator in the Docetaxel group.
Time Frame	Randomization until progression of disease or death from any cause up to 59.6 months

Outcome Measure Data

Analysis Population Description

The intent-to-treat population (ITT) included all participants classified according to the treatment arms into which they were randomized, regardless of the actual treatment received.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab & Docetaxel	Docetaxel
Arm/Group Description:	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously every 3 weeks cycle for up to six (3-week) cycles, after 6 cycles participants on the chemotherapy/cetuximab combination may continue cetuximab alone. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.
Overall Number of Participants Analyzed	301	304	167	166
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: proportion of participants
	0.066; (0.038 to 0.095)	0.043; (0.020 to 0.066)	0.078; (0.037 to 0.118)	0.066; (0.028 to 0.104)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Pemetrexed, Pemetrexed
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.200
	Comments	The 2-sided unstratified Mantel Haenszel test was employed at the 5% significance level.
	Method	Mantel Haenszel
	Comments	HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.59
	Confidence Interval	(2-Sided) 95%; 0.78 to 3.26
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Docetaxel, Docetaxel
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.683
	Comments	The 2-sided unstratified Mantel Haenszel test was employed at the 5% significance level.
	Method	Mantel Haenszel
	Comments	HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.52 to 2.74
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Proportion of Randomized Participants With Best Overall Response (OR) of Partial Response (PR), Complete Response (CR), or Stable Disease (SD)
Description	The disease control rate (DCR) was the proportion of randomized participants with a best OR of CR, PR or SD according to modified World Health Organization (WHO) guidelines. It was calculated as the total number of participants with CR, PR or SD divided by the total number of participants randomized in that arm. The tumor response was assessed by the independent review committee (IRC) in the Pemetrexed group and by the investigator in the Docetaxel group.
Time Frame	Randomization to progression of disease or death due to any cause up to 59.6 months

Outcome Measure Data

Analysis Population Description

The intent-to-treat population (ITT) included all participants classified according to the treatment arms into which they were randomized, regardless of the actual treatment received.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab & Docetaxel	Docetaxel
Arm/Group Description:	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week cycles).	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously every 3 weeks cycle for up to six (3-week) cycles, after 6 cycles participants on the chemotherapy/cetuximab combination may continue cetuximab alone. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.
Overall Number of Participants Analyzed	301	304	167	166
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: proportion of participants
	0.522; (0.465 to 0.578)	0.480; (0.424 to 0.536)	0.335; (0.264 to 0.407)	0.253; (0.187 to 0.319)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Pemetrexed, Pemetrexed
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.310
	Comments	The 2-sided unstratified Mantel Haenszel test was employed at the 5% significance level.
	Method	Mantel Haenszel
	Comments	HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.62
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Docetaxel, Docetaxel
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.100
	Comments	The 2-sided unstratified Mantel Haenszel test was employed at the 5% significance level.
	Method	Mantel Haenszel
	Comments	HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 0.93 to 2.40
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Percentage of Participants With Symptomatic Response (Symptom Response Rates) Using the Lung Cancer Subscale (LCS) Scores of Functional Assessment of Cancer Therapy for Participants With Lung Cancer (FACT-L)
Description	The FACT-LCS is a set of 7 questions to inventory problems specific to lung cancer symptoms. Participants rate each item on a 5-point Likert-type scale from 0 (not at all) to 4 (very much). Scores range from 0-28 and higher score indicates fewer symptoms. Symptom response (improvement) was defined as ≥2 point increase from baseline in the 7-item LCS score that was maintained for 2 consecutive assessments at least 3 weeks, and not >5 weeks apart for participants, whose baseline LCS score was ≤26. Symptom response rate was the percentage of participants with symptomatic response.
Time Frame	At baseline, every 3 weeks and 30 days after end of therapy up to 50 months

Outcome Measure Data

Analysis Population Description

The randomized participants with baseline LCS scores less than or equal to 26.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab & Docetaxel	Docetaxel
Arm/Group Description:	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously every 3 weeks cycle for up to six (3-week) cycles, after 6 cycles participants on the chemotherapy/cetuximab combination may continue cetuximab alone. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.
Overall Number of Participants Analyzed	280	280	150	155
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	17.1; (12.7 to 21.6)	22.9; (17.9 to 27.8)	17.3; (11.3 to 23.4)	13.5; (8.2 to 18.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Pemetrexed, Pemetrexed
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.091
	Comments	The 2-sided unstratified Mantel Haenszel test was employed at the 5% significance level.
	Method	Mantel Haenszel
	Comments	HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.06
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Docetaxel, Docetaxel
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.361
	Comments	The 2-sided unstratified Mantel Haenszel test was employed at the 5% significance level.
	Method	Mantel Haenszel
	Comments	HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 95%; 0.72 to 2.50
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Time to Symptomatic Progression
Description	The FACT-LCS (see description in Outcome measure 5) inventories problems specific to lung cancer symptoms. Using this Scale, Symptom progression = a ≥ 2 point decrease from baseline in LCS score maintained for 2 consecutive assessments ≥3 weeks, and <5 weeks, apart. The symptom progression date = the first of 2 consecutive assessments with a ≥2 point decline. Time to symptomatic progression = the time from randomization to the symptom progression date. For participants with no symptom progression, time to symptomatic progression was censored the date of last symptom assessment.
Time Frame	Randomization until symptomatic progression up to 48.3 months

Outcome Measure Data

Analysis Population Description

All randomized participants with a baseline LCS >= 2 were included. Censored participants: 237 in Cetuximab plus Pemetrexed arm; 244 in Pemetrexed arm; 126 in Cetuximab plus Docetaxel arm; 131 in Docetaxel arm.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab & Docetaxel	Docetaxel
Arm/Group Description:	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously every 3 weeks cycle for up to six (3-week cycles), after 6 cycles participants on the chemotherapy/cetuximab combination may continue cetuximab alone. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.
Overall Number of Participants Analyzed	289	287	152	158
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (7.00 to NA)	NA [1]; (NA to NA)

[1]

The median time to symptomatic progression is not estimable because the probability of symptomatic progression free never decreased to 0.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Pemetrexed, Pemetrexed
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.472
	Comments	The 2-sided unstratified log-rank test was employed at the 5% significance level.
	Method	Log Rank
	Comments	Kaplan-Meier estimated time to symptomatic progression. HR was calculated using unstratified Cox proportional hazards model. HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.74
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Docetaxel, Docetaxel
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.272
	Comments	The 2-sided unstratified log-rank test was employed at the 5% significance level.
	Method	Log Rank
	Comments	Kaplan-Meier estimated time to symptomatic progression. HR was calculated using unstratified Cox proportional hazards model. HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.42 to 1.27
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Duration of Overall Response (OR)
Description	The duration of response, in participants with best OR of complete response (CR) or partial response (PR), was measured from the date criteria are met for CR/PR (not confirmation date, whichever was first recorded), until the first occurrence date that the criteria of progressive disease (PD) was met, or death. Participants who were alive and without progression were censored at the date of their last independent review committee (IRC) tumor assessment. The tumor response and progression were assessed by the IRC in the Pemetrexed group and by the investigator in the Docetaxel group.
Time Frame	Time of first occurrence of either (PR) or (CR) to the first date of progressive disease or death up to 32.5 months

Outcome Measure Data

Analysis Population Description

All randomized participants with a best overall response of CR or PR. Censored participants: 1 in Cetuximab plus Pemetrexed arm; 2 in Pemetrexed arm; 1 in Cetuximab plus Docetaxel arm; 0 in Docetaxel arm.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab & Docetaxel	Docetaxel
Arm/Group Description:	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week cycles).	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m2 (initial/weekly) administered intravenously every 3 weeks cycle for up to six (3-week) cycles, after 6 cycles participants on the chemotherapy/cetuximab combination may continue cetuximab alone. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week cycles).	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.
Overall Number of Participants Analyzed	20	13	13	11
Median (95% Confidence Interval); Unit of Measure: months
	4.17; (2.92 to 5.45)	6.93; (3.98 to 16.36)	5.36; (2.73 to 6.93)	5.39; (3.12 to 7.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Pemetrexed, Pemetrexed
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.236
	Comments	The 2-sided unstratified log-rank test was employed at the 5% significance level.
	Method	Log Rank
	Comments	The Kaplan-Meier method estimated duration of response. HR was calculated using unstratified Cox proportional hazards model. HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.58
	Confidence Interval	(2-Sided) 95%; 0.74 to 3.36
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cetuximab & Docetaxel, Docetaxel
	Comments	The Pemetrexed comparisons (Cetuximab + Pemetrexed vs Pemetrexed) were considered the primary comparisons. The Docetaxel comparisons (Cetuximab + Docetaxel vs Docetaxel) were considered supportive as Docetaxel comparisons remained underpowered by design. No tests were conducted to compare participants who received Docetaxel to those who received Pemetrexed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.887
	Comments	The 2-sided unstratified log-rank test was employed at the 5% significance level.
	Method	Log Rank
	Comments	The Kaplan-Meier method estimated duration of response. HR was calculated using unstratified Cox proportional hazards model. HR<1 favors Cetuximab arm
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.42 to 2.18
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Number of Participants With Common Toxicity Criteria (CTC) Grade 3 or 4 Toxicities
Description	National Cancer Institutes-Common Toxicity Criteria version 3.0 was used by investigators to assess participant toxicities. Mapping of investigator verbatim terms to CTCAE terms was done by the sponsor/designee using CTCAE v4.0. Participants reported had grade 3 or 4 toxicities (or both potentially). Grade 3 AEs: severe or medically significant but not immediately life-threatening;hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 AEs: life-threatening consequences; urgent intervention indicated.
Time Frame	Time from first dose to 30 days after last dose of study therapy up to 28.3 months for Cetuximab & Pemetrexed (versus Pemetrexed alone) and up to 54.3 months for Cetuximab + Docetaxel (versus Docetaxel alone)

Outcome Measure Data

Analysis Population Description

All randomized participants receiving at least 1 dose of study drug made up the safety population for this outcome measure. Investigators graded events using CTCAE v3.0. Mapping of investigator verbatim terms for toxicity to CTCAE terms was done by the sponsor/designee using CTCAE v4.0.

Arm/Group Title	Cetuximab & Pemetrexed	Pemetrexed	Cetuximab + Docetaxel	Docetaxel
Arm/Group Description:	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week cycles) until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.	Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Day 1 of every 3 weeks cycle for up to six (3-week) cycles, after 6 cycles participants on the chemotherapy/cetuximab combination may continue cetuximab alone. Docetaxel 75 mg/m2 administered intravenously on Day 1 of 3 week cycle for up to six (3-week) cycles.	Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.
Overall Number of Participants Analyzed	292	289	159	149
Measure Type: Number; Unit of Measure: participants
	179	143	112	97

Adverse Events

Time Frame	Randomization to 30 days after study therapy up to 72.8 months for Cetuximab & Pemetrexed (versus just Pemetrexed) and up to 64.3 months for Cetuximab + Docetaxel (versus just Docetaxel)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Cetuximab & Pemetrexed		Pemetrexed		Cetuximab and Docetaxel		Docetaxel
Arm/Group Description	Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles, until disease progression or unacceptable toxicity. Pemetrexed 500 mg/m^2 administered intravenously on day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.		Pemetrexed 500 mg/m^2 administered intravenously on Day 1 of 3 week cycle for up to six (3-week) cycles.		Cetuximab 400/250 mg/m^2 (initial/weekly) administered intravenously on Days 1, 8, and 15 (3-week) cycles until disease progression or unacceptable toxicity. Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle for up to six (3-week) cycles.		Docetaxel 75 mg/m^2 administered intravenously on Day 1 of 3 weeks cycle until disease progression or unacceptable toxicity for up to six (3-week) cycles.
All-Cause Mortality
	Cetuximab & Pemetrexed		Pemetrexed		Cetuximab and Docetaxel		Docetaxel
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--		--/--
Serious Adverse Events
	Cetuximab & Pemetrexed		Pemetrexed		Cetuximab and Docetaxel		Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	119/292 (40.75%)		86/289 (29.76%)		84/159 (52.83%)		60/149 (40.27%)
Blood and lymphatic system disorders
Anaemia † 1	4/292 (1.37%)	5	6/289 (2.08%)	7	2/159 (1.26%)	2	2/149 (1.34%)	2
Coagulopathy † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Febrile neutropenia † 1	2/292 (0.68%)	2	4/289 (1.38%)	4	13/159 (8.18%)	14	11/149 (7.38%)	11
Hypercoagulation † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Leukocytosis † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Leukopenia † 1	0/292 (0.00%)	0	2/289 (0.69%)	2	2/159 (1.26%)	2	0/149 (0.00%)	0
Neutropenia † 1	4/292 (1.37%)	4	4/289 (1.38%)	4	10/159 (6.29%)	11	3/149 (2.01%)	3
Pancytopenia † 1	2/292 (0.68%)	2	2/289 (0.69%)	2	0/159 (0.00%)	0	0/149 (0.00%)	0
Thrombocytopenia † 1	2/292 (0.68%)	2	3/289 (1.04%)	4	0/159 (0.00%)	0	0/149 (0.00%)	0
Cardiac disorders
Angina pectoris † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Atrial fibrillation † 1	10/292 (3.42%)	12	2/289 (0.69%)	2	0/159 (0.00%)	0	5/149 (3.36%)	7
Atrial flutter † 1	1/292 (0.34%)	1	2/289 (0.69%)	2	1/159 (0.63%)	1	1/149 (0.67%)	1
Atrial tachycardia † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Cardiac arrest † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Cardiac failure † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Cardiac failure congestive † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	3/159 (1.89%)	3	2/149 (1.34%)	2
Cardiac tamponade † 1	1/292 (0.34%)	2	1/289 (0.35%)	2	0/159 (0.00%)	0	0/149 (0.00%)	0
Cardio-respiratory arrest † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	1/159 (0.63%)	2	1/149 (0.67%)	1
Left ventricular dysfunction † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Myocardial infarction † 1	2/292 (0.68%)	2	1/289 (0.35%)	1	1/159 (0.63%)	2	0/149 (0.00%)	0
Myocardial ischaemia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Palpitations † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Pericardial effusion † 1	2/292 (0.68%)	2	2/289 (0.69%)	3	1/159 (0.63%)	1	2/149 (1.34%)	3
Sinus tachycardia † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Supraventricular tachycardia † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Tachycardia † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Ventricular fibrillation † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Ventricular tachycardia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	2/292 (0.68%)	2	2/289 (0.69%)	3	0/159 (0.00%)	0	1/149 (0.67%)	1
Abdominal pain upper † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Ascites † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Caecitis † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Colitis † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	2/159 (1.26%)	2	0/149 (0.00%)	0
Constipation † 1	2/292 (0.68%)	2	3/289 (1.04%)	3	1/159 (0.63%)	1	0/149 (0.00%)	0
Diarrhoea † 1	0/292 (0.00%)	0	2/289 (0.69%)	2	2/159 (1.26%)	2	1/149 (0.67%)	1
Diverticular perforation † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Duodenal ulcer † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Dysphagia † 1	0/292 (0.00%)	0	2/289 (0.69%)	2	0/159 (0.00%)	0	0/149 (0.00%)	0
Gastric haemorrhage † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Gastric ulcer † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Gastritis erosive † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Gastrointestinal haemorrhage † 1	4/292 (1.37%)	4	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Gastrointestinal pain † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Ileus † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	0/159 (0.00%)	0	1/149 (0.67%)	1
Nausea † 1	5/292 (1.71%)	5	1/289 (0.35%)	1	3/159 (1.89%)	4	0/149 (0.00%)	0
Oesophageal ulcer † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Small intestinal obstruction † 1	2/292 (0.68%)	2	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Stomatitis † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Vomiting † 1	5/292 (1.71%)	5	2/289 (0.69%)	2	6/159 (3.77%)	7	1/149 (0.67%)	1
General disorders
Asthenia † 1	6/292 (2.05%)	6	1/289 (0.35%)	1	4/159 (2.52%)	4	1/149 (0.67%)	1
Chest discomfort † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Chest pain † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Chills † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Disease progression † 1	6/292 (2.05%)	6	2/289 (0.69%)	2	5/159 (3.14%)	5	5/149 (3.36%)	5
Fatigue † 1	3/292 (1.03%)	3	1/289 (0.35%)	1	3/159 (1.89%)	3	2/149 (1.34%)	2
Hypothermia † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Impaired healing † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Multi-organ failure † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Non-cardiac chest pain † 1	1/292 (0.34%)	1	3/289 (1.04%)	4	1/159 (0.63%)	1	0/149 (0.00%)	0
Oedema † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Oedema peripheral † 1	2/292 (0.68%)	2	1/289 (0.35%)	1	2/159 (1.26%)	2	1/149 (0.67%)	1
Pain † 1	5/292 (1.71%)	5	4/289 (1.38%)	4	4/159 (2.52%)	4	1/149 (0.67%)	1
Pyrexia † 1	7/292 (2.40%)	8	5/289 (1.73%)	5	10/159 (6.29%)	10	3/149 (2.01%)	3
Sudden death † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	1/149 (0.67%)	1
Systemic inflammatory response syndrome † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Immune system disorders
Hypersensitivity † 1	3/292 (1.03%)	3	0/289 (0.00%)	0	2/159 (1.26%)	2	1/149 (0.67%)	1
Infections and infestations
Abdominal infection † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Appendicitis † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	1/149 (0.67%)	1
Bacteraemia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Bronchitis † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	1/149 (0.67%)	1
Bronchopneumonia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Catheter site infection † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Cellulitis † 1	2/292 (0.68%)	2	2/289 (0.69%)	2	1/159 (0.63%)	1	1/149 (0.67%)	1
Cellulitis staphylococcal † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Clostridial infection † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	2	0/149 (0.00%)	0
Diverticulitis † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Empyema † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	2/149 (1.34%)	2
Gangrene † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Gastroenteritis † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Herpes zoster † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Incision site infection † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Infection † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Lobar pneumonia † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Lung infection † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Lung infection pseudomonal † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Meningitis † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Necrotising fasciitis † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Oral candidiasis † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Pelvic abscess † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Peridiverticular abscess † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	2
Pneumonia † 1	16/292 (5.48%)	16	17/289 (5.88%)	17	9/159 (5.66%)	11	10/149 (6.71%)	10
Pneumonia klebsiella † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Postoperative wound infection † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Sepsis † 1	3/292 (1.03%)	3	0/289 (0.00%)	0	3/159 (1.89%)	3	3/149 (2.01%)	3
Sepsis syndrome † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Septic shock † 1	3/292 (1.03%)	3	0/289 (0.00%)	0	2/159 (1.26%)	2	1/149 (0.67%)	1
Staphylococcal bacteraemia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Staphylococcal sepsis † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	1/149 (0.67%)	1
Subcutaneous abscess † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Urinary tract infection † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Urosepsis † 1	2/292 (0.68%)	2	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Injury, poisoning and procedural complications
Collapse of lung † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Fall † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Femoral neck fracture † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Femur fracture † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Hip fracture † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Humerus fracture † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Infusion related reaction † 1	4/292 (1.37%)	4	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Overdose † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Pneumonitis chemical † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Sternal fracture † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Toxicity to various agents † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Traumatic lung injury † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Investigations
Activated partial thromboplastin time prolonged † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Haemoglobin decreased † 1	1/292 (0.34%)	2	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
International normalised ratio increased † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	1/159 (0.63%)	1	1/149 (0.67%)	1
Platelet count decreased † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Weight decreased † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	0/292 (0.00%)	0	3/289 (1.04%)	3	1/159 (0.63%)	1	0/149 (0.00%)	0
Dehydration † 1	11/292 (3.77%)	11	6/289 (2.08%)	7	17/159 (10.69%)	19	4/149 (2.68%)	4
Electrolyte imbalance † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Failure to thrive † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	1/159 (0.63%)	1	1/149 (0.67%)	1
Hypercalcaemia † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	1/149 (0.67%)	1
Hyperglycaemia † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	2/149 (1.34%)	2
Hypoglycaemia † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Hypokalaemia † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Hypomagnesaemia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Hyponatraemia † 1	2/292 (0.68%)	3	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Hypophosphataemia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Hypovolaemia † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Metabolic acidosis † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	1/159 (0.63%)	1	1/149 (0.67%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/292 (0.34%)	1	2/289 (0.69%)	2	0/159 (0.00%)	0	0/149 (0.00%)	0
Back pain † 1	4/292 (1.37%)	4	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Bone pain † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Mobility decreased † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Muscular weakness † 1	0/292 (0.00%)	0	3/289 (1.04%)	3	0/159 (0.00%)	0	0/149 (0.00%)	0
Musculoskeletal pain † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Myalgia † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Pain in extremity † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Pain in jaw † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion † 1	1/292 (0.34%)	2	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Metastases to bone † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Metastases to central nervous system † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Neoplasm malignant † 1	3/292 (1.03%)	3	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Non-small cell lung cancer † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Ovarian cancer † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Nervous system disorders
Ataxia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Brain injury † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Brain stem haemorrhage † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Cerebral infarction † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Cerebral ischaemia † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Cerebrovascular accident † 1	0/292 (0.00%)	0	3/289 (1.04%)	3	1/159 (0.63%)	1	1/149 (0.67%)	1
Cognitive disorder † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Convulsion † 1	2/292 (0.68%)	2	3/289 (1.04%)	3	2/159 (1.26%)	2	0/149 (0.00%)	0
Depressed level of consciousness † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	2/149 (1.34%)	2
Dizziness † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Dysarthria † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Dyskinesia † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Headache † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Hemiparesis † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Hydrocephalus † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Neuropathy peripheral † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Partial seizures † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Presyncope † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Somnolence † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Speech disorder † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Spinal cord compression † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Syncope † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	1/149 (0.67%)	1
Transient ischaemic attack † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Psychiatric disorders
Confusional state † 1	6/292 (2.05%)	6	4/289 (1.38%)	5	5/159 (3.14%)	5	0/149 (0.00%)	0
Delirium † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Depression † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Disorientation † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Drug abuse † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Mental status changes † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	1/159 (0.63%)	1	1/149 (0.67%)	1
Schizoaffective disorder † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Renal and urinary disorders
Pollakiuria † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Renal failure † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Renal failure acute † 1	1/292 (0.34%)	1	5/289 (1.73%)	5	2/159 (1.26%)	2	0/149 (0.00%)	0
Renal pain † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Urinary retention † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Acute respiratory failure † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Apnoeic attack † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Asthma † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Bronchial haemorrhage † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Bronchospasm † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Chronic obstructive pulmonary disease † 1	5/292 (1.71%)	6	4/289 (1.38%)	5	1/159 (0.63%)	1	3/149 (2.01%)	4
Cough † 1	0/292 (0.00%)	0	3/289 (1.04%)	3	1/159 (0.63%)	1	1/149 (0.67%)	1
Dyspnoea † 1	14/292 (4.79%)	18	11/289 (3.81%)	14	12/159 (7.55%)	13	6/149 (4.03%)	8
Epistaxis † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Haemoptysis † 1	1/292 (0.34%)	2	2/289 (0.69%)	3	7/159 (4.40%)	7	3/149 (2.01%)	3
Hydropneumothorax † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Hypercapnia † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Hypoxia † 1	4/292 (1.37%)	4	3/289 (1.04%)	3	4/159 (2.52%)	5	3/149 (2.01%)	3
Interstitial lung disease † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	2/159 (1.26%)	2	1/149 (0.67%)	1
Pleural effusion † 1	9/292 (3.08%)	11	3/289 (1.04%)	3	4/159 (2.52%)	4	7/149 (4.70%)	10
Pneumonia aspiration † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	1/149 (0.67%)	1
Pneumonitis † 1	1/292 (0.34%)	3	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Pneumothorax † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	2/159 (1.26%)	2	0/149 (0.00%)	0
Pulmonary embolism † 1	6/292 (2.05%)	6	3/289 (1.04%)	3	4/159 (2.52%)	4	2/149 (1.34%)	2
Pulmonary fibrosis † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Respiratory arrest † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Respiratory distress † 1	2/292 (0.68%)	2	2/289 (0.69%)	2	1/159 (0.63%)	1	0/149 (0.00%)	0
Respiratory failure † 1	7/292 (2.40%)	8	2/289 (0.69%)	3	7/159 (4.40%)	8	3/149 (2.01%)	6
Respiratory tract haemorrhage † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Skin and subcutaneous tissue disorders
Angioedema † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Dermatitis acneiform † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Purpura † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Rash † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Urticaria † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Surgical and medical procedures
Leg amputation † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Pain management † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Ventriculo-peritoneal shunt † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Vascular disorders
Deep vein thrombosis † 1	5/292 (1.71%)	6	0/289 (0.00%)	0	8/159 (5.03%)	8	2/149 (1.34%)	2
Exsanguination † 1	0/292 (0.00%)	0	0/289 (0.00%)	0	1/159 (0.63%)	1	0/149 (0.00%)	0
Hypertension † 1	0/292 (0.00%)	0	1/289 (0.35%)	1	0/159 (0.00%)	0	0/149 (0.00%)	0
Hypotension † 1	7/292 (2.40%)	7	0/289 (0.00%)	0	5/159 (3.14%)	6	5/149 (3.36%)	5
Ischaemic limb pain † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Orthostatic hypotension † 1	1/292 (0.34%)	1	1/289 (0.35%)	1	1/159 (0.63%)	1	0/149 (0.00%)	0
Peripheral ischaemia † 1	2/292 (0.68%)	2	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
Superior vena cava syndrome † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	1/149 (0.67%)	1
Thrombosis † 1	1/292 (0.34%)	1	0/289 (0.00%)	0	0/159 (0.00%)	0	0/149 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 14.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Cetuximab & Pemetrexed		Pemetrexed		Cetuximab and Docetaxel		Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	289/292 (98.97%)		281/289 (97.23%)		159/159 (100.00%)		147/149 (98.66%)
Blood and lymphatic system disorders
Anaemia † 1	70/292 (23.97%)	90	64/289 (22.15%)	93	40/159 (25.16%)	75	35/149 (23.49%)	48
Leukopenia † 1	10/292 (3.42%)	14	11/289 (3.81%)	17	15/159 (9.43%)	31	7/149 (4.70%)	13
Neutropenia † 1	32/292 (10.96%)	51	32/289 (11.07%)	58	74/159 (46.54%)	121	46/149 (30.87%)	95
Thrombocytopenia † 1	14/292 (4.79%)	26	22/289 (7.61%)	48	7/159 (4.40%)	11	2/149 (1.34%)	7
Cardiac disorders
Tachycardia † 1	13/292 (4.45%)	16	12/289 (4.15%)	12	15/159 (9.43%)	15	8/149 (5.37%)	8
Eye disorders
Lacrimation increased † 1	20/292 (6.85%)	21	16/289 (5.54%)	16	7/159 (4.40%)	7	7/149 (4.70%)	7
Gastrointestinal disorders
Abdominal pain † 1	19/292 (6.51%)	22	16/289 (5.54%)	19	15/159 (9.43%)	16	6/149 (4.03%)	7
Abdominal pain upper † 1	16/292 (5.48%)	18	10/289 (3.46%)	10	4/159 (2.52%)	9	3/149 (2.01%)	3
Constipation † 1	75/292 (25.68%)	94	60/289 (20.76%)	66	41/159 (25.79%)	48	25/149 (16.78%)	27
Diarrhoea † 1	81/292 (27.74%)	108	36/289 (12.46%)	38	63/159 (39.62%)	91	22/149 (14.77%)	28
Dyspepsia † 1	21/292 (7.19%)	26	15/289 (5.19%)	16	12/159 (7.55%)	16	7/149 (4.70%)	7
Nausea † 1	112/292 (38.36%)	146	89/289 (30.80%)	128	53/159 (33.33%)	68	38/149 (25.50%)	48
Oral pain † 1	11/292 (3.77%)	12	7/289 (2.42%)	7	8/159 (5.03%)	8	7/149 (4.70%)	8
Stomatitis † 1	54/292 (18.49%)	78	21/289 (7.27%)	21	53/159 (33.33%)	74	23/149 (15.44%)	26
Vomiting † 1	59/292 (20.21%)	83	44/289 (15.22%)	54	25/159 (15.72%)	32	19/149 (12.75%)	22
General disorders
Asthenia † 1	37/292 (12.67%)	40	33/289 (11.42%)	42	29/159 (18.24%)	41	15/149 (10.07%)	20
Chills † 1	12/292 (4.11%)	14	13/289 (4.50%)	13	9/159 (5.66%)	12	15/149 (10.07%)	16
Fatigue † 1	158/292 (54.11%)	209	133/289 (46.02%)	191	88/159 (55.35%)	146	74/149 (49.66%)	99
Non-cardiac chest pain † 1	14/292 (4.79%)	14	18/289 (6.23%)	22	6/159 (3.77%)	7	7/149 (4.70%)	9
Oedema peripheral † 1	51/292 (17.47%)	70	32/289 (11.07%)	35	23/159 (14.47%)	28	27/149 (18.12%)	28
Pain † 1	12/292 (4.11%)	20	14/289 (4.84%)	15	10/159 (6.29%)	12	11/149 (7.38%)	12
Pyrexia † 1	46/292 (15.75%)	60	37/289 (12.80%)	43	22/159 (13.84%)	29	14/149 (9.40%)	14
Infections and infestations
Candidiasis † 1	11/292 (3.77%)	13	5/289 (1.73%)	6	8/159 (5.03%)	9	6/149 (4.03%)	6
Oral candidiasis † 1	9/292 (3.08%)	11	6/289 (2.08%)	6	10/159 (6.29%)	13	5/149 (3.36%)	7
Paronychia † 1	15/292 (5.14%)	21	0/289 (0.00%)	0	3/159 (1.89%)	6	0/149 (0.00%)	0
Urinary tract infection † 1	18/292 (6.16%)	20	9/289 (3.11%)	10	8/159 (5.03%)	9	6/149 (4.03%)	7
Injury, poisoning and procedural complications
Infusion related reaction † 1	15/292 (5.14%)	19	0/289 (0.00%)	0	4/159 (2.52%)	5	2/149 (1.34%)	2
Investigations
Weight decreased † 1	19/292 (6.51%)	25	15/289 (5.19%)	15	18/159 (11.32%)	20	7/149 (4.70%)	8
Metabolism and nutrition disorders
Decreased appetite † 1	86/292 (29.45%)	102	58/289 (20.07%)	63	54/159 (33.96%)	68	45/149 (30.20%)	47
Dehydration † 1	27/292 (9.25%)	28	17/289 (5.88%)	21	24/159 (15.09%)	28	14/149 (9.40%)	26
Hyperglycaemia † 1	11/292 (3.77%)	14	20/289 (6.92%)	28	6/159 (3.77%)	7	4/149 (2.68%)	6
Hypokalaemia † 1	29/292 (9.93%)	33	11/289 (3.81%)	12	26/159 (16.35%)	32	4/149 (2.68%)	5
Hypomagnesaemia † 1	57/292 (19.52%)	91	17/289 (5.88%)	20	36/159 (22.64%)	55	6/149 (4.03%)	6
Musculoskeletal and connective tissue disorders
Arthralgia † 1	16/292 (5.48%)	18	22/289 (7.61%)	23	14/159 (8.81%)	18	17/149 (11.41%)	18
Back pain † 1	36/292 (12.33%)	44	14/289 (4.84%)	16	17/159 (10.69%)	19	7/149 (4.70%)	8
Muscle spasms † 1	10/292 (3.42%)	12	1/289 (0.35%)	1	9/159 (5.66%)	12	2/149 (1.34%)	2
Muscular weakness † 1	11/292 (3.77%)	12	10/289 (3.46%)	10	10/159 (6.29%)	11	6/149 (4.03%)	7
Musculoskeletal chest pain † 1	19/292 (6.51%)	22	13/289 (4.50%)	13	7/159 (4.40%)	9	6/149 (4.03%)	6
Musculoskeletal pain † 1	11/292 (3.77%)	13	13/289 (4.50%)	14	8/159 (5.03%)	9	9/149 (6.04%)	9
Myalgia † 1	14/292 (4.79%)	25	11/289 (3.81%)	11	21/159 (13.21%)	23	14/149 (9.40%)	19
Pain in extremity † 1	21/292 (7.19%)	25	16/289 (5.54%)	16	11/159 (6.92%)	14	6/149 (4.03%)	6
Nervous system disorders
Dizziness † 1	41/292 (14.04%)	49	14/289 (4.84%)	18	21/159 (13.21%)	26	18/149 (12.08%)	22
Dysgeusia † 1	25/292 (8.56%)	25	12/289 (4.15%)	12	23/159 (14.47%)	30	13/149 (8.72%)	13
Headache † 1	20/292 (6.85%)	28	21/289 (7.27%)	22	8/159 (5.03%)	8	15/149 (10.07%)	16
Neuropathy peripheral † 1	14/292 (4.79%)	14	15/289 (5.19%)	15	16/159 (10.06%)	18	13/149 (8.72%)	15
Psychiatric disorders
Anxiety † 1	20/292 (6.85%)	22	16/289 (5.54%)	18	8/159 (5.03%)	8	6/149 (4.03%)	6
Confusional state † 1	17/292 (5.82%)	21	13/289 (4.50%)	15	7/159 (4.40%)	7	7/149 (4.70%)	7
Depression † 1	16/292 (5.48%)	17	20/289 (6.92%)	20	8/159 (5.03%)	9	9/149 (6.04%)	9
Insomnia † 1	27/292 (9.25%)	29	27/289 (9.34%)	27	11/159 (6.92%)	12	19/149 (12.75%)	23
Respiratory, thoracic and mediastinal disorders
Cough † 1	46/292 (15.75%)	50	43/289 (14.88%)	46	28/159 (17.61%)	31	23/149 (15.44%)	24
Dysphonia † 1	17/292 (5.82%)	18	5/289 (1.73%)	5	5/159 (3.14%)	7	6/149 (4.03%)	6
Dyspnoea † 1	66/292 (22.60%)	84	60/289 (20.76%)	71	43/159 (27.04%)	61	38/149 (25.50%)	43
Epistaxis † 1	32/292 (10.96%)	34	11/289 (3.81%)	13	19/159 (11.95%)	21	5/149 (3.36%)	6
Haemoptysis † 1	20/292 (6.85%)	25	9/289 (3.11%)	9	10/159 (6.29%)	15	8/149 (5.37%)	9
Hypoxia † 1	9/292 (3.08%)	9	6/289 (2.08%)	8	8/159 (5.03%)	9	3/149 (2.01%)	3
Oropharyngeal pain † 1	20/292 (6.85%)	21	13/289 (4.50%)	15	12/159 (7.55%)	14	11/149 (7.38%)	12
Productive cough † 1	9/292 (3.08%)	11	9/289 (3.11%)	11	8/159 (5.03%)	9	2/149 (1.34%)	2
Skin and subcutaneous tissue disorders
Alopecia † 1	17/292 (5.82%)	20	5/289 (1.73%)	5	29/159 (18.24%)	32	36/149 (24.16%)	36
Dermatitis acneiform † 1	223/292 (76.37%)	444	5/289 (1.73%)	5	100/159 (62.89%)	160	4/149 (2.68%)	5
Dry skin † 1	62/292 (21.23%)	70	8/289 (2.77%)	8	27/159 (16.98%)	34	7/149 (4.70%)	7
Erythema † 1	12/292 (4.11%)	13	3/289 (1.04%)	3	9/159 (5.66%)	12	7/149 (4.70%)	7
Nail disorder † 1	17/292 (5.82%)	20	0/289 (0.00%)	0	8/159 (5.03%)	8	4/149 (2.68%)	4
Pruritus † 1	30/292 (10.27%)	36	6/289 (2.08%)	7	13/159 (8.18%)	16	2/149 (1.34%)	2
Rash † 1	20/292 (6.85%)	35	32/289 (11.07%)	38	8/159 (5.03%)	10	12/149 (8.05%)	13
Skin disorder † 1	24/292 (8.22%)	33	0/289 (0.00%)	0	13/159 (8.18%)	17	1/149 (0.67%)	1
Skin fissures † 1	15/292 (5.14%)	22	0/289 (0.00%)	0	2/159 (1.26%)	2	0/149 (0.00%)	0
Vascular disorders
Hypotension † 1	29/292 (9.93%)	34	9/289 (3.11%)	9	15/159 (9.43%)	17	11/149 (7.38%)	11
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 14.0

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.

Results Point of Contact

• Name/Title: Chief Medical Officer
• Organization: Eli Lilly and Company
• Phone: 800-545-5979

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

Kim ES, Neubauer M, Cohn A, Schwartzberg L, Garbo L, Caton J, Robert F, Reynolds C, Katz T, Chittoor S, Simms L, Saxman S. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Lancet Oncol. 2013 Dec;14(13):1326-36. doi: 10.1016/S1470-2045(13)70473-X. Epub 2013 Nov 12. Erratum In: Lancet Oncol. 2014 Jan;15(1):e4.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00095199
• Other Study ID Numbers: 13423; I4E-MC-JXBC ( Other Identifier: Eli Lilly and Company ); CP02-0452 ( Other Identifier: ImClone )
• First Submitted: November 1, 2004
• First Posted: November 2, 2004
• Results First Submitted: June 19, 2012
• Results First Posted: October 15, 2012
• Last Update Posted: October 15, 2012