S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT00946712
• Recruitment Status: Terminated
• First Posted: July 27, 2009
• Results First Posted: March 7, 2019
• Last Update Posted: May 23, 2023
• Sponsor: SWOG Cancer Research Network
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): SWOG Cancer Research Network

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Recurrent Large Cell Lung Carcinoma; Recurrent Lung Adenocarcinoma; Recurrent Squamous Cell Lung Carcinoma; Stage IV Large Cell Lung Carcinoma; Stage IV Lung Adenocarcinoma; Stage IV Squamous Cell Lung Carcinoma
• Interventions: Biological: Bevacizumab; Drug: Carboplatin; Biological: Cetuximab; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel
• Enrollment: 1333

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Period Title: Overall Study
Started	671	662
Completed	124	0
Not Completed	547	662
Reason Not Completed
Adverse Event	118	124
Disease progression	308	404
Death	21	22
No treatment given	25	29
Other reasons	61	73
On Treatment	0	4
Ineligible	14	6

Baseline Characteristics

Arm/Group Title		Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)	Total
Arm/Group Description		Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Total of all reporting groups
Overall Number of Baseline Participants		657	656	1313
Baseline Analysis Population Description		Only eligible patients are included in the analysis.
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	657 participants	656 participants	1313 participants
		63; (30 to 86)	63; (19 to 84)	63; (19 to 86)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Age, Categorized	Number Analyzed	657 participants	656 participants	1313 participants
	Age <= 65	379 57.7%	381 58.1%	760 57.9%
	Age > 65	278 42.3%	275 41.9%	553 42.1%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	657 participants	656 participants	1313 participants
	Female	298 45.4%	271 41.3%	569 43.3%
	Male	359 54.6%	385 58.7%	744 56.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	657 participants	656 participants	1313 participants
	Hispanic or Latino	26 4.0%	16 2.4%	42 3.2%
	Not Hispanic or Latino	606 92.2%	618 94.2%	1224 93.2%
	Unknown or Not Reported	25 3.8%	22 3.4%	47 3.6%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	657 participants	656 participants	1313 participants
	White	565 86.0%	568 86.6%	1133 86.3%
	Black	61 9.3%	55 8.4%	116 8.8%
	Asian	10 1.5%	18 2.7%	28 2.1%
	Pacific Islander	3 0.5%	6 0.9%	9 0.7%
	Native American	2 0.3%	1 0.2%	3 0.2%
	Unknown	16 2.4%	8 1.2%	24 1.8%
M-stage [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	657 participants	656 participants	1313 participants
	M1a	148 22.5%	150 22.9%	298 22.7%
	M1b	509 77.5%	506 77.1%	1015 77.3%
		[1] Measure Description: M staging per AJCC Cancer Staging Manual, 7th Edition, 2009. M1a: Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion. M1b: Distant metastases
Bevacizumab treatment; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	657 participants	656 participants	1313 participants
	Yes	277 42.2%	283 43.1%	560 42.7%
	No	380 57.8%	373 56.9%	753 57.3%
Smoking History; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	657 participants	656 participants	1313 participants
	Current	297 45.2%	292 44.5%	589 44.9%
	Former	303 46.1%	305 46.5%	608 46.3%
	Never	57 8.7%	59 9.0%	116 8.8%
Histology [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	657 participants	656 participants	1313 participants
	Squamous cell carcinoma	161 24.5%	160 24.4%	321 24.4%
	Adenocarcinoma	408 62.1%	411 62.7%	819 62.4%
	Other	88 13.4%	85 13.0%	173 13.2%
		[1] Measure Description: 'Other' includes large-cell carcinoma, bronchioloalveolar carcinoma, mixed, other, and not reported.
Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	657 participants	656 participants	1313 participants
	0	229 34.9%	256 39.0%	485 36.9%
	1	427 65.0%	400 61.0%	827 63.0%
	Missing Data	1 0.2%	0 0.0%	1 0.1%
		[1] Measure Description: Patients will be graded according to the Zubrod Performance Status Scale. 0 Fully active, able to carry on all pre-disease performance without restriction. 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.
EGFR (Epidermal Growth Factor Receptor) FISH (Fluorescence In Situ Hybridization) status; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	657 participants	656 participants	1313 participants
	Positive	201 30.6%	199 30.3%	400 30.5%
	Negative	293 44.6%	283 43.1%	576 43.9%
	Unknown	163 24.8%	174 26.5%	337 25.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) in the Entire Study Population
Description	From date of randomization to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
Time Frame	Patients will be followed every 3 weeks while on protocol treatment. Once off all protocol treatment, patients will be followed every 6 months until death or up to 3 years

Outcome Measure Data

Analysis Population Description

All eligible patients are included in the analysis.

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	657	656
Median (95% Confidence Interval); Unit of Measure: months
	9.2; (8.7 to 10.3)	10.9; (9.5 to 12.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemo +/- Bevacizumab), Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.22
	Comments	[Not Specified]
	Method	Log Rank
	Comments	A stratified log rank test was used.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.04
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Progression-free Survival (PFS) of EGFR FISH-positive Patients by Institutional Review
Description	From date of randomization to date of first documentation of progression or symptomatic deterioration, or death due to any cause, whichever comes first by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as assessed by the treating investigator.Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using RECIST 1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Disease assessment will be repeated every 6 weeks for the first 9 months and every 3 months thereafter, until disease progression.

Outcome Measure Data

Analysis Population Description

Eligible patients with EGFR FISH positive are included in the analysis.

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	201	199
Median (95% Confidence Interval); Unit of Measure: months
	4.8; (3.9 to 5.5)	5.4; (4.5 to 5.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemo +/- Bevacizumab), Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.40
	Comments	[Not Specified]
	Method	Log Rank
	Comments	A stratified log rank test was used.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.12
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Overall Survival (OS) of EGFR FISH-positive Patients
Description	From date of randomization to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
Time Frame	Patients will be followed every 3 weeks while on protocol treatment. Once off all protocol treatment, patients will be followed every 6 months until death or up to 3 years

Outcome Measure Data

Analysis Population Description

Eligible and evaluable participants who were EGFR-FISH positive

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	201	199
Median (95% Confidence Interval); Unit of Measure: Months
	9.8; (8.7 to 12.1)	13.4; (11.5 to 14.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemo +/- Bevacizumab), Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.054
	Comments	[Not Specified]
	Method	Log Rank
	Comments	A stratified log rank test was used.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.00
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Progression-Free Survival (PFS) of EGFR FISH-positive Patients by Centralized Review
Description	From date of randomization to date of first documentation of progression or symptomatic deterioration, or death due to any cause, whichever comes first by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as assessed by the treating investigator.Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using RECIST 1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Disease assessment will be repeated every 6 weeks until disease progression while on treatment. After off treatment, the frequency of disease assessment may be reduced to every 3 months until disease progression.

Outcome Measure Data

Analysis Population Description

Data are not available for this outcome as central image review was not performed. The study was closed for futility at the interim analysis and therefore there was no need to confirm PFS by central review.

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

5. Secondary Outcome

Title	Progression-Free Survival (PFS) of the Entire Study Population by Institutional Review
Description	From date of randomization to date of first documentation of progression or symptomatic deterioration, or death due to any cause, whichever comes first by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as assessed by the treating investigator.Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using RECIST 1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Disease assessment will be repeated every 6 weeks until disease progression while on treatment. After off treatment, the frequency of disease assessment may be reduced to every 3 months until disease progression.

Outcome Measure Data

Analysis Population Description

Eligible and evaluable participants

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	657	656
Median (95% Confidence Interval); Unit of Measure: Months
	4.5; (4.2 to 5.1)	4.6; (4.2 to 5.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemo +/- Bevacizumab), Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.83
	Comments	[Not Specified]
	Method	Log Rank
	Comments	A stratified log rank test was used.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.10
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Progression-Free Survival (PFS) of the Entire Study Population by Centralized Review
Description	From date of randomization to date of first documentation of progression or symptomatic deterioration, or death due to any cause, whichever comes first by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as assessed by the treating investigator.Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using RECIST 1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Disease assessment will be repeated every 6 weeks until disease progression while on treatment. After off treatment, the frequency of disease assessment may be reduced to every 3 months until disease progression.

Outcome Measure Data

Analysis Population Description

Data are not available for this outcome as central image review was not performed. The study was closed for futility at the interim analysis and therefore there was no need to confirm PFS by central review.

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

7. Secondary Outcome

Title	Response Rate (Confirmed Plus Unconfirmed, Complete and Partial Responses) in the Subset of Patients With Measurable Disease in EGFR FISH-positive Patients
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	Disease assessment will be repeated every 6 weeks for the first 9 months and every 3 months thereafter, until disease progression.

Outcome Measure Data

Analysis Population Description

Eligible EGFR FISH positive patients with baseline measurable disease are included in the analysis.

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	191	187
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of analyzed participants
	43; (36 to 50)	47; (39 to 54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemo +/- Bevacizumab), Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.48
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	A stratified Cochran-Mantel-Haenszel test was conducted.

8. Secondary Outcome

Title	Response Rate (Confirmed Plus Unconfirmed, Complete and Partial Responses) in the Subset of Patients With Measurable Disease in the Entire Study Population
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	Disease assessment will be repeated every 6 weeks for the first 9 months and every 3 months thereafter, until disease progression.

Outcome Measure Data

Analysis Population Description

Eligible patients with baseline measurable disease are included in the analysis.

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	623	617
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of analyzed participants
	36; (33 to 40)	42; (38 to 46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemo +/- Bevacizumab), Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.060
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	A stratified Cochran-Mantel-Haenszel test was conducted.

9. Secondary Outcome

Title	Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
Description	Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Time Frame	Toxicity assessment was evaluated every 3 weeks while one protocol treatment. Chemo and cetuximab is treated for 6 cycles (1 cycle =3 weeks) and Bevacizumab is treated until progression or unacceptable toxicity.

Outcome Measure Data

Analysis Population Description

Limited to eligible patients who started treatment, who did not have a major deviation in the treatment protocol, and whose toxicity profile has been completed.

Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description:	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
Overall Number of Participants Analyzed	632	627
Measure Type: Count of Participants; Unit of Measure: Participants
ALT, SGPT (serum glutamic pyruvic transaminase)	5 0.8%	8 1.3%
AST, SGOT	6 0.9%	8 1.3%
Acidosis (metabolic or respiratory)	0 0.0%	1 0.2%
Adrenal insufficiency	0 0.0%	1 0.2%
Albumin, serum-low (hypoalbuminemia)	8 1.3%	7 1.1%
Alkaline phosphatase	2 0.3%	1 0.2%
Allergic reaction/hypersensitivity	9 1.4%	41 6.5%
Allergy/Immunology-Other (Specify)	0 0.0%	2 0.3%
Anorexia	22 3.5%	25 4.0%
Apnea	0 0.0%	1 0.2%
Aspiration	0 0.0%	2 0.3%
Ataxia (incoordination)	1 0.2%	0 0.0%
Bilirubin (hyperbilirubinemia)	2 0.3%	0 0.0%
Blood/Bone Marrow-Other (Specify)	2 0.3%	3 0.5%
Bronchospasm, wheezing	0 0.0%	2 0.3%
CNS cerebrovascular ischemia	2 0.3%	4 0.6%
Calcium, serum-high (hypercalcemia)	2 0.3%	0 0.0%
Calcium, serum-low (hypocalcemia)	1 0.2%	8 1.3%
Carbon monoxide diffusion capacity (DL(co))	3 0.5%	2 0.3%
Cardiac General-Other (Specify)	2 0.3%	3 0.5%
Cardiac troponin I (cTnI)	0 0.0%	2 0.3%
Cardiac-ischemia/infarction	1 0.2%	1 0.2%
Cardiopulmonary arrest, cause unknown (non-fatal)	1 0.2%	2 0.3%
Cognitive disturbance	1 0.2%	1 0.2%
Colitis	0 0.0%	2 0.3%
Colitis, infectious (e.g., Clostridium difficile)	0 0.0%	1 0.2%
Conduction abnormality - Asystole	1 0.2%	0 0.0%
Confusion	1 0.2%	4 0.6%
Constipation	4 0.6%	4 0.6%
Cough	1 0.2%	2 0.3%
Creatinine	0 0.0%	1 0.2%
Cytokine release syndrome/acute infusion reaction	0 0.0%	10 1.6%
Death - Multi-organ failure	0 0.0%	2 0.3%
Death not associated with CTCAE term - Death NOS	1 0.2%	7 1.1%
Dehydration	27 4.3%	31 4.9%
Dermatology/Skin-Other (Specify)	0 0.0%	3 0.5%
Diarrhea	15 2.4%	19 3.0%
Dizziness	10 1.6%	7 1.1%
Dry eye syndrome	0 0.0%	1 0.2%
Dry mouth/salivary gland (xerostomia)	1 0.2%	0 0.0%
Dry skin	0 0.0%	6 1.0%
Dysphagia (difficulty swallowing)	1 0.2%	2 0.3%
Dyspnea (shortness of breath)	21 3.3%	33 5.3%
Edema: limb	1 0.2%	3 0.5%
Encephalopathy	1 0.2%	0 0.0%
Esophagitis	0 0.0%	2 0.3%
Extrapyramidal/involuntary movement/restlessness	0 0.0%	1 0.2%
Eyelid dysfunction	0 0.0%	1 0.2%
Fatigue (asthenia, lethargy, malaise)	74 11.7%	81 12.9%
Febrile neutropenia	27 4.3%	29 4.6%
Fever in absence of neutropenia, ANC lt1.0x10e9/L	2 0.3%	0 0.0%
GGT (gamma-glutamyl transpeptidase)	0 0.0%	1 0.2%
Gastritis (including bile reflux gastritis)	0 0.0%	3 0.5%
Gastrointestinal-Other (Specify)	1 0.2%	3 0.5%
Glucose, serum-high (hyperglycemia)	20 3.2%	13 2.1%
Glucose, serum-low (hypoglycemia)	2 0.3%	2 0.3%
Heartburn/dyspepsia	0 0.0%	1 0.2%
Hemoglobin	60 9.5%	48 7.7%
Hemolysis	0 0.0%	3 0.5%
Hemorrhage, GI - Abdomen NOS	0 0.0%	1 0.2%
Hemorrhage, GI - Duodenum	1 0.2%	1 0.2%
Hemorrhage, GI - Esophagus	1 0.2%	0 0.0%
Hemorrhage, GI - Jejunum	0 0.0%	1 0.2%
Hemorrhage, GI - Lower GI NOS	1 0.2%	0 0.0%
Hemorrhage, GI - Upper GI NOS	1 0.2%	2 0.3%
Hemorrhage, GI - Varices (esophageal)	1 0.2%	0 0.0%
Hemorrhage, GI - Varices (rectal)	1 0.2%	0 0.0%
Hemorrhage, pulmo/upper resp- Bronchopulmonary NOS	1 0.2%	1 0.2%
Hemorrhage, pulmonary/upper respiratory - Lung	1 0.2%	3 0.5%
Hemorrhage, pulmonary/upper respiratory - Nose	2 0.3%	1 0.2%
Hemorrhage, pulmonary/upper respiratory - Pleura	1 0.2%	0 0.0%
Hemorrhage/Bleeding-Other (Specify)	1 0.2%	0 0.0%
Hiccoughs (hiccups, singultus)	1 0.2%	1 0.2%
Hot flashes/flushes	1 0.2%	1 0.2%
Hypertension	28 4.4%	17 2.7%
Hypotension	5 0.8%	11 1.8%
Hypoxia	2 0.3%	6 1.0%
INR (of prothrombin time)	0 0.0%	1 0.2%
Inf (clin/microbio) w/Gr 3-4 neuts - Blood	8 1.3%	10 1.6%
Inf (clin/microbio) w/Gr 3-4 neuts - Bronchus	1 0.2%	0 0.0%
Inf (clin/microbio) w/Gr 3-4 neuts - Catheter-rel	0 0.0%	1 0.2%
Inf (clin/microbio) w/Gr 3-4 neuts - Colon	1 0.2%	0 0.0%
Inf (clin/microbio) w/Gr 3-4 neuts - Duodenum	0 0.0%	1 0.2%
Inf (clin/microbio) w/Gr 3-4 neuts - Esophagus	0 0.0%	1 0.2%
Inf (clin/microbio) w/Gr 3-4 neuts - Lung	9 1.4%	7 1.1%
Inf (clin/microbio) w/Gr 3-4 neuts - Oral cav-gums	0 0.0%	1 0.2%
Inf (clin/microbio) w/Gr 3-4 neuts - Pleura	1 0.2%	0 0.0%
Inf (clin/microbio) w/Gr 3-4 neuts - Skin	1 0.2%	2 0.3%
Inf (clin/microbio) w/Gr 3-4 neuts - UTI	1 0.2%	2 0.3%
Inf w/normal ANC or Gr 1-2 neutrophils - Bladder	0 0.0%	1 0.2%
Inf w/normal ANC or Gr 1-2 neutrophils - Blood	2 0.3%	4 0.6%
Inf w/normal ANC or Gr 1-2 neutrophils - Catheter	1 0.2%	0 0.0%
Inf w/normal ANC or Gr 1-2 neutrophils - Dental	1 0.2%	0 0.0%
Inf w/normal ANC or Gr 1-2 neutrophils - Joint	1 0.2%	0 0.0%
Inf w/normal ANC or Gr 1-2 neutrophils - Lung	11 1.7%	8 1.3%
Inf w/normal ANC or Gr 1-2 neutrophils - Mucosa	1 0.2%	0 0.0%
Inf w/normal ANC or Gr 1-2 neutrophils - Pelvis	0 0.0%	1 0.2%
Inf w/normal ANC or Gr 1-2 neutrophils - Perit cav	1 0.2%	0 0.0%
Inf w/normal ANC or Gr 1-2 neutrophils - Pleura	0 0.0%	1 0.2%
Inf w/normal ANC or Gr 1-2 neutrophils - Skin	0 0.0%	5 0.8%
Inf w/normal ANC or Gr 1-2 neutrophils - UTI	1 0.2%	0 0.0%
Infection with unknown ANC - Blood	1 0.2%	1 0.2%
Infection with unknown ANC - Eye NOS	0 0.0%	1 0.2%
Infection with unknown ANC - Lung (pneumonia)	5 0.8%	3 0.5%
Infection with unknown ANC - Sinus	2 0.3%	0 0.0%
Infection with unknown ANC - Skin (cellulitis)	0 0.0%	1 0.2%
Infection with unknown ANC - Upper airway NOS	0 0.0%	1 0.2%
Infection with unknown ANC - Urinary tract NOS	2 0.3%	1 0.2%
Infection with unknown ANC - Wound	0 0.0%	1 0.2%
Infection-Other (Specify)	4 0.6%	2 0.3%
Insomnia	1 0.2%	5 0.8%
Irregular menses (change from baseline)	0 0.0%	1 0.2%
Leukocytes (total WBC)	74 11.7%	103 16.4%
Leukoencephalopathy (radiolographic findings)	1 0.2%	0 0.0%
Local complication - device/prosthesis-related	0 0.0%	1 0.2%
Lymphopenia	39 6.2%	60 9.6%
Magnesium, serum-high (hypermagnesemia)	0 0.0%	1 0.2%
Magnesium, serum-low (hypomagnesemia)	6 0.9%	28 4.5%
Memory impairment	0 0.0%	1 0.2%
Mental status	0 0.0%	1 0.2%
Metabolic/Laboratory-Other (Specify)	1 0.2%	0 0.0%
Mood alteration - anxiety	0 0.0%	1 0.2%
Mood alteration - depression	3 0.5%	2 0.3%
Mucositis/stomatitis (clinical exam) - Esophagus	1 0.2%	0 0.0%
Mucositis/stomatitis (clinical exam) - Oral cavity	2 0.3%	6 1.0%
Mucositis/stomatitis (functional/symp) - Oral cav	0 0.0%	4 0.6%
Muscle weakness, not d/t neuropathy - Extrem-lower	6 0.9%	9 1.4%
Muscle weakness, not d/t neuropathy - Extrem-upper	0 0.0%	1 0.2%
Muscle weakness, not d/t neuropathy - Pelvic	0 0.0%	1 0.2%
Muscle weakness, not d/t neuropathy - body/general	21 3.3%	33 5.3%
Nail changes	0 0.0%	4 0.6%
Nasal cavity/paranasal sinus reactions	0 0.0%	1 0.2%
Nausea	26 4.1%	30 4.8%
Neuroendocrine: ADH secretion abnormality	0 0.0%	2 0.3%
Neuropathy: motor	18 2.8%	10 1.6%
Neuropathy: sensory	57 9.0%	36 5.7%
Neutrophils/granulocytes (ANC/AGC)	158 25.0%	210 33.5%
Obstruction, GI - Small bowel NOS	0 0.0%	1 0.2%
Obstruction/stenosis of airway - Bronchus	1 0.2%	0 0.0%
Ocular/Visual-Other (Specify)	1 0.2%	1 0.2%
Opportunistic inf associated w/gt=Gr 2 lymphopenia	1 0.2%	0 0.0%
Pain - Abdomen NOS	5 0.8%	9 1.4%
Pain - Back	1 0.2%	2 0.3%
Pain - Bone	2 0.3%	1 0.2%
Pain - Chest wall	1 0.2%	2 0.3%
Pain - Chest/thorax NOS	1 0.2%	2 0.3%
Pain - Extremity-limb	10 1.6%	12 1.9%
Pain - Head/headache	2 0.3%	1 0.2%
Pain - Joint	19 3.0%	19 3.0%
Pain - Muscle	24 3.8%	14 2.2%
Pain - Neck	1 0.2%	0 0.0%
Pain - Neuralgia/peripheral nerve	1 0.2%	1 0.2%
Pain - Oral cavity	0 0.0%	1 0.2%
Pain - Peritoneum	1 0.2%	0 0.0%
Pain - Scrotum	1 0.2%	0 0.0%
Pain - Skin	0 0.0%	1 0.2%
Pain - Stomach	0 0.0%	1 0.2%
Pain-Other (Specify)	2 0.3%	3 0.5%
Pancreatitis	0 0.0%	1 0.2%
Perforation, GI - Colon	1 0.2%	6 1.0%
Perforation, GI - Duodenum	1 0.2%	0 0.0%
Perforation, GI - Small bowel NOS	0 0.0%	1 0.2%
Pericardial effusion (non-malignant)	0 0.0%	1 0.2%
Phosphate, serum-low (hypophosphatemia)	2 0.3%	8 1.3%
Platelets	51 8.1%	43 6.9%
Pleural effusion (non-malignant)	1 0.2%	0 0.0%
Pneumonitis/pulmonary infiltrates	2 0.3%	8 1.3%
Potassium, serum-high (hyperkalemia)	1 0.2%	4 0.6%
Potassium, serum-low (hypokalemia)	22 3.5%	35 5.6%
Proteinuria	4 0.6%	7 1.1%
Pruritus/itching	0 0.0%	7 1.1%
Pulmonary/Upper Respiratory-Other (Specify)	2 0.3%	2 0.3%
Rash/desquamation	1 0.2%	6 1.0%
Rash: acne/acneiform	0 0.0%	50 8.0%
Rash: hand-foot skin reaction	0 0.0%	4 0.6%
Renal failure	0 0.0%	2 0.3%
Renal/Genitourinary-Other (Specify)	3 0.5%	0 0.0%
SVT and nodal arrhythmia - Atrial fibrillation	2 0.3%	0 0.0%
SVT and nodal arrhythmia - Atrial flutter	1 0.2%	1 0.2%
SVT and nodal arrhythmia - SVT tachycardia	1 0.2%	1 0.2%
SVT and nodal arrhythmia - Sinus tachycardia	1 0.2%	0 0.0%
Seizure	0 0.0%	2 0.3%
Sodium, serum-low (hyponatremia)	29 4.6%	27 4.3%
Somnolence/depressed level of consciousness	1 0.2%	2 0.3%
Sudden death	0 0.0%	1 0.2%
Syncope (fainting)	8 1.3%	7 1.1%
Syndromes-Other (Specify)	0 0.0%	2 0.3%
Thrombosis/embolism (vascular access-related)	0 0.0%	4 0.6%
Thrombosis/thrombus/embolism	26 4.1%	37 5.9%
Tinnitus	0 0.0%	1 0.2%
Tremor	0 0.0%	1 0.2%
Tumor lysis syndrome	0 0.0%	1 0.2%
Typhlitis (cecal inflammation)	1 0.2%	0 0.0%
Ulcer, GI - Duodenum	1 0.2%	1 0.2%
Ulcer, GI - Stomach	0 0.0%	1 0.2%
Ulceration	0 0.0%	1 0.2%
Uric acid, serum-high (hyperuricemia)	1 0.2%	0 0.0%
Urticaria (hives, welts, wheals)	0 0.0%	4 0.6%
Ventricular arrhythmia - Ventricular tachycardia	1 0.2%	0 0.0%
Ventricular arrhythmia NOS	0 0.0%	1 0.2%
Visceral arterial ischemia (non-myocardial)	0 0.0%	1 0.2%
Vomiting	19 3.0%	18 2.9%
Weight gain	0 0.0%	1 0.2%
Weight loss	8 1.3%	4 0.6%
Wound complication, non-infectious	0 0.0%	1 0.2%

Adverse Events

Time Frame	Toxicity assessment was evaluated every 3 weeks while on protocol treatment. Chemo and cetuximab is treated for 6 cycles (1 cycle =3 weeks) and Bevacizumab is treated until progression, an average of 6 months.
Adverse Event Reporting Description	Limited to eligible patients who started treatment, who did not have a major deviation in the treatment protocol, and whose toxicity profile has been completed.
Arm/Group Title	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
Arm/Group Description	Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV	Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Carboplatin: Given IV Cetuximab: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV
All-Cause Mortality
	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	593/657 (90.26%)	570/656 (86.89%)
Serious Adverse Events
	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	66/632 (10.44%)	97/627 (15.47%)
Blood and lymphatic system disorders
DIC (disseminated intravascular coagulation) † 1	0/632 (0.00%)	1/627 (0.16%)
Febrile neutropenia † 1	5/632 (0.79%)	3/627 (0.48%)
Hemoglobin † 1	2/632 (0.32%)	1/627 (0.16%)
Thrombotic microangiopathy † 1	0/632 (0.00%)	1/627 (0.16%)
Cardiac disorders
Cardiac General-Other † 1	3/632 (0.47%)	3/627 (0.48%)
Cardiac-ischemia/infarction † 1	2/632 (0.32%)	1/627 (0.16%)
Cardiopulmonary arrest, cause unknown (non-fatal) † 1	1/632 (0.16%)	2/627 (0.32%)
SVT and nodal arrhythmia - Atrial fibrillation † 1	2/632 (0.32%)	0/627 (0.00%)
Ventricular arrhythmia NOS † 1	0/632 (0.00%)	1/627 (0.16%)
Endocrine disorders
Adrenal insufficiency † 1	0/632 (0.00%)	1/627 (0.16%)
Gastrointestinal disorders
Colitis † 1	1/632 (0.16%)	0/627 (0.00%)
Constipation † 1	0/632 (0.00%)	1/627 (0.16%)
Diarrhea † 1	0/632 (0.00%)	1/627 (0.16%)
Gastrointestinal-Other † 1	1/632 (0.16%)	2/627 (0.32%)
Hemorrhage, GI - Duodenum † 1	1/632 (0.16%)	0/627 (0.00%)
Hemorrhage, GI - Esophagus † 1	1/632 (0.16%)	0/627 (0.00%)
Hemorrhage, GI - Upper GI NOS † 1	0/632 (0.00%)	1/627 (0.16%)
Perforation, GI - Colon † 1	0/632 (0.00%)	4/627 (0.64%)
Perforation, GI - Duodenum † 1	1/632 (0.16%)	0/627 (0.00%)
Perforation, GI - Stomach † 1	1/632 (0.16%)	0/627 (0.00%)
Ulcer, GI - Duodenum † 1	1/632 (0.16%)	0/627 (0.00%)
General disorders
Death - Multi-organ failure † 1	0/632 (0.00%)	2/627 (0.32%)
Death not associated with CTCAE term - Death NOS † 1	12/632 (1.90%)	12/627 (1.91%)
Sudden death † 1	0/632 (0.00%)	1/627 (0.16%)
Syndromes-Other † 1	1/632 (0.16%)	1/627 (0.16%)
Hepatobiliary disorders
Liver dysfunction/failure (clinical) † 1	0/632 (0.00%)	1/627 (0.16%)
Immune system disorders
Allergic reaction/hypersensitivity † 1	0/632 (0.00%)	8/627 (1.28%)
Cytokine release syndrome/acute infusion reaction † 1	0/632 (0.00%)	3/627 (0.48%)
Infections and infestations
Inf (clin/microbio) w/Gr 3-4 neuts - Blood † 1	0/632 (0.00%)	5/627 (0.80%)
Inf (clin/microbio) w/Gr 3-4 neuts - Esophagus † 1	0/632 (0.00%)	1/627 (0.16%)
Inf (clin/microbio) w/Gr 3-4 neuts - Lung † 1	1/632 (0.16%)	0/627 (0.00%)
Inf w/normal ANC or Gr 1-2 neutrophils - Blood † 1	1/632 (0.16%)	1/627 (0.16%)
Inf w/normal ANC or Gr 1-2 neutrophils - Lung † 1	0/632 (0.00%)	2/627 (0.32%)
Infection with unknown ANC - Blood † 1	2/632 (0.32%)	1/627 (0.16%)
Injury, poisoning and procedural complications
Intra-operative Injury-Other † 1	1/632 (0.16%)	0/627 (0.00%)
Vessel injury-artery - Aorta † 1	1/632 (0.16%)	0/627 (0.00%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase) † 1	0/632 (0.00%)	1/627 (0.16%)
AST, SGOT † 1	0/632 (0.00%)	1/627 (0.16%)
Carbon monoxide diffusion capacity (DL(co)) † 1	8/632 (1.27%)	8/627 (1.28%)
Creatinine † 1	1/632 (0.16%)	0/627 (0.00%)
Leukocytes (total WBC) † 1	0/632 (0.00%)	1/627 (0.16%)
Lymphopenia † 1	0/632 (0.00%)	1/627 (0.16%)
Neuroendocrine: ADH secretion abnormality † 1	0/632 (0.00%)	1/627 (0.16%)
Neutrophils/granulocytes (ANC/AGC) † 1	1/632 (0.16%)	1/627 (0.16%)
Platelets † 1	0/632 (0.00%)	3/627 (0.48%)
Metabolism and nutrition disorders
Acidosis (metabolic or respiratory) † 1	1/632 (0.16%)	0/627 (0.00%)
Anorexia † 1	0/632 (0.00%)	1/627 (0.16%)
Dehydration † 1	1/632 (0.16%)	1/627 (0.16%)
Magnesium, serum-low (hypomagnesemia) † 1	0/632 (0.00%)	1/627 (0.16%)
Potassium, serum-high (hyperkalemia) † 1	0/632 (0.00%)	2/627 (0.32%)
Potassium, serum-low (hypokalemia) † 1	1/632 (0.16%)	1/627 (0.16%)
Sodium, serum-low (hyponatremia) † 1	2/632 (0.32%)	3/627 (0.48%)
Uric acid, serum-high (hyperuricemia) † 1	1/632 (0.16%)	0/627 (0.00%)
Musculoskeletal and connective tissue disorders
Muscle weakness, not d/t neuropathy - body/general † 1	1/632 (0.16%)	0/627 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death - Disease progression NOS † 1	9/632 (1.42%)	17/627 (2.71%)
Tumor flare † 1	1/632 (0.16%)	0/627 (0.00%)
Nervous system disorders
CNS cerebrovascular ischemia † 1	1/632 (0.16%)	3/627 (0.48%)
Neurology-Other † 1	0/632 (0.00%)	1/627 (0.16%)
Renal and urinary disorders
Renal failure † 1	1/632 (0.16%)	0/627 (0.00%)
Respiratory, thoracic and mediastinal disorders
Aspiration † 1	0/632 (0.00%)	2/627 (0.32%)
Carbon monoxide diffusion capacity (DL(co)) † 1	8/632 (1.27%)	8/627 (1.28%)
Dyspnea (shortness of breath) † 1	6/632 (0.95%)	5/627 (0.80%)
Hemorrhage, pulmo/upper resp- Bronchopulmonary NOS † 1	1/632 (0.16%)	2/627 (0.32%)
Hemorrhage, pulmonary/upper respiratory - Lung † 1	0/632 (0.00%)	1/627 (0.16%)
Hemorrhage, pulmonary/upper respiratory - Pleura † 1	1/632 (0.16%)	0/627 (0.00%)
Hypoxia † 1	2/632 (0.32%)	2/627 (0.32%)
Obstruction/stenosis of airway - Bronchus † 1	1/632 (0.16%)	0/627 (0.00%)
Pleural effusion (non-malignant) † 1	0/632 (0.00%)	3/627 (0.48%)
Pneumonitis/pulmonary infiltrates † 1	1/632 (0.16%)	2/627 (0.32%)
Pulmonary/Upper Respiratory-Other † 1	2/632 (0.32%)	2/627 (0.32%)
Voice changes/dysarthria † 1	0/632 (0.00%)	1/627 (0.16%)
Vascular disorders
Hypertension † 1	1/632 (0.16%)	0/627 (0.00%)
Hypotension † 1	0/632 (0.00%)	4/627 (0.64%)
Thrombosis/thrombus/embolism † 1	4/632 (0.63%)	4/627 (0.64%)
Visceral arterial ischemia (non-myocardial) † 1	0/632 (0.00%)	1/627 (0.16%)
1 Term from vocabulary, CTCAE (3.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Arm I (Chemo +/- Bevacizumab)	Arm II (Chemo, Cetuximab, +/- Bevacizumab)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	619/632 (97.94%)	611/627 (97.45%)
Blood and lymphatic system disorders
Hemoglobin † 1	434/632 (68.67%)	384/627 (61.24%)
Eye disorders
Vision-blurred vision † 1	38/632 (6.01%)	33/627 (5.26%)
Gastrointestinal disorders
Constipation † 1	261/632 (41.30%)	302/627 (48.17%)
Diarrhea † 1	195/632 (30.85%)	243/627 (38.76%)
Heartburn/dyspepsia † 1	70/632 (11.08%)	109/627 (17.38%)
Mucositis/stomatitis (clinical exam) - Oral cavity † 1	74/632 (11.71%)	162/627 (25.84%)
Mucositis/stomatitis (functional/symp) - Oral cav † 1	36/632 (5.70%)	74/627 (11.80%)
Nausea † 1	304/632 (48.10%)	318/627 (50.72%)
Pain - Abdomen NOS † 1	60/632 (9.49%)	86/627 (13.72%)
Vomiting † 1	150/632 (23.73%)	168/627 (26.79%)
General disorders
Edema: limb † 1	80/632 (12.66%)	84/627 (13.40%)
Fatigue (asthenia, lethargy, malaise) † 1	494/632 (78.16%)	474/627 (75.60%)
Fever in absence of neutropenia, ANC lt1.0x10e9/L † 1	56/632 (8.86%)	47/627 (7.50%)
Pain - Chest/thorax NOS † 1	72/632 (11.39%)	72/627 (11.48%)
Pain-Other † 1	63/632 (9.97%)	80/627 (12.76%)
Rigors/chills † 1	49/632 (7.75%)	56/627 (8.93%)
Immune system disorders
Allergic reaction/hypersensitivity † 1	37/632 (5.85%)	90/627 (14.35%)
Infections and infestations
Infection-Other † 1	35/632 (5.54%)	53/627 (8.45%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase) † 1	82/632 (12.97%)	148/627 (23.60%)
AST, SGOT † 1	81/632 (12.82%)	141/627 (22.49%)
Alkaline phosphatase † 1	138/632 (21.84%)	169/627 (26.95%)
Bilirubin (hyperbilirubinemia) † 1	30/632 (4.75%)	32/627 (5.10%)
Creatinine † 1	52/632 (8.23%)	45/627 (7.18%)
Leukocytes (total WBC) † 1	258/632 (40.82%)	289/627 (46.09%)
Lymphopenia † 1	139/632 (21.99%)	166/627 (26.48%)
Metabolic/Laboratory-Other † 1	39/632 (6.17%)	49/627 (7.81%)
Neutrophils/granulocytes (ANC/AGC) † 1	252/632 (39.87%)	305/627 (48.64%)
Platelets † 1	270/632 (42.72%)	233/627 (37.16%)
Weight loss † 1	163/632 (25.79%)	181/627 (28.87%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia) † 1	211/632 (33.39%)	244/627 (38.92%)
Anorexia † 1	245/632 (38.77%)	241/627 (38.44%)
Calcium, serum-low (hypocalcemia) † 1	117/632 (18.51%)	179/627 (28.55%)
Dehydration † 1	104/632 (16.46%)	118/627 (18.82%)
Glucose, serum-high (hyperglycemia) † 1	290/632 (45.89%)	266/627 (42.42%)
Magnesium, serum-low (hypomagnesemia) † 1	201/632 (31.80%)	349/627 (55.66%)
Potassium, serum-high (hyperkalemia) † 1	34/632 (5.38%)	34/627 (5.42%)
Potassium, serum-low (hypokalemia) † 1	135/632 (21.36%)	200/627 (31.90%)
Sodium, serum-low (hyponatremia) † 1	194/632 (30.70%)	205/627 (32.70%)
Musculoskeletal and connective tissue disorders
Muscle weakness, not d/t neuropathy - Extrem-lower † 1	56/632 (8.86%)	59/627 (9.41%)
Muscle weakness, not d/t neuropathy - body/general † 1	110/632 (17.41%)	122/627 (19.46%)
Pain - Back † 1	109/632 (17.25%)	126/627 (20.10%)
Pain - Bone † 1	50/632 (7.91%)	60/627 (9.57%)
Pain - Chest wall † 1	43/632 (6.80%)	38/627 (6.06%)
Pain - Extremity-limb † 1	131/632 (20.73%)	150/627 (23.92%)
Pain - Joint † 1	192/632 (30.38%)	194/627 (30.94%)
Pain - Muscle † 1	160/632 (25.32%)	149/627 (23.76%)
Nervous system disorders
Dizziness † 1	129/632 (20.41%)	167/627 (26.63%)
Neuropathy: motor † 1	62/632 (9.81%)	67/627 (10.69%)
Neuropathy: sensory † 1	386/632 (61.08%)	368/627 (58.69%)
Pain - Head/headache † 1	80/632 (12.66%)	84/627 (13.40%)
Taste alteration (dysgeusia) † 1	131/632 (20.73%)	147/627 (23.44%)
Psychiatric disorders
Confusion † 1	31/632 (4.91%)	40/627 (6.38%)
Insomnia † 1	95/632 (15.03%)	131/627 (20.89%)
Mood alteration - anxiety † 1	61/632 (9.65%)	70/627 (11.16%)
Mood alteration - depression † 1	58/632 (9.18%)	60/627 (9.57%)
Renal and urinary disorders
Proteinuria † 1	36/632 (5.70%)	50/627 (7.97%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis † 1	48/632 (7.59%)	66/627 (10.53%)
Cough † 1	239/632 (37.82%)	248/627 (39.55%)
Dyspnea (shortness of breath) † 1	285/632 (45.09%)	290/627 (46.25%)
Hemorrhage, pulmonary/upper respiratory - Nose † 1	86/632 (13.61%)	115/627 (18.34%)
Pulmonary/Upper Respiratory-Other † 1	23/632 (3.64%)	38/627 (6.06%)
Voice changes/dysarthria † 1	40/632 (6.33%)	37/627 (5.90%)
Skin and subcutaneous tissue disorders
Dermatology/Skin-Other † 1	17/632 (2.69%)	82/627 (13.08%)
Dry skin † 1	64/632 (10.13%)	220/627 (35.09%)
Hair loss/Alopecia (scalp or body) † 1	315/632 (49.84%)	293/627 (46.73%)
Nail changes † 1	37/632 (5.85%)	67/627 (10.69%)
Pruritus/itching † 1	49/632 (7.75%)	122/627 (19.46%)
Rash/desquamation † 1	42/632 (6.65%)	155/627 (24.72%)
Rash: acne/acneiform † 1	40/632 (6.33%)	425/627 (67.78%)
Rash: hand-foot skin reaction † 1	4/632 (0.63%)	54/627 (8.61%)
Vascular disorders
Hypertension † 1	124/632 (19.62%)	96/627 (15.31%)
Hypotension † 1	55/632 (8.70%)	79/627 (12.60%)
Thrombosis/thrombus/embolism † 1	54/632 (8.54%)	68/627 (10.85%)
1 Term from vocabulary, CTCAE (3.0); † 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.

Results Point of Contact

• Name/Title: Lung Committee Statistican
• Organization: SWOG Statistics & Data Management Center
• Phone: 2066675712
• EMail: jmiao@fredhutch.org

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

Hirsch FR, Redman MW, Moon J, Agustoni F, Herbst RS, Semrad TJ, Varella-Garcia M, Rivard CJ, Kelly K, Gandara DR, Mack PC. EGFR High Copy Number Together With High EGFR Protein Expression Predicts Improved Outcome for Cetuximab-based Therapy in Squamous Cell Lung Cancer: Analysis From SWOG S0819, a Phase III Trial of Chemotherapy With or Without Cetuximab in Advanced NSCLC. Clin Lung Cancer. 2022 Jan;23(1):60-71. doi: 10.1016/j.cllc.2021.10.002. Epub 2021 Oct 10.

Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. doi: 10.1016/S1470-2045(17)30694-0. Epub 2017 Nov 20.

• Responsible Party: SWOG Cancer Research Network
• ClinicalTrials.gov Identifier: NCT00946712
• Other Study ID Numbers: S0819; NCI-2009-01664 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000649817; S0819 ( Other Identifier: SWOG ); S0819 ( Other Identifier: CTEP ); U10CA180888 ( U.S. NIH Grant/Contract ); U10CA032102 ( U.S. NIH Grant/Contract )
• First Submitted: July 24, 2009
• First Posted: July 27, 2009
• Results First Submitted: December 6, 2018
• Results First Posted: March 7, 2019
• Last Update Posted: May 23, 2023