A Study of Pemetrexed, Carboplatin and Bevacizumab in Participants With Nonsquamous Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT00762034
• Recruitment Status: Completed
• First Posted: September 30, 2008
• Results First Posted: November 28, 2013
• Last Update Posted: December 21, 2015
• 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; Drug: Paclitaxel; Drug: Carboplatin; Biological: Bevacizumab
• Enrollment: 939

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Period Title: Induction Period
Started	472	467
Received at Least 1 Dose of Study Drug	442	443
Completed	294	298
Not Completed	178	169
Reason Not Completed
Protocol Violation	1	2
Entry Criterion Not Met	12	11
Adverse Event	27	38
Lost to Follow-up	1	1
Progressive Disease	73	55
Physician Decision	21	20
Withdrawal by Subject	15	19
Deaths Not Due to Study Disease	19	14
Deaths Due to Study Disease	9	9
Period Title: Maintenance Period
Started	294	298
Received at Least 1 Dose of Study Drug	294	298
Completed	0	0
Not Completed	294	298
Reason Not Completed
Protocol Violation	1	3
Entry Criterion Not Met	0	2
Adverse Event	42	26
Progressive Disease	186	224
Physician Decision	25	20
Withdrawal by Subject	34	14
Death not due to study disease	2	5
Death due to study disease	3	3
Other	1	1

Baseline Characteristics

Arm/Group Title		Pem/Carbo/Bev	Pac/Carbo/Bev	Total
Arm/Group Description		Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Total of all reporting groups
Overall Number of Baseline Participants		472	467	939
Baseline Analysis Population Description		All randomized participants.
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	472 participants	467 participants	939 participants
<=65 years		249	236	485
>65 years		223	231	454
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	472 participants	467 participants	939 participants
	Female	221 46.8%	218 46.7%	439 46.8%
	Male	251 53.2%	249 53.3%	500 53.2%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	472 participants	467 participants	939 participants
Caucasian		409	396	805
Black or African American		42	52	94
Asian		15	14	29
American Indian or Alaska Native		1	1	2
Multiple race/ethnicities		2	3	5
Information not provided		3	1	4
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	472 participants	467 participants	939 participants
		472	467	939
Previously Treated Brain Metastasis; Measure Type: Number; Unit of measure: Participants	Number Analyzed	472 participants	467 participants	939 participants
Yes		52	52	104
No		420	415	835
Histological Subtype [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	472 participants	467 participants	939 participants
Adenocarcinoma, Lung		367	360	727
Bronchioalveolar Carcinoma		4	3	7
Large Cell Lung Carcinoma		8	15	23
NSCLC Not Otherwise Specified		47	39	86
NSCLC Poorly Differentiated		39	47	86
Predominantly Adenocarcinoma		7	2	9
Unknown		0	1	1
		[1] Measure Description: Non-small Cell Lung Carcinoma (NSCLC)
Histological Category for Subgroup Analyses; Measure Type: Number; Unit of measure: Participants	Number Analyzed	472 participants	467 participants	939 participants
Adenocarcinoma		378	365	743
Large Cell Carcinoma		8	15	23
Other or Indeterminant		86	86	172
Unknown		0	1	1

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time Frame	Baseline to date of death from any cause (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants using the intent-to-treat principle. Number of participants censored: n=131, 127 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	467
Median (95% Confidence Interval); Unit of Measure: months
	12.55; (11.30 to 14.03)	13.40; (11.86 to 14.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.94896
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.16
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Percentage of Participants With a Complete Response (CR) and Partial Response (PR) (Overall Response Rate)
Description	Overall Response Rate (ORR) is the number of participants with a Complete Response (CR) and Partial Response (PR) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared to baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions.
Time Frame	Baseline to measured progressive disease (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants using the intent-to-treat principle

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	467
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	34.1; (29.8 to 38.6)	33.0; (28.7 to 37.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.72997
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

3. Secondary Outcome

Title	Percentage of Participants With a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate)
Description	Disease Control Rate (DCR) is the number of participants with a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared with baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions. Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions compared with the smallest sum of the longest diameter recorded since the start of treatment or the appearance of 1 or more new lesion(s). Stable Disease (SD) was defined as small changes that did not meet above criteria.
Time Frame	Baseline to measured progressive disease (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants using the intent-to-treat principle

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	467
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	65.9; (61.4 to 70.2)	69.8; (65.4 to 73.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.20892
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

4. Secondary Outcome

Title	Progression Free Survival Time
Description	Progression free survival (PFS) is defined as the time from date of randomization to the date of objective disease progression or death due to any cause. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier.
Time Frame	Baseline to measured progressive disease or date of death from any cause (up to 33.54 months)

Outcome Measure Data

Analysis Population Description

All randomized participants using the intent-to-treat principle. Number of participants censored: n=127, 109 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	467
Median (95% Confidence Interval); Unit of Measure: months
	6.04; (5.55 to 6.87)	5.55; (5.39 to 5.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.01206
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.71 to 0.96
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Time to Progressive Disease
Description	Time to progressive disease was defined as the time from randomization to the first date of objective disease progression. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier.
Time Frame	Baseline to measured progressive disease (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants using the intent-to-treat principle. Number of participants censored: n=198, 172 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	467
Median (95% Confidence Interval); Unit of Measure: months
	7.03; (6.24 to 8.05)	6.04; (5.58 to 6.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.006
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.94
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Safety and Toxicity Profile of Study Treatments
Description	Safety and toxicity profile was defined as serious and other non-serious adverse events. A summary of serious and all other non-serious adverse events is located in the Reported Adverse Event module.
Time Frame	Baseline to study endpoint (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug during the specified treatment phase.

Arm/Group Title	Pem/Carbo/Bev; Induction Phase	Pem/Carbo/Bev; Maintenance Phase	Pac/Carbo/Bev; Induction Phase	Pac/Carbo/Bev; Maintenance Phase
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	442	292	443	298
Measure Type: Number; Unit of Measure: participants
Serious Adverse Events (SAEs)	111	83	123	68
Other Adverse Events (AEs)	432	288	431	296

7. Secondary Outcome

Title	Duration of Hospitalizations Per Participant
Description	Length of hospitalization in participants hospitalized during the study or within 30 days of discontinuation regardless of whether the hospitalization was or was not due to study drug.
Time Frame	Baseline to study endpoint (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had at least one hospitalization while on study or within 30 days of discontinuation.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	177	172
Mean (Standard Deviation); Unit of Measure: days
	9.4 (9.8)	8.0 (6.7)

8. Secondary Outcome

Title	Number of Participants Who Received a Transfusion
Description	[Not Specified]
Time Frame	Baseline to study endpoint (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	442	443
Measure Type: Number; Unit of Measure: participants
	116	44

9. Secondary Outcome

Title	Number of Participants Receiving Concomitant Medication
Description	[Not Specified]
Time Frame	Baseline to study endpoint (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	467
Measure Type: Number; Unit of Measure: participants
	406	421

10. Secondary Outcome

Title	Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - General (FACT-G)
Description	The FACT-G is a validated instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item questionnaire and is organized into subscales, each designed to assess a QOL domain: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items. Each item uses a 5 point rating scale (0="not at all" and 4=equals "very much"). FACT-G Total is the sum of the scores of all 4 subscales and ranges from 0 to 108. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time Frame	Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)

Outcome Measure Data

Analysis Population Description

The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT-G data, using the intent-to-treat principle.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	462
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	0.51 (0.54)	0.18 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.667
	Comments	Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

11. Secondary Outcome

Title	Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L)
Description	FACT-L is a valid instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item FACT-General (G) and 9-item lung cancer subscale (LCS). FACT-G is organized into subscales: physical well-being (PWB)–7 items; social/family well-being (SWB)–7 items; emotional well-being (EWB)–6 items; functional well-being (FWB)–7 items. Each item uses a 5 point rating scale (0=“not at all” and 4=equals “very much”). FACT-L Total Score=4 subscales + LCS and ranges from 0 to 144. Trial Outcome Index-Lung (TOI-L)=PWB+FWB+LCS and ranges from 0 to 92. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time Frame	Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)

Outcome Measure Data

Analysis Population Description

The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT-L, using the intent-to-treat principle.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	467
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
FACT-L Total Score (n=397, 392)	1.88 (0.65)	1.66 (0.66)
Trial Outcome Index-Lung (TOI-L) (n=396, 394)	-0.38 (0.50)	-0.40 (0.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.815
	Comments	p-value for FACT-L Total; Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.978
	Comments	p-value for FACT-L TOI; Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

12. Secondary Outcome

Title	Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx)
Description	FACT/GOG-Ntx is a validated instrument used to measure quality of life (QOL) in participants with cancer and neurotoxicity (Ntx) consisting of 27-item FACT-General (G) and 11-item Ntx subscale. FACT-G is organized into domain subscales: physical well-being (PWB)–7 items; social/family well-being (SWB)–7 items; emotional well-being (EWB)–6 items; functional well-being (FWB)–7 items; each uses a 5 point rating scale (0=“not at all” and 4=equals “very much”). FACT/GOG-Ntx Total Score=sum 5 subscales and ranges from 0-152. Ntx Trial Outcome Index (TOI-Ntx)=PWB+FWB+NTX and range from 0-100. For all FACT scales, higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time Frame	Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)

Outcome Measure Data

Analysis Population Description

The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT/GOG-Ntx data, using the intent-to-treat principle.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	472	467
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
FACT/GOG-Ntx Total Score (n=393, 389)	-0.60 (0.70)	-5.48 (0.70)
Ntx Trial Outcome Index (TOI-Ntx)(n=393, 390)	-2.79 (0.55)	-7.60 (0.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	p-value for FACT/GOG-Ntx Total; Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	p-value for FACT/GOG-Ntx TOI; Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

13. Secondary Outcome

Title	Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Pemetrexed
Description	[Not Specified]
Time Frame	Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable Cmax data.

Arm/Group Title	Pem/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev)followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	14
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: micrograms per milliliter (μg/mL)
	122; (20%)

14. Secondary Outcome

Title	Pharmacokinetics (PK): Elimination Half-life (t1/2) for Pemetrexed
Description	[Not Specified]
Time Frame	Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable t1/2 data.

Arm/Group Title	Pem/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	15
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: hours (hr)
	2.88; (13%)

15. Secondary Outcome

Title	Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Pemetrexed
Description	[Not Specified]
Time Frame	Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable AUC(0-∞) data.

Arm/Group Title	Pem/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	15
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: microgram*hour per milliliter (μg•hr/mL)
	203; (23%)

16. Secondary Outcome

Title	Pharmacokinetics (PK): Pemetrexed Clearance (CL)
Description	[Not Specified]
Time Frame	Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable CL data.

Arm/Group Title	Pem/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	15
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: milliliters per minute (mL/min)
	72.1; (25%)

17. Secondary Outcome

Title	Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum
Description	Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time Frame	Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)

Outcome Measure Data

Analysis Population Description

Randomized participants who received study drug and had evaluable Cmax data.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	20	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: micrograms per milliliter (μg/mL)
Total (Bound and Unbound)	18.4; (24%)	17.8; (33%)
Unbound (n=18, 15)	21.1; (31%)	17.1; (34%)

18. Secondary Outcome

Title	Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum
Description	Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time Frame	Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)

Outcome Measure Data

Analysis Population Description

Randomized participants who received study drug and had evaluable t1/2 data.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	18	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: hours (hr)
Total (Bound and Unbound)	65.6; (69%)	86.4; (21%)
Unbound (n=17, 13)	2.03; (15%)	1.95; (21%)

19. Secondary Outcome

Title	Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum
Description	Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time Frame	Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)

Outcome Measure Data

Analysis Population Description

Randomized participants who received study drug and had evaluable AUC(0-∞) data.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	18	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: microgram*hour per milliliter (μg•hr/mL)
Total (Bound and Unbound)	160; (32%)	182; (24%)
Unbound (n=17, 13)	55.7; (33%)	62.9; (34%)

20. Secondary Outcome

Title	Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms
Description	Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time Frame	Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)

Outcome Measure Data

Analysis Population Description

Randomized participants who received study drug and had evaluable CL data.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	18	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: liters per hour (L/hr)
Total (Bound and Unbound)	2.02; (39%)	1.87; (28%)
Unbound (n=17, 13)	5.81; (35%)	5.36; (47%)

21. Secondary Outcome

Title	Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Bevacizumab
Description	[Not Specified]
Time Frame	Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)

Outcome Measure Data

Analysis Population Description

Randomized participants who received study drug and had evaluable Cmax data.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	20	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: micrograms per milliliter (μg/mL)
	276; (18%)	302; (20%)

22. Secondary Outcome

Title	Pharmacokinetics (PK): Elimination Half-life (t1/2) for Bevacizumab
Description	[Not Specified]
Time Frame	Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)

Outcome Measure Data

Analysis Population Description

Randomized participants who received study drug and had evaluable t1/2 data.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	17	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: days
	14.8; (36%)	12.8; (46%)

23. Secondary Outcome

Title	Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) Bevacizumab
Description	[Not Specified]
Time Frame	Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)

Outcome Measure Data

Analysis Population Description

Randomized participants who received study drug and had evaluable AUC(0-∞) data.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	17	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: microgram*day per milliliter (μg•day/mL)
	3070; (29%)	3160; (33%)

24. Secondary Outcome

Title	Pharmacokinetics (PK): Bevacizumab Clearance (CL)
Description	[Not Specified]
Time Frame	Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)

Outcome Measure Data

Analysis Population Description

Randomized participants who received study drug and had evaluable CL data.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	17	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: liters per day (L/day)
	0.341; (31%)	0.376; (38%)

25. Secondary Outcome

Title	Translational Research: Number of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations
Description	Epidermal Growth Factor Receptor (EGFR) mutations were measured by polymerase chain reaction (PCR).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

All randomized participants with EGFR data regardless of study treatment.

Arm/Group Title	Pem or Pac Plus Carbo/Bev
Arm/Group Description:	Participants who received either Pem/Carbo/Bev or Pac/Carbo/Bev treatment. Pem/Carbo/Bev Treatment-500 mg per meter squared (mg/m^2) Pem IV every 21 days, plus Carbo AUC 6 IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21. OR Pac/Carbo/Bev Treatment-200 mg/m^2 Pac IV and AUC 6 Carbo IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21 days.
Overall Number of Participants Analyzed	132
Measure Type: Number; Unit of Measure: participants
EGFR mutation positive	11
EGFR mutation negative	121

26. Secondary Outcome

Title	Translational Research: Overall Survival (OS) Based on Nuclear Thyroid Transcription Factor-1 (TTF-1) Expression Regardless of Study Treatment
Description	Nuclear Thyroid Transcription Factor-1 (TTF-1) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TTF-1 Positive have an H score >0 and TTF-1 Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time Frame	Baseline to date of death from any cause (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with TTF-1 H scores regardless of study treatment. Participants censored: n=38, 11 in the TTF-1 Nuclear Positive and Negative arms, respectively.

Arm/Group Title	TTF-1 Positive (H Score > 0)	TTF-1 Negative (H Score = 0)
Arm/Group Description:	Participants who were TTF-1 Positive (H score > 0) and received either Pem/Carbo/Bev or Pac/Carbo/Bev treatment. Pem/Carbo/Bev Treatment-500 mg per meter squared (mg/m^2) Pem IV every 21 days, plus Carbo AUC 6 IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21. OR Pac/Carbo/Bev Treatment-200 mg/m^2 Pac IV and AUC 6 Carbo IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21 days.	Participants who were TTF-1 Negative (H score = 0) and received either Pem/Carbo/Bev or Pac/Carbo/Bev treatment. Pem/Carbo/Bev Treatment-500 mg per meter squared (mg/m^2) Pem IV every 21 days, plus Carbo AUC 6 IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21. OR Pac/Carbo/Bev Treatment-200 mg/m^2 Pac IV and AUC 6 Carbo IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21 days.
Overall Number of Participants Analyzed	139	66
Median (95% Confidence Interval); Unit of Measure: months
	14.9; (12.8 to 17.6)	8.7; (6.4 to 10.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TTF-1 Positive (H Score > 0), TTF-1 Negative (H Score = 0)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	p-value was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.480
	Confidence Interval	(2-Sided) 95%; 0.338 to 0.681
	Estimation Comments	[Not Specified]

27. Secondary Outcome

Title	Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression
Description	Cytoplasmic and nuclear Thymidylate Synthase (TS) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic and nuclear staining, and H score was calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TS Positive have an H score >0 and TS Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time Frame	Baseline to date of death from any cause (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with TS Cytoplasm and Nucleus H scores. Participants censored: TS Cytoplasm Positive n=23, 20 and Negative n=4, 1; TS Nucleus Positive n=17, 9 and Negative n=10, 12 for the Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	100	89
Median (95% Confidence Interval); Unit of Measure: months
TS Cytoplasm Positive (H score > 0; n=90, 83)	12.9; (10.8 to 16.9)	12.4; (10.9 to 15.5)
TS Cytoplasm Negative (H score = 0; n=10, 6)	18.2 [1]; (12.5 to NA)	11.6; (9.1 to 14.7)
TS Nucleus Positive (H score > 0; n=68, 51)	12.7; (9.7 to 15.4)	12.4; (8.4 to 15.5)
TS Nucleus Negative (H score = 0; n=32, 38)	19.2; (12.5 to 24.1)	12.4; (10.1 to 17.1)

[1]

Not calculable due to the low number of participants reaching endpoint event of death.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.673
	Comments	p-value is for TS Cytoplasm Positive (H score > 0) comparing treatment arms and was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.927
	Confidence Interval	(2-Sided) 95%; 0.654 to 1.316
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.287
	Comments	p-value is for TS Cytoplasm Negative (H score = 0) comparing treatment arms and was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.521
	Confidence Interval	(2-Sided) 95%; 0.157 to 1.729
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2
	Comments	p-value is for TS Nucleus Positive (H score > 0) comparing treatment arms and was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.759
	Confidence Interval	(2-Sided) 95%; 0.498 to 1.157
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.915
	Comments	p-value is for TS Nucleus Negative (H score = 0) comparing treatment arms and was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.969
	Confidence Interval	(2-Sided) 95%; 0.540 to 1.738
	Estimation Comments	[Not Specified]

28. Secondary Outcome

Title	Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression
Description	Cytoplasmic and membrane Folate Receptor Alpha (FR-α) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic or membrane staining, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). FR-α Positive have an H score >0 and FR-α Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time Frame	Baseline to date of death from any cause (up to 37.06 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with FR-α Cytoplasm or Membrane H scores. Participants censored: FR-α Positive Cytoplasm n=21, 15 and Negative n=4, 3; FR-α Membrane Positive n=16, 8 and Negative n=9, 10 for Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.

Arm/Group Title	Pem/Carbo/Bev	Pac/Carbo/Bev
Arm/Group Description:	Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days	Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation. Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days
Overall Number of Participants Analyzed	98	82
Median (95% Confidence Interval); Unit of Measure: months
FR-α Cytoplasm Positive (H score > 0; n=64, 53)	14.4; (11.4 to 22.2)	14.3; (11.2 to 18.2)
FR-α Cytoplasm Negative (H score = 0; n=34, 29)	12.0; (9.6 to 16.9)	11.2; (5.7 to 14.4)
FR-α Membrane Positive (H score > 0; n=39, 22)	19.2; (10.5 to 30.8)	15.5 [1]; (11.2 to NA)
FR-α Membrane Negative (H score = 0; n=59, 60)	12.9; (9.6 to 16.7)	11.3; (8.8 to 14.7)

[1]

Not calculable due to the low number of participants reaching endpoint event of death.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.891
	Comments	p-value for FR-α Cytoplasm Positive (H score > 0) comparing treatment arms and was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.970
	Confidence Interval	(2-Sided) 95%; 0.622 to 1.511
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.060
	Comments	p-value for FR-α Cytoplasm Negative (H score = 0) comparing treatment arms and was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.592
	Confidence Interval	(2-Sided) 95%; 0.342 to 1.023
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.905
	Comments	p-value for FR-α Membrane Positive (H score > 0) comparing treatment arms and was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.960
	Confidence Interval	(2-Sided) 95%; 0.490 to 1.880
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pem/Carbo/Bev, Pac/Carbo/Bev
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.455
	Comments	p-value for FR-α Membrane Negative (H score = 0) comparing treatment arms and was not adjusted for multiple comparisons.
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.859
	Confidence Interval	(2-Sided) 95%; 0.575 to 1.281
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Deaths due to progressive disease are not considered adverse events and reported in the participant flow. All randomized participants who received at least 1 dose of study drug during the specified treatment phase.
Arm/Group Title	Pem/Carbo/Bev		Pac/Carbo/Bev
Arm/Group Description	Induction: Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days Maintenance: Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.		Induction: Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m ²) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days Maintenance: Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.
All-Cause Mortality
	Pem/Carbo/Bev		Pac/Carbo/Bev
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Pem/Carbo/Bev		Pac/Carbo/Bev
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	188/442 (42.53%)		181/443 (40.86%)
Blood and lymphatic system disorders
Anaemia † 1	18/442 (4.07%)	50	5/443 (1.13%)	10
Febrile neutropenia † 1	6/442 (1.36%)	7	13/443 (2.93%)	13
Haemorrhagic anaemia † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Leukocytosis † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Leukopenia † 1	3/442 (0.68%)	7	0/443 (0.00%)	0
Microangiopathic haemolytic anaemia † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Neutropenia † 1	10/442 (2.26%)	15	9/443 (2.03%)	9
Pancytopenia † 1	3/442 (0.68%)	5	3/443 (0.68%)	3
Thrombocytopenia † 1	12/442 (2.71%)	20	3/443 (0.68%)	3
Cardiac disorders
Acute myocardial infarction † 1	0/442 (0.00%)	0	2/443 (0.45%)	4
Angina pectoris † 1	1/442 (0.23%)	1	3/443 (0.68%)	3
Atrial fibrillation † 1	1/442 (0.23%)	4	3/443 (0.68%)	3
Atrial flutter † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Cardiac arrest † 1	3/442 (0.68%)	3	2/443 (0.45%)	3
Cardiac failure congestive † 1	3/442 (0.68%)	3	3/443 (0.68%)	3
Cardio-respiratory arrest † 1	0/442 (0.00%)	0	3/443 (0.68%)	3
Cardiomegaly † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Cardiomyopathy † 1	1/442 (0.23%)	4	1/443 (0.23%)	2
Myocardial infarction † 1	6/442 (1.36%)	6	2/443 (0.45%)	2
Myocardial ischaemia † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Palpitations † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Pericardial effusion † 1	1/442 (0.23%)	1	2/443 (0.45%)	3
Pericarditis † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Sinus bradycardia † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Supraventricular tachycardia † 1	4/442 (0.90%)	4	1/443 (0.23%)	2
Ear and labyrinth disorders
Vertigo † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Endocrine disorders
Addison's disease † 1	0/442 (0.00%)	0	1/443 (0.23%)	8
Goitre † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Hypercalcaemia of malignancy † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Inappropriate antidiuretic hormone secretion † 1	2/442 (0.45%)	3	1/443 (0.23%)	1
Eye disorders
Diplopia † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Gastrointestinal disorders
Abdominal pain † 1	3/442 (0.68%)	5	6/443 (1.35%)	7
Abdominal pain upper † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Anal haemorrhage † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Constipation † 1	5/442 (1.13%)	6	4/443 (0.90%)	4
Diarrhoea † 1	4/442 (0.90%)	9	7/443 (1.58%)	9
Diverticular perforation † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Duodenal ulcer † 1	0/442 (0.00%)	0	1/443 (0.23%)	6
Duodenal ulcer haemorrhage † 1	2/442 (0.45%)	2	0/443 (0.00%)	0
Duodenitis † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Dysphagia † 1	1/442 (0.23%)	4	0/443 (0.00%)	0
Faecaloma † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Gastric ulcer † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Gastritis † 1	1/442 (0.23%)	1	1/443 (0.23%)	1
Gastrointestinal haemorrhage † 1	3/442 (0.68%)	4	5/443 (1.13%)	5
Gastrointestinal perforation † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Haematemesis † 1	1/442 (0.23%)	1	1/443 (0.23%)	1
Haemorrhoids † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Ileus † 1	1/442 (0.23%)	1	2/443 (0.45%)	4
Ileus paralytic † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Inguinal hernia † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Intestinal perforation † 1	2/442 (0.45%)	7	1/443 (0.23%)	1
Large intestine perforation † 1	1/442 (0.23%)	1	1/443 (0.23%)	1
Lower gastrointestinal haemorrhage † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Nausea † 1	9/442 (2.04%)	17	11/443 (2.48%)	21
Oesophageal obstruction † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Oesophagitis † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Pancreatitis † 1	0/442 (0.00%)	0	2/443 (0.45%)	2
Peptic ulcer † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Proctalgia † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Rectal haemorrhage † 1	2/442 (0.45%)	4	1/443 (0.23%)	1
Small intestinal obstruction † 1	2/442 (0.45%)	3	1/443 (0.23%)	1
Small intestinal perforation † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Stomatitis † 1	0/442 (0.00%)	0	2/443 (0.45%)	3
Upper gastrointestinal haemorrhage † 1	3/442 (0.68%)	6	1/443 (0.23%)	1
Vomiting † 1	13/442 (2.94%)	20	11/443 (2.48%)	12
General disorders
Asthenia † 1	2/442 (0.45%)	4	9/443 (2.03%)	15
Chest pain † 1	1/442 (0.23%)	1	2/443 (0.45%)	2
Death † 1	1/442 (0.23%)	1	2/443 (0.45%)	2
Device dislocation † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Device malfunction † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Fatigue † 1	1/442 (0.23%)	4	3/443 (0.68%)	5
Hypothermia † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Impaired healing † 1	0/442 (0.00%)	0	1/443 (0.23%)	7
Malaise † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Mucosal inflammation † 1	2/442 (0.45%)	3	0/443 (0.00%)	0
Multi-organ failure † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Non-cardiac chest pain † 1	5/442 (1.13%)	6	1/443 (0.23%)	1
Pain † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Pyrexia † 1	3/442 (0.68%)	4	4/443 (0.90%)	5
Hepatobiliary disorders
Acute hepatic failure † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Bile duct obstruction † 1	1/442 (0.23%)	1	1/443 (0.23%)	1
Cholecystitis † 1	0/442 (0.00%)	0	2/443 (0.45%)	3
Cholelithiasis † 1	0/442 (0.00%)	0	3/443 (0.68%)	3
Hepatic haemorrhage † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Hyperbilirubinaemia † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Immune system disorders
Drug hypersensitivity † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Hypersensitivity † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Infections and infestations
Appendicitis perforated † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Bacteraemia † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Bronchitis † 1	1/442 (0.23%)	1	2/443 (0.45%)	3
Cellulitis † 1	3/442 (0.68%)	5	3/443 (0.68%)	3
Clostridial infection † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Clostridium colitis † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Clostridium difficile colitis † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Device related sepsis † 1	2/442 (0.45%)	2	0/443 (0.00%)	0
Diverticulitis † 1	1/442 (0.23%)	1	3/443 (0.68%)	8
Empyema † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Enterobacter sepsis † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Gastroenteritis † 1	1/442 (0.23%)	1	2/443 (0.45%)	2
Hepatitis c † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Infection † 1	2/442 (0.45%)	2	0/443 (0.00%)	0
Infectious peritonitis † 1	2/442 (0.45%)	2	0/443 (0.00%)	0
Liver abscess † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Lobar pneumonia † 1	2/442 (0.45%)	2	1/443 (0.23%)	1
Lung infection pseudomonal † 1	1/442 (0.23%)	7	0/443 (0.00%)	0
Meningitis herpes † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Osteomyelitis † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Perirectal abscess † 1	1/442 (0.23%)	10	1/443 (0.23%)	2
Pneumonia † 1	28/442 (6.33%)	39	27/443 (6.09%)	42
Pneumonia pneumococcal † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Pneumonia streptococcal † 1	0/442 (0.00%)	0	1/443 (0.23%)	17
Pseudomonal sepsis † 1	1/442 (0.23%)	1	1/443 (0.23%)	2
Respiratory tract infection † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Retroperitoneal abscess † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Sepsis † 1	6/442 (1.36%)	7	2/443 (0.45%)	2
Sepsis syndrome † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Septic shock † 1	2/442 (0.45%)	3	0/443 (0.00%)	0
Staphylococcal bacteraemia † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Staphylococcal infection † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Staphylococcal sepsis † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Streptococcal bacteraemia † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Tooth abscess † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Upper respiratory tract infection † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Urinary tract infection † 1	0/442 (0.00%)	0	3/443 (0.68%)	4
Urinary tract infection bacterial † 1	1/442 (0.23%)	1	1/443 (0.23%)	1
Viral upper respiratory tract infection † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Wound abscess † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Injury, poisoning and procedural complications
Accidental overdose † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Compression fracture † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Fall † 1	1/442 (0.23%)	1	2/443 (0.45%)	3
Femur fracture † 1	2/442 (0.45%)	2	0/443 (0.00%)	0
Head injury † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Hip fracture † 1	1/442 (0.23%)	1	1/443 (0.23%)	2
Humerus fracture † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Lower limb fracture † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Overdose † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Radiation oesophagitis † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Rib fracture † 1	0/442 (0.00%)	0	1/443 (0.23%)	14
Road traffic accident † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Spinal compression fracture † 1	2/442 (0.45%)	15	1/443 (0.23%)	2
Wrong drug administered † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Investigations
Alanine aminotransferase increased † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Aspartate aminotransferase increased † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Aspiration pleural cavity † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
International normalised ratio increased † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Platelet count decreased † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Troponin i increased † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Metabolism and nutrition disorders
Decreased appetite † 1	1/442 (0.23%)	2	2/443 (0.45%)	3
Dehydration † 1	20/442 (4.52%)	27	21/443 (4.74%)	26
Electrolyte imbalance † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Failure to thrive † 1	1/442 (0.23%)	3	0/443 (0.00%)	0
Hypercalcaemia † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Hyperglycaemia † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Hyperkalaemia † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Hypocalcaemia † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Hypoglycaemia † 1	2/442 (0.45%)	3	1/443 (0.23%)	1
Hypokalaemia † 1	5/442 (1.13%)	8	2/443 (0.45%)	2
Hypomagnesaemia † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Hyponatraemia † 1	3/442 (0.68%)	4	8/443 (1.81%)	9
Hypophosphataemia † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Lactic acidosis † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Malnutrition † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Metabolic acidosis † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Metabolic alkalosis † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Starvation † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Tumour lysis syndrome † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/442 (0.23%)	2	2/443 (0.45%)	11
Back pain † 1	2/442 (0.45%)	8	4/443 (0.90%)	9
Bone pain † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Fracture nonunion † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Groin pain † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Muscular weakness † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Musculoskeletal pain † 1	1/442 (0.23%)	1	2/443 (0.45%)	3
Pathological fracture † 1	1/442 (0.23%)	1	1/443 (0.23%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Malignant pleural effusion † 1	2/442 (0.45%)	6	1/443 (0.23%)	1
Metastases to central nervous system † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Metastases to liver † 1	0/442 (0.00%)	0	1/443 (0.23%)	8
Metastases to meninges † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Metastatic pain † 1	3/442 (0.68%)	5	1/443 (0.23%)	1
Neoplasm malignant † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Neurilemmoma † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Pericardial effusion malignant † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Prostate cancer † 1	0/442 (0.00%)	0	1/235 (0.43%)	3
Tumour pain † 1	2/442 (0.45%)	2	0/443 (0.00%)	0
Nervous system disorders
Ataxia † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Cerebral haemorrhage † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Cerebral infarction † 1	1/442 (0.23%)	1	2/443 (0.45%)	3
Cerebral ischaemia † 1	1/442 (0.23%)	2	2/443 (0.45%)	3
Cerebrovascular accident † 1	5/442 (1.13%)	9	3/443 (0.68%)	4
Convulsion † 1	0/442 (0.00%)	0	2/443 (0.45%)	2
Dizziness † 1	1/442 (0.23%)	1	2/443 (0.45%)	2
Encephalopathy † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Grand mal convulsion † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Haemorrhage intracranial † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Haemorrhagic stroke † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Ischaemic cerebral infarction † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Lethargy † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Metabolic encephalopathy † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Nerve compression † 1	0/442 (0.00%)	0	1/443 (0.23%)	7
Neuropathy peripheral † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Paraesthesia † 1	0/442 (0.00%)	0	1/443 (0.23%)	3
Parkinson's disease † 1	0/442 (0.00%)	0	1/443 (0.23%)	11
Somnolence † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Status epilepticus † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Subarachnoid haemorrhage † 1	2/442 (0.45%)	2	0/443 (0.00%)	0
Syncope † 1	3/442 (0.68%)	3	1/443 (0.23%)	1
Transient ischaemic attack † 1	3/442 (0.68%)	3	2/443 (0.45%)	2
Unresponsive to stimuli † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Psychiatric disorders
Anxiety † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Confusional state † 1	5/442 (1.13%)	5	2/443 (0.45%)	2
Delirium † 1	0/442 (0.00%)	0	1/443 (0.23%)	2
Mental status changes † 1	4/442 (0.90%)	4	2/443 (0.45%)	3
Renal and urinary disorders
Nephrotic syndrome † 1	1/442 (0.23%)	3	0/443 (0.00%)	0
Renal failure † 1	1/442 (0.23%)	7	0/443 (0.00%)	0
Renal failure acute † 1	7/442 (1.58%)	10	4/443 (0.90%)	5
Renal tubular necrosis † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Urinary retention † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Urinary tract obstruction † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Respiratory, thoracic and mediastinal disorders
Acquired tracheo-oesophageal fistula † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Acute respiratory distress syndrome † 1	1/442 (0.23%)	1	2/443 (0.45%)	2
Acute respiratory failure † 1	1/442 (0.23%)	3	2/443 (0.45%)	2
Aspiration † 1	1/442 (0.23%)	4	0/443 (0.00%)	0
Bronchial fistula † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Bronchospasm † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Chronic obstructive pulmonary disease † 1	7/442 (1.58%)	30	2/443 (0.45%)	22
Dyspnoea † 1	7/442 (1.58%)	14	8/443 (1.81%)	18
Emphysema † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Epistaxis † 1	6/442 (1.36%)	7	2/443 (0.45%)	2
Haemoptysis † 1	8/442 (1.81%)	11	3/443 (0.68%)	6
Hydropneumothorax † 1	0/442 (0.00%)	0	4/443 (0.90%)	10
Hypoxia † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Pleural effusion † 1	3/442 (0.68%)	6	6/443 (1.35%)	9
Pleuritic pain † 1	1/442 (0.23%)	1	1/443 (0.23%)	2
Pneumonia aspiration † 1	1/442 (0.23%)	2	3/443 (0.68%)	3
Pneumothorax † 1	2/442 (0.45%)	2	2/443 (0.45%)	2
Pulmonary embolism † 1	10/442 (2.26%)	21	9/443 (2.03%)	14
Pulmonary haemorrhage † 1	2/442 (0.45%)	2	1/443 (0.23%)	1
Pulmonary hypertension † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Respiratory distress † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Respiratory failure † 1	11/442 (2.49%)	13	4/443 (0.90%)	4
Skin and subcutaneous tissue disorders
Skin disorder † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Surgical and medical procedures
Lung neoplasm surgery † 1	1/442 (0.23%)	2	0/443 (0.00%)	0
Vascular disorders
Arterial thrombosis † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Deep vein thrombosis † 1	5/442 (1.13%)	16	14/443 (3.16%)	34
Haemorrhage † 1	1/442 (0.23%)	1	1/443 (0.23%)	1
Hypertension † 1	2/442 (0.45%)	5	1/443 (0.23%)	7
Hypertensive crisis † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Hypotension † 1	3/442 (0.68%)	3	3/443 (0.68%)	5
Intra-abdominal haemorrhage † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Jugular vein thrombosis † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Orthostatic hypotension † 1	0/442 (0.00%)	0	1/443 (0.23%)	1
Post thrombotic syndrome † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Shock † 1	1/442 (0.23%)	1	0/443 (0.00%)	0
Superior vena cava syndrome † 1	1/442 (0.23%)	5	0/443 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 14.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pem/Carbo/Bev		Pac/Carbo/Bev
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	430/442 (97.29%)		433/443 (97.74%)
Blood and lymphatic system disorders
Anaemia † 1	177/442 (40.05%)	1367	136/443 (30.70%)	793
Leukopenia † 1	73/442 (16.52%)	387	76/443 (17.16%)	362
Neutropenia † 1	170/442 (38.46%)	733	219/443 (49.44%)	790
Thrombocytopenia † 1	159/442 (35.97%)	829	105/443 (23.70%)	452
Eye disorders
Lacrimation increased † 1	31/442 (7.01%)	405	2/443 (0.45%)	12
Gastrointestinal disorders
Abdominal pain † 1	42/442 (9.50%)	171	39/443 (8.80%)	113
Constipation † 1	181/442 (40.95%)	1380	166/443 (37.47%)	931
Diarrhoea † 1	100/442 (22.62%)	536	118/443 (26.64%)	338
Dyspepsia † 1	49/442 (11.09%)	419	30/443 (6.77%)	155
Gastrooesophageal reflux disease † 1	25/442 (5.66%)	249	22/443 (4.97%)	178
Nausea † 1	236/442 (53.39%)	1465	223/443 (50.34%)	1157
Stomatitis † 1	61/442 (13.80%)	321	44/443 (9.93%)	159
Vomiting † 1	114/442 (25.79%)	369	108/443 (24.38%)	310
General disorders
Asthenia † 1	40/442 (9.05%)	230	29/443 (6.55%)	178
Fatigue † 1	268/442 (60.63%)	2793	257/443 (58.01%)	2273
Mucosal inflammation † 1	51/442 (11.54%)	229	35/443 (7.90%)	110
Oedema peripheral † 1	66/442 (14.93%)	466	40/443 (9.03%)	249
Pain † 1	22/442 (4.98%)	87	31/443 (7.00%)	196
Pyrexia † 1	35/442 (7.92%)	104	42/443 (9.48%)	57
Infections and infestations
Sinusitis † 1	33/442 (7.47%)	111	19/443 (4.29%)	53
Upper respiratory tract infection † 1	32/442 (7.24%)	103	26/443 (5.87%)	53
Urinary tract infection † 1	32/442 (7.24%)	84	42/443 (9.48%)	108
Investigations
Alanine aminotransferase increased † 1	37/442 (8.37%)	291	12/443 (2.71%)	47
Aspartate aminotransferase increased † 1	33/442 (7.47%)	207	17/443 (3.84%)	52
Blood creatinine increased † 1	25/442 (5.66%)	163	13/443 (2.93%)	29
Haemoglobin decreased † 1	39/442 (8.82%)	322	22/443 (4.97%)	102
Platelet count decreased † 1	29/442 (6.56%)	106	14/443 (3.16%)	39
Weight decreased † 1	77/442 (17.42%)	464	68/443 (15.35%)	470
Metabolism and nutrition disorders
Decreased appetite † 1	133/442 (30.09%)	865	145/443 (32.73%)	912
Dehydration † 1	68/442 (15.38%)	194	54/443 (12.19%)	155
Hyperglycaemia † 1	38/442 (8.60%)	251	45/443 (10.16%)	236
Hypokalaemia † 1	28/442 (6.33%)	70	33/443 (7.45%)	76
Hypomagnesaemia † 1	34/442 (7.69%)	169	30/443 (6.77%)	186
Musculoskeletal and connective tissue disorders
Arthralgia † 1	46/442 (10.41%)	272	107/443 (24.15%)	967
Back pain † 1	60/442 (13.57%)	299	64/443 (14.45%)	441
Bone pain † 1	16/442 (3.62%)	83	33/443 (7.45%)	204
Musculoskeletal chest pain † 1	33/442 (7.47%)	197	21/443 (4.74%)	141
Musculoskeletal pain † 1	42/442 (9.50%)	273	31/443 (7.00%)	246
Myalgia † 1	25/442 (5.66%)	150	60/443 (13.54%)	394
Pain in extremity † 1	25/442 (5.66%)	200	44/443 (9.93%)	413
Nervous system disorders
Dizziness † 1	77/442 (17.42%)	404	63/443 (14.22%)	298
Dysgeusia † 1	67/442 (15.16%)	551	47/443 (10.61%)	283
Headache † 1	82/442 (18.55%)	516	67/443 (15.12%)	343
Neuropathy peripheral † 1	42/442 (9.50%)	413	145/443 (32.73%)	1394
Paraesthesia † 1	11/442 (2.49%)	85	24/443 (5.42%)	255
Peripheral sensory neuropathy † 1	19/442 (4.30%)	218	73/443 (16.48%)	888
Psychiatric disorders
Anxiety † 1	52/442 (11.76%)	407	44/443 (9.93%)	379
Confusional state † 1	19/442 (4.30%)	95	23/443 (5.19%)	48
Depression † 1	52/442 (11.76%)	402	47/443 (10.61%)	414
Insomnia † 1	69/442 (15.61%)	535	87/443 (19.64%)	719
Renal and urinary disorders
Proteinuria † 1	63/442 (14.25%)	435	54/443 (12.19%)	449
Respiratory, thoracic and mediastinal disorders
Cough † 1	91/442 (20.59%)	549	86/443 (19.41%)	568
Dysphonia † 1	32/442 (7.24%)	257	17/443 (3.84%)	126
Dyspnoea † 1	88/442 (19.91%)	558	85/443 (19.19%)	503
Epistaxis † 1	117/442 (26.47%)	800	98/443 (22.12%)	599
Oropharyngeal pain † 1	41/442 (9.28%)	140	33/443 (7.45%)	115
Rhinorrhoea † 1	29/442 (6.56%)	205	19/443 (4.29%)	153
Skin and subcutaneous tissue disorders
Alopecia † 1	34/442 (7.69%)	445	193/443 (43.57%)	2024
Pruritus † 1	15/442 (3.39%)	72	30/443 (6.77%)	91
Rash † 1	42/442 (9.50%)	239	56/443 (12.64%)	177
Vascular disorders
Hypertension † 1	74/442 (16.74%)	800	70/443 (15.80%)	678
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 14.1

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):

Spigel DR, Patel JD, Reynolds CH, Garon EB, Hermann RC, Govindan R, Olsen MR, Winfree KB, Chen J, Liu J, Guba SC, Socinski MA, Bonomi P. Quality of life analyses from the randomized, open-label, phase III PointBreak study of pemetrexed-carboplatin-bevacizumab followed by maintenance pemetrexed-bevacizumab versus paclitaxel-carboplatin-bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Feb;10(2):353-9. doi: 10.1097/JTO.0000000000000277.

Reynolds CH, Patel JD, Garon EB, Olsen MR, Bonomi P, Govindan R, Pennella EJ, Liu J, Guba SC, Li S, Spigel DR, Hermann RC, Socinski MA, Obasaju CK. Exploratory Subset Analysis of African Americans From the PointBreak Study: Pemetrexed-Carboplatin-Bevacizumab Followed by Maintenance Pemetrexed-Bevacizumab Versus Paclitaxel-Carboplatin-Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB/IV Nonsquamous Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2015 May;16(3):200-8. doi: 10.1016/j.cllc.2014.11.004. Epub 2014 Nov 18.

Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. doi: 10.1200/JCO.2012.47.9626. Epub 2013 Oct 21.

Patel JD, Bonomi P, Socinski MA, Govindan R, Hong S, Obasaju C, Pennella EJ, Girvan AC, Guba SC. Treatment rationale and study design for the pointbreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2009 Jul;10(4):252-6. doi: 10.3816/CLC.2009.n.035.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00762034 History of Changes
• Other Study ID Numbers: 9707; H3E-MC-JMHD ( Other Identifier: Eli Lilly and Company )
• First Submitted: September 26, 2008
• First Posted: September 30, 2008
• Results First Submitted: March 28, 2013
• Results First Posted: November 28, 2013
• Last Update Posted: December 21, 2015