Evaluation of FKB238 and Avastin in Patients With Advanced/Recurrent Non-squamous Non-small Cell Lung Cancer (AVANA)

• ClinicalTrials.gov Identifier: NCT02810457
• Recruitment Status: Completed
• First Posted: June 23, 2016
• Results First Posted: March 19, 2020
• Last Update Posted: March 10, 2022
• Sponsor: Centus Biotherapeutics Limited
• Information provided by (Responsible Party): Centus Biotherapeutics Limited

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Carcinoma, Non-Small-Cell Lung
• Interventions: Drug: FKB238 (bevacizumab); Drug: Avastin (bevacizumab); Drug: Paclitaxel; Drug: Carboplatin
• Enrollment: 731

Participant Flow

Recruitment Details	Screening occurred at 146 centers in 24 countries (randomized at 136 centers, 24 countries) in Belarus, Bosnia & Herzegovina, Bulgaria, Croatia, Georgia, Germany, Greece, Hungary, Italy, Japan, South Korea, Peru, Philippines, Poland, Romania, Russia, Serbia, Spain, Taiwan, Thailand, Turkey, Ukraine, US and Vietnam. No screening occurred in Canada.
Pre-assignment Details	Of a total of 1023 patients who signed informed consent and were screened, 292 patients were not randomized. Of the 731 randomized patients, 2 patients were randomized in error and never received any study treatment, and 1 patient was randomized but withdrew consent prior to receiving any study treatment.

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: Area under the curve (AUC) = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Period Title: Overall Study
Started	364 [1]	367 [2]
Completed [3]	37	38
Not Completed	327	329
Reason Not Completed
Randomised but no treatment received	2	1
Objective PD assessed by RECIST v1.1	191	199
Adverse Event	37	43
Patient decision	31	35
Patient lost to follow-up	2	2
Death	39	28
Ongoing at data cutoff and discontinued	3	2
Clinical progression	15	16
Investigator decision	3	2
Patient ineligibility	3	0
Miscalculated PD	1	0
Physician Decision	0	1
[1] 362 patients received study treatment; [2] 366 patients received study treatment; [3] Patients still in the study at DCO

Baseline Characteristics

Arm/Group Title		FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin	Total
Arm/Group Description		Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin	Total of all reporting groups
Overall Number of Baseline Participants		364	367	731
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	364 participants	367 participants	731 participants
Adults (18-64 years)		238 65.4%	224 61.0%	462 63.2%
From 65-84 years		126 34.6%	143 39.0%	269 36.8%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	364 participants	367 participants	731 participants
	Female	119 32.7%	129 35.1%	248 33.9%
	Male	245 67.3%	238 64.9%	483 66.1%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	364 participants	367 participants	731 participants
White		316 86.8%	320 87.2%	636 87.0%
Black and African American		1 0.3%	0 0.0%	1 0.1%
Asian, other than Japanese		37 10.2%	37 10.1%	74 10.1%
Japanese		2 0.5%	3 0.8%	5 0.7%
American Indian or Alaska Native		1 0.3%	4 1.1%	5 0.7%
Other		7 1.9%	3 0.8%	10 1.4%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) Assessed as the Proportion of Patients With a Best Overall Response (BOR) of Either Complete Response (CR) or Partial Response (PR)
Description	The primary variable in this study was ORR, defined as the proportion of patients with a BOR of CR or PR (by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)). A BOR was defined as the best response (in the order of CR, PR, stable disease (SD), no evidence of disease (NED), progressive disease (PD), and not evaluable (NE)) among all post-baseline disease assessments that occurred until progression, or last evaluable assessment in the absence of progression prior to the initiation of subsequent anti-cancer therapy, irrespective of whether or not patients discontinued the study treatment. The 95% Pearson-Clopper confidence interval (CI) of ORR for each treatment arm was provided. Per RECIST v1.1 for target lesions and assessed by computed tomography (CT) or, if contraindicated, magnetic resonance imaging (MRI): CR=disappearance of all target lesions; PR=at least 30% decrease from baseline in the sum of diameters of target lesions. Overall Response=CR+PR.
Time Frame	Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

In order to meet the Food and Drug Administration (FDA) requirement, the primary efficacy analysis of ORR was performed using the Intent-to-Treat (ITT) population (patients included in each treatment arm as randomized), and the blinded independent central review (BICR) radiological assessments.

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description:	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Overall Number of Participants Analyzed	364	367
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	51.6; (46.38 to 56.89)	53.7; (48.43 to 58.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	A 90% CI for the ORR ratio between FKB238 and Avastin was estimated and compared to the margin (0.73 to 1.38), which was deemed to represent a clinically acceptable difference with respect to ORR. If the 90% CI was within the equivalence margin (0.73 to 1.38), an equivalence between FKB238 and Avastin, with respect to the ORR, was confirmed.
Method of Estimation	Estimation Parameter	Ratio in ORR
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 90%; 0.86 to 1.08
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	ORR at Week 19
Description	ORR (by RECIST v1.1) at Week 19 was defined as the proportion of patients with a BOR of CR or PR assessed at Week 19. Only tumor assessments performed up until 19 weeks (i.e. Week 18 assessment + 7 day assessment window) from randomization were considered in this analysis. Per RECIST v1.1 for target lesions and assessed by CT or, if contraindicated, MRI: CR=disappearance of all target lesions; PR=at least 30% decrease from baseline in the sum of diameters of target lesions. Overall Response=CR+PR.
Time Frame	From the date of randomization up to Week 19.

Outcome Measure Data

Analysis Population Description

In order to meet the FDA requirement, the secondary efficacy analysis of ORR was performed using the ITT population (patients included in each treatment arm as randomized), and the BICR radiological assessments.

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description:	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Overall Number of Participants Analyzed	364	367
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	47.8; (42.57 to 53.07)	51.0; (45.71 to 56.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
	Comments	Comparison between groups: Risk ratio in ORR at Week 19 by BICR.
	Type of Statistical Test	Other
	Comments	Ratio in ORR analysis of FKB238 versus Avastin.
Method of Estimation	Estimation Parameter	Ratio in ORR
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 90%; 0.83 to 1.06
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	The event of interest for PFS was defined as the interval from the date of randomization until first documented disease progression or death from any cause, whichever occurs first. Disease progression was based on tumor assessments according to RECIST v1.1 criteria. The items of the overall response CR, PR, SD and NED were taken as progression-free whereas PD denoted disease progression. PFS was summarized using Kaplan-Meier estimates of the quartiles for each treatment arm, and 95% CIs for the medians were calculated. Per RECIST v1.1 for target lesions and assessed by CT or, if contraindicated, MRI: PD=at least a 20% increase in the sum of the longest diameter of target lesions, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.
Time Frame	Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

This assessment was performed using the ITT population (patients included in each treatment arm as randomized) and the BICR radiological assessments.

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description:	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Overall Number of Participants Analyzed	364	367
Median (95% Confidence Interval); Unit of Measure: Months
	7.72; (7.46 to 7.98)	7.62; (6.90 to 7.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
	Comments	Hazard ratio and its 95% CI were calculated using the Cox regression model adjusting for baseline characteristics (randomization stratification factors, Eastern Cooperative Oncology Group (ECOG) performance status at baseline, gender, smoking history and age) with ties handled by the Efron method.
	Type of Statistical Test	Other
	Comments	Hazard ratio analysis of FKB238 versus Avastin.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.16
	Estimation Comments	Treatment hazard ratio <1 favors FKB238.

4. Secondary Outcome

Title	Overall Survival (OS)
Description	The event of interest was defined as death from any cause. OS was defined as the interval from date of randomization until the date of death due to any cause. OS was summarized using Kaplan-Meier estimates of the quartiles for each treatment arm, and 95% CIs for the medians were calculated.
Time Frame	Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

This assessment was performed using the ITT population (patients included in each treatment arm as randomized).

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description:	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Overall Number of Participants Analyzed	364	367
Median (95% Confidence Interval); Unit of Measure: Months
	14.13; (12.52 to 16.56)	16.95; (14.65 to 19.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
	Comments	Hazard ratio and its 95% CI were calculated using the Cox regression model adjusting for baseline characteristics (randomization stratification factors, ECOG performance status at baseline, gender, smoking history and age) with ties handled by the Efron method.
	Type of Statistical Test	Other
	Comments	Hazard ratio analysis of FKB238 versus Avastin.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.96 to 1.45
	Estimation Comments	Treatment hazard ratio <1 favors FKB238.

5. Secondary Outcome

Title	Duration Of Response (DOR)
Description	DOR was evaluated in this study as a secondary efficacy endpoint. Only the patients defined as responders in the primary analysis of ORR were taken into account for the analysis of DOR. The event of interest was defined as first documented disease progression or death due to any reason, whichever occurred first. DOR was defined as the interval from the first documented response (as defined per RECIST v1.1) until the earlier date of the first documented disease progression or death due to any reason. The date of first documented response was taken as the date of the first tumor assessment with an overall visit response of CR or PR. Per RECIST v1.1 for target lesions and assessed by CT or, if contraindicated, MRI: CR=disappearance of all target lesions; PR=at least 30% decrease from baseline in the sum of diameters of target lesions. DOR was calculated in units of months.
Time Frame	Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

This assessment of DOR was based on patients with events in the ITT population (patients included in each treatment arm as randomized), and the BICR radiological assessments.

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description:	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Overall Number of Participants Analyzed	188	197
Median (95% Confidence Interval); Unit of Measure: months
	6.47; (5.39 to 7.69)	6.31; (4.93 to 7.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
	Comments	Hazard ratio and its 95% CI were calculated using the Cox regression model adjusting for baseline characteristics (randomization stratification factors, ECOG performance status at baseline, gender, smoking history and age) with ties handled by the Efron method.
	Type of Statistical Test	Other
	Comments	Hazard ratio analysis of FKB238 versus Avastin.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.23
	Estimation Comments	Treatment hazard ratio <1 favors FKB238.

6. Secondary Outcome

Title	Disease Control Rate (DCR) Assessed as the Proportion of Patients With a BOR of Either CR, PR, SD or NED
Description	The DCR was defined as the proportion of patients defined as responders. The number and percentage of responders and non-responders and the 95% Pearson-Clopper CI of DCR for each treatment arm was provided. The odds ratio for treatment (FKB238 arm versus Avastin arm) and the corresponding 95% Wald CI were produced based on a logistic regression analysis of DCR. Per RECIST v1.1 for target lesions and assessed by CT or, if contraindicated, MRI: CR=disappearance of all target lesions; PR=at least 30% decrease from baseline in the sum of diameters of target lesions; SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. DCR=CR+PR+SD (≥ 6 weeks).
Time Frame	Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

This assessment of DCR was based on patients in the ITT population (patients included in each treatment arm as randomized), and the BICR radiological assessments.

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description:	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Overall Number of Participants Analyzed	364	367
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants with response
	87.6; (83.81 to 90.84)	87.5; (83.64 to 90.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
	Comments	The DCR was compared between treatment arms using logistic regression adjusting for baseline characteristics (randomization stratification factors, ECOG performance status at baseline, gender, smoking history and age).
	Type of Statistical Test	Other
	Comments	Comparison between arms: Odds ratio.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.58
	Estimation Comments	Odds ratio >1 favors FKB238.

7. Other Pre-specified Outcome

Title	Serum Trough Concentration (Ctrough)
Description	Ctrough (pre-infusion) and serum maximum concentration (Cmax; at completion of infusion) were compared between treatment arms and time points, and descriptive statistics provided. Ctrough and Cmax concentrations were summarized using the pharmacokinetics (PK) population for each visit at which samples were taken. The pre-dose serum concentrations at Cycles 2, 4, and 6 were considered as Ctrough values and the post-dose serum concentrations at Cycles 1 and 4 were considered as Cmax values. PK data at Cycle 1 Day 1 pre-infusion were not calculable and are therefore not presented in the outcome measure data table. Data are only provided for the time points at which the serum trough concentration was measured.
Time Frame	Cycle 1 Day 1 (pre- and post-infusion), Cycle 2 Day 1 (pre), Cycle 4 Day 1 (pre and post), Cycle 6 Day 1 (pre), discontinuation visit, and every 12 weeks (up to 1 year [±14 days] after randomisation) until death, or the patient was lost to follow-up.

Outcome Measure Data

Analysis Population Description

All patients randomized to treatment who received at least 1 dose of investigational product with no important protocol deviations, and at least 1 serum drug concentration data after investigational product administration (PK population).

Arm/Group Title		FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description:		Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Overall Number of Participants Analyzed		345	351
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ug/ml
Cycle 1, Day 1 end of infusion	Number Analyzed	343 participants	347 participants
		255.15; (184.3%)	245.11; (206.8%)
Cycle 2, Day 1 pre-infusion	Number Analyzed	325 participants	327 participants
		42.74; (91.9%)	48.48; (77.3%)
Cycle 4, Day 1 pre-infusion	Number Analyzed	280 participants	284 participants
		77.16; (69.4%)	83.26; (85.5%)
Cycle 4, Day 1 end of infusion	Number Analyzed	278 participants	283 participants
		339.91; (91.3%)	373.92; (51.6%)
Cycle 6, Day 1 pre-infusion	Number Analyzed	247 participants	253 participants
		87.25; (124.5%)	108.22; (69.8%)

8. Other Pre-specified Outcome

Title	Proportion of Patients Developing Anti-drug Antibodies (ADAs)
Description	The ADA levels were summarized at baseline and post-baseline time points using descriptive statistics.
Time Frame	Pre-dose at Cycles 1, 2, 4 and 6, discontinuation visit, and every 12 weeks (up to 1 year [±14 days] after randomisation) until death, or the patient was lost to follow-up, whichever occurred first.

Outcome Measure Data

Analysis Population Description

Includes all patients randomized to treatment who received at least 1 dose of investigational product with no important protocol deviations, and who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result (ADA evaluable population).

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin
Arm/Group Description:	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin	Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
Overall Number of Participants Analyzed	305	305
Measure Type: Number; Unit of Measure: percentage of participants
ADA prevalence (ADA positive, baseline or post)	3.0	3.0
Treatment-emergent ADA positive (ADA incidence)	2.3	2.3

9. Other Pre-specified Outcome

Title	Adverse Events (AEs)
Description	[Not Specified]
Time Frame	From the time of signature of informed consent, throughout the treatment period and up to and including the 30-days after the last dose of study treatment, for a total estimated period of time of up to approximately 30 months.

Outcome Measure Data Not Reported

10. Other Pre-specified Outcome

Title	Vital Signs
Description	[Not Specified]
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data Not Reported

11. Other Pre-specified Outcome

Title	Hematology
Description	[Not Specified]
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data Not Reported

12. Other Pre-specified Outcome

Title	Clinical Chemistry
Description	[Not Specified]
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data Not Reported

13. Other Pre-specified Outcome

Title	Urinalysis
Description	[Not Specified]
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data Not Reported

14. Other Pre-specified Outcome

Title	Electrocardiogram
Description	[Not Specified]
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data Not Reported

15. Other Pre-specified Outcome

Title	Eastern Collaborative Oncology Group Performance Status
Description	[Not Specified]
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data Not Reported

16. Other Pre-specified Outcome

Title	Physical Examination
Description	[Not Specified]
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data Not Reported

Adverse Events

Time Frame	From the time of signature of informed consent, throughout the treatment period and up to and including the 30-days after the last dose of study treatment, for a total estimated period of time of up to approximately 30 months. All ongoing and any new AEs/serious AEs (SAEs) identified during the 30 days after last dose were followed to resolution unless the event was considered by the investigator to be unlikely to resolve, or if the patient was lost to follow-up.
Adverse Event Reporting Description	All safety summaries and analyses were based on the Safety Population. Adverse events (AEs) were coded using the latest Medical Dictionary for Regulatory Activities(MedDRA) version (21.1). AEs were categorized as treatment-emergent AEs. Intensity of AEs was assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 grading system.
Arm/Group Title	FKB238 / Paclitaxel / Carboplatin		Avastin / Paclitaxel / Carboplatin
Arm/Group Description	Drug: FKB238: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. FKB238 (bevacizumab) Paclitaxel Carboplatin		Drug: Avastin: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. Drug: Paclitaxel: 200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Drug: Carboplatin: AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. Avastin (bevacizumab) Paclitaxel Carboplatin
All-Cause Mortality
	FKB238 / Paclitaxel / Carboplatin		Avastin / Paclitaxel / Carboplatin
	Affected / at Risk (%)		Affected / at Risk (%)
Total	195/362 (53.87%)		177/366 (48.36%)
Serious Adverse Events
	FKB238 / Paclitaxel / Carboplatin		Avastin / Paclitaxel / Carboplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	91/362 (25.14%)		95/366 (25.96%)
Blood and lymphatic system disorders
Anaemia † 1	5/362 (1.38%)	5	9/366 (2.46%)	10
Febrile neutropenia † 1	7/362 (1.93%)	7	5/366 (1.37%)	5
Neutropenia † 1	7/362 (1.93%)	8	18/366 (4.92%)	19
Pancytopenia † 1	0/362 (0.00%)	0	2/366 (0.55%)	2
Thrombocytopenia † 1	2/362 (0.55%)	2	2/366 (0.55%)	2
Cardiac disorders
Acute coronary syndrome † 1	3/362 (0.83%)	3	1/366 (0.27%)	1
Acute myocardial infarction † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Atrial fibrillation † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Cardiac disorder † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Cardio-respiratory arrest † 1	2/362 (0.55%)	2	0/366 (0.00%)	0
Cor pulmonale † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Myocardial infarction † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Supraventricular tachycardia † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Tachyarrhythmia † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Endocrine disorders
Adrenal insufficiency † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Gastrointestinal disorders
Diarrhoea † 1	1/362 (0.28%)	1	3/366 (0.82%)	3
Diverticulum intestinal haemorrhagic † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Dyspepsia † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Enterocolitis † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Gastric haemorrhage † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Gastrointestinal haemorrhage † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Haematemesis † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Ileal perforation † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Rectal haemorrhage † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Small intestinal obstruction † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Small intestinal perforation † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Stomatitis † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Upper gastrointestinal haemorrhage † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Vomiting † 1	3/362 (0.83%)	3	2/366 (0.55%)	2
General disorders
Asthenia † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Death † 1	5/362 (1.38%)	5	3/366 (0.82%)	3
Fatigue † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
General physical health deterioration † 1	1/362 (0.28%)	1	2/366 (0.55%)	2
Mucosal inflammation † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Oedema peripheral † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Pyrexia † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Sudden death † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Hepatobiliary disorders
Cholecystitis † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Cholelithiasis † 1	0/362 (0.00%)	0	2/366 (0.55%)	2
Drug-induced liver injury † 1	1/362 (0.28%)	1	1/366 (0.27%)	1
Immune system disorders
Hypersensitivity † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Infections and infestations
Cellulitis † 1	0/362 (0.00%)	0	2/366 (0.55%)	2
Empyema † 1	1/362 (0.28%)	1	1/366 (0.27%)	1
Liver abscess † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Lung infection † 1	2/362 (0.55%)	2	1/366 (0.27%)	1
Peritonitis † 1	1/362 (0.28%)	1	1/366 (0.27%)	1
Pneumonia † 1	10/362 (2.76%)	12	9/366 (2.46%)	10
Pneumonia fungal † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Pseudomonal sepsis † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Sepsis † 1	0/362 (0.00%)	0	2/366 (0.55%)	2
Septic shock † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Tuberculosis † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Injury, poisoning and procedural complications
Femur fracture † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Hip fracture † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Spinal fracture † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Upper limb fracture † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Investigations
Neutrophil count decreased † 1	3/362 (0.83%)	4	2/366 (0.55%)	2
Platelet count decreased † 1	1/362 (0.28%)	1	1/366 (0.27%)	1
White blood cell count decreased † 1	2/362 (0.55%)	2	2/366 (0.55%)	2
Metabolism and nutrition disorders
Hypocalcaemia † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Hyponatraemia † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Musculoskeletal and connective tissue disorders
Back pain † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Pathological fracture † 1	0/362 (0.00%)	0	2/366 (0.55%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Thyroid cancer † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Nervous system disorders
Cerebral arteriosclerosis † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Cerebral atrophy † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Cerebrovascular accident † 1	2/362 (0.55%)	2	3/366 (0.82%)	3
Dizziness † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Epilepsy † 1	2/362 (0.55%)	2	0/366 (0.00%)	0
Facial paresis † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Guillain-Barre syndrome † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Haemorrhagic stroke † 1	1/362 (0.28%)	1	1/366 (0.27%)	1
Ischaemic stroke † 1	0/362 (0.00%)	0	1/366 (0.27%)	2
Polyneuropathy † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Posterior reversible encephalopathy syndrome † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Presyncope † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Seizure † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Transient ischaemic attack † 1	1/362 (0.28%)	1	1/366 (0.27%)	1
Uraemic encephalopathy † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Renal and urinary disorders
Acute kidney injury † 1	1/362 (0.28%)	1	2/366 (0.55%)	2
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Acute respiratory failure † 1	2/362 (0.55%)	2	0/366 (0.00%)	0
Dyspnoea † 1	2/362 (0.55%)	2	3/366 (0.82%)	3
Haemoptysis † 1	2/362 (0.55%)	2	0/366 (0.00%)	0
Oesophagobronchial fistula † 1	2/362 (0.55%)	2	0/366 (0.00%)	0
Pleural effusion † 1	1/362 (0.28%)	2	0/366 (0.00%)	0
Pneumonia aspiration † 1	2/362 (0.55%)	2	0/366 (0.00%)	0
Pneumothorax † 1	0/362 (0.00%)	0	4/366 (1.09%)	4
Pulmonary embolism † 1	6/362 (1.66%)	6	5/366 (1.37%)	5
Pulmonary fibrosis † 1	1/362 (0.28%)	1	0/366 (0.00%)	0
Pulmonary haemorrhage † 1	3/362 (0.83%)	4	1/366 (0.27%)	1
Pulmonary mass † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Pulmonary oedema † 1	2/362 (0.55%)	2	0/366 (0.00%)	0
Respiratory failure † 1	1/362 (0.28%)	1	3/366 (0.82%)	3
Vascular disorders
Deep vein thrombosis † 1	0/362 (0.00%)	0	1/366 (0.27%)	1
Hypertension † 1	2/362 (0.55%)	2	1/366 (0.27%)	1
Hypertensive crisis † 1	0/362 (0.00%)	0	2/366 (0.55%)	2
1 Term from vocabulary, MedDRA 21.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	FKB238 / Paclitaxel / Carboplatin		Avastin / Paclitaxel / Carboplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	341/362 (94.20%)		348/366 (95.08%)
Blood and lymphatic system disorders
Anaemia † 1	105/362 (29.01%)	135	119/366 (32.51%)	146
Leukopenia † 1	43/362 (11.88%)	58	50/366 (13.66%)	89
Neutropenia † 1	109/362 (30.11%)	163	145/366 (39.62%)	212
Thrombocytopenia † 1	44/362 (12.15%)	78	66/366 (18.03%)	102
Gastrointestinal disorders
Constipation † 1	19/362 (5.25%)	23	21/366 (5.74%)	23
Diarrhoea † 1	35/362 (9.67%)	44	35/366 (9.56%)	41
Nausea † 1	52/362 (14.36%)	72	45/366 (12.30%)	57
Vomiting † 1	24/362 (6.63%)	29	18/366 (4.92%)	24
General disorders
Asthenia † 1	37/362 (10.22%)	45	59/366 (16.12%)	71
Fatigue † 1	41/362 (11.33%)	55	45/366 (12.30%)	48
Non-cardiac chest pain † 1	18/362 (4.97%)	18	11/366 (3.01%)	15
Pyrexia † 1	15/362 (4.14%)	17	21/366 (5.74%)	24
Infections and infestations
Pneumonia † 1	18/362 (4.97%)	20	20/366 (5.46%)	24
Investigations
Alanine aminotransferase increased † 1	38/362 (10.50%)	53	35/366 (9.56%)	45
Aspartate aminotransferase † 1	32/362 (8.84%)	43	35/366 (9.56%)	45
Blood alkaline phosphatase increased † 1	19/362 (5.25%)	24	27/366 (7.38%)	39
Gamma-glutamyltransferase † 1	38/362 (10.50%)	48	31/366 (8.47%)	46
Neutrophil count decreased † 1	24/362 (6.63%)	32	25/366 (6.83%)	30
Platelet count decreased † 1	30/362 (8.29%)	48	25/366 (6.83%)	38
Weight decreased † 1	41/362 (11.33%)	48	56/366 (15.30%)	62
White blood cell count decreased † 1	24/362 (6.63%)	36	26/366 (7.10%)	36
Metabolism and nutrition disorders
Decreased appetite † 1	43/362 (11.88%)	56	42/366 (11.48%)	48
Hyperglycaemia † 1	14/362 (3.87%)	18	22/366 (6.01%)	29
Musculoskeletal and connective tissue disorders
Arthralgia † 1	32/362 (8.84%)	49	36/366 (9.84%)	48
Back pain † 1	22/362 (6.08%)	25	14/366 (3.83%)	14
Myalgia † 1	29/362 (8.01%)	61	32/366 (8.74%)	73
Nervous system disorders
Headache † 1	18/362 (4.97%)	21	23/366 (6.28%)	24
Neuropathy peripheral † 1	58/362 (16.02%)	63	52/366 (14.21%)	60
Paraesthesia † 1	24/362 (6.63%)	26	22/366 (6.01%)	22
Peripheral sensory neuropathy † 1	28/362 (7.73%)	28	25/366 (6.83%)	25
Polyneuropathy † 1	16/362 (4.42%)	18	23/366 (6.28%)	31
Renal and urinary disorders
Proteinuria † 1	24/362 (6.63%)	31	41/366 (11.20%)	52
Respiratory, thoracic and mediastinal disorders
Cough † 1	17/362 (4.70%)	20	25/366 (6.83%)	26
Dyspnoea † 1	17/362 (4.70%)	17	29/366 (7.92%)	29
Epistaxis † 1	16/362 (4.42%)	20	23/366 (6.28%)	36
Skin and subcutaneous tissue disorders
Alopecia † 1	154/362 (42.54%)	157	159/366 (43.44%)	162
Vascular disorders
Hypertension † 1	42/362 (11.60%)	47	44/366 (12.02%)	54
1 Term from vocabulary, MedDRA 21.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

Any publications/presentations made within 2 years of study completion require the Sponsor or CRO's prior written consent. The Sponsor shall be provided with copies of any materials relating to the study that they intend to publish/present at least 30 days in advance of publication, submission or presentation and the Institution shall withhold publication, submission or presentation for 90 days from the date on which the Sponsor receives the material (total time-frame of 120 days).

Results Point of Contact

• Name/Title: Clinical Trial Information
• Organization: Centus Biotherapeutics Limited
• Phone: +353 1 609 7100
• EMail: Clinical-Trial@centusbio.com

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

Syrigos K, Abert I, Andric Z, Bondarenko IN, Dvorkin M, Galic K, Galiulin R, Kuchava V, Sriuranpong V, Trukhin D, Zhavrid E, Fu D, Kassalow LM, Jones S, Bashir Z; AVANA Investigators. Efficacy and Safety of Bevacizumab Biosimilar FKB238 Versus Originator Bevacizumab: Results from AVANA, a Phase III Trial in Patients with Non-Squamous Non-Small-Cell Lung Cancer (non-sq-NSCLC). BioDrugs. 2021 Jul;35(4):417-428. doi: 10.1007/s40259-021-00489-4. Epub 2021 Jul 15.

• Responsible Party: Centus Biotherapeutics Limited
• ClinicalTrials.gov Identifier: NCT02810457
• Other Study ID Numbers: FKB238-002; 2015-004104-33 ( EudraCT Number )
• First Submitted: June 3, 2016
• First Posted: June 23, 2016
• Results First Submitted: January 24, 2020
• Results First Posted: March 19, 2020
• Last Update Posted: March 10, 2022