Purpose: This phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer. Patients and methods: Patients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks). Results: A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was −1.6 (CI −9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%). Conclusions: MYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints. Trial Registry Information EU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32 Plain language summary Previous studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O ( n = 337) demonstrated comparable efficacy to bevacizumab ( n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was −1.6 (95% CI −9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months ( p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

e21087 Background: MYL-1402O (MYL) is a proposed biosimilar to bevacizumab reference product. A multicenter, double blind randomized, phase 3 study compared the efficacy, safety, PK, and immunogenicity of MYL and Avastin in patients with Stage IV metastatic nsNSCLC. Patients received either MYL or reference product, in combination with carboplatin-paclitaxel up to 18 weeks (6 cycles) followed by monotherapy for up to an additional 24 weeks (8 cycles). The objective was to develop a Pop PK model based on data from a phase 3 study pooled with a single dose healthy volunteer phase 1 study data; to assess PK linearity across the dose levels of 1 mg/kg to 15 mg/kg in 2 clinical studies; to assess the PK similarity of MYL and reference product in patients with nsNSCLC; and to explore potential covariates to account for variability in Pop PK model parameters. Methods: A Pop PK model was developed based on preliminary analyses of MYL phase 1 data and published population analyses of reference product using a 2-compartment linear model (Han K et al., 2016). Individual empiric Bayesian parameter estimates of nsNSCLC patients were used to predict PK measures reflecting exposure to drug and were compared qualitatively between treatments. Results: The data subset used for model development consisted of 8724 records from 771 subjects. Population PK analyses indicated no differences between PK profiles of patients in the MYL and reference product arms. Importantly, treatment was not a significant covariate of clearance ( P = 0.453) or volume of the central compartment ( P = 0.161) using the likelihood ratio χ2 test. Model-based steady state exposure measures, predicted based on the final model for all patients, were also similar between treatment arms (Table). Conclusions: The model supported linear PK at clinical doses in patients with nsNSCLC; there were no clinically relevant/significant differences between the PK of MYL and reference product; and the findings were consistent with the PK study in normal, healthy volunteers. Bayesian Parameter Clinical trial information: 2015-005141-32. [Table: see text]

2 (n¼11, 69%), and only one patient experienced a grade 3 AE (pemphigoid at cycle 27). No opportunistic infection or unexpected clinical immune-related events were observed. Blood CD4 cell count and HIV viral load were not modified during Nivolumab treatment.Conclusions: Nivolumab after platinum based-chemotherapy was associated with outcomes comparable to registration trials and was well tolerated in PLHIV with NSCLC. Clinical trial identification: NCT03304093.Legal entity responsible for the study: French Cooperative Thoracic Intergroup (IFCT).

Background: Mylan trastuzumab (MYL-1401O) is a biosimilar to trastuzumab (Herceptin®). A multicenter, double blind, randomized, phase III study (HERITAGE) compared the efficacy, safety, Pop PK and immunogenicity of MYL-1401O and trastuzumab in patients with HER2-positive mBC. Patients were randomized 1:1 to receive either MYL-1401O or Herceptin®, in combination with taxane Q3W for 24 weeks followed by monotherapy until unacceptable toxicity, disease progression or early discontinuation.Objectives: The objectives of the Pop PK analysis were to compare the Pop PK derived AUC, Cmax, clearance, Vd, and T1/2 profiles of MYL1401O and Herceptin® and to perform an exploratory assessment of the impact of shed extracellular domain (ECD) fragments of the HER2 receptor (HER2/ ECD) on PK parameters.Methods: One end of infusion PK sample was collected at Cycle 1 and Cycle 6, and 1 trough sample per cycle from all patients; additional samples were taken in a Pop PK subset (MYL-1401O: 45; Herceptin®: 37) in the first dosing interval and at subsequent times. Pop PK modeling was performed using NONMEM. Individual patient empiric Bayesian parameter estimates were used to estimate PK measures. The impact of HER2/ECD presence on PK levels was evaluated in the primary covariate analysis. Results: Two hundred forty-five (245) patients in the PK population received MYL-1401O, while 240 received Herceptin® of which 482 were included in the base model Pop PK analysis. 3170 concentration records with sufficient information were included in the Pop PK analysis. There were no notable demographic differences between the treatment groups. Bayesian parameter based exposure estimates at or near steady-state dosing were comparable between treatments, confirming similar PK (Table 1). Treatment was not a significant covariate of clearance (p=0.177) or volume of the central compartment (p=0.584) using the likelihood ratio Chi-square test.The test-to reference mean ratios of Cmin for Cycle 1 and Cycle 6 (end of cycle) were 103.11(90% CI = 90.61, 117.33) and 104.16 (90% CI = 94.00, 115.42), respectively.The HER2/ECD concentrations were a significant covariate of trastuzumab clearance. Conclusion: Pop PK profiles of MYL-1401O vs. Herceptin® were similar in patients with HER2positive mBC. Model-based exposure measures were similar between treatments. HER2/ECD concentrations were a strong determinant of trastuzumab clearance, and clearance was similar between treatments. The observed trough concentrations were similar between treatments at the end of Cycle 1 and at Cycle 6.Clinical trial identification: EudraCT Number: 2011-001965-42Legal entity responsible for the study: Mylan GmbHFunding: Mylan GmbH Table 1:Bayesian Parameter Based Exposure Estimates at Cycle 6MYL-1401O (N=245)Herceptin®(N=240)Total(N=485)Parametern*213202415Dose (mg)Mean (SD)420.70 (90.46)421.25 (97.67)420.97 (93.92)Clearance (L/day)0.27 (0.10)0.28 (0.08)0.27 (0.09)Volume of Central Compartment (L)3.16 (0.60)3.20 (0.60)3.18 (0.60)Volume at Steady State (L)6.36 (1.19)6.32 (1.14)6.34 (1.16)AUC (ug*day/mL)40501.40 (13037.04)38816.90 (11966.26)39681.40 (12540.58)Dose-normalized AUC (ug*day/mL/mg)98.50 (30.56)94.41 (28.90)96.51 (29.80)Cmax,ss (ug/mL)177.00 (37.76)171.52 (34.61)174.33 (36.32)Dose-normalized Cmax,ss (ug/mL/mg)0.43 (0.10)0.42 (0.09)0.43 (0.10)Half-life (day)Median (SD)25.12 (7.50)24.34 (6.89)24.74 (7.21)*concentrations below lower limit of quantification and samples before first dose with values >zero were excluded from Pop PK analysis, as were some patients with incomplete information for covariates significant in the final model. Citation Format: Joel Owen, Russell Rackley, Mark Liu, Adolfo Fuentes-Alburo, Tazeen Idris, Subramanian Loganathan, Abhijit Barve, Cornelius F. Waller, Hope S. Rugo. Population pharmacokinetics (Pop PK) of MYL-1401O (a trastuzumab biosimilar) and reference trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-23.