Candidate Bevacizumab Biosimilar CT-P16 versus European Union Reference Bevacizumab in Patients with Metastatic or Recurrent Non-Small Cell Lung Cancer: A Randomized Controlled Trial

Study Design

This ongoing, randomized, active-controlled, double-blind, parallel-group, phase III study (NCT03676192) was conducted at 164 hospitals or clinics in 21 countries (electronic supplementary material [ESM] Table S1). Screening of eligible participants occurred within 28 days prior to randomization, or up to 8 weeks for patients with central nervous system (CNS) metastases to provide sufficient time for CNS treatment. During the induction period, patients were randomized (1:1) to receive either CT-P16 15 mg/kg or EU-bevacizumab 15 mg/kg; both treatments were administered intravenously every 3 weeks for ≤ 6 cycles. Patients in both treatment groups received concurrent intravenous paclitaxel 200 mg/m2 and intravenous carboplatin area under the curve 6.0 every 3 weeks for 4–6 cycles. Patients with controlled disease (i.e., complete response [CR], partial response [PR], or stable disease) at the end of the induction period entered the maintenance period and received monotherapy with their assigned treatment until disease progression or intolerable toxicity. The end of treatment (EOT) visit occurred 3 weeks after the final dose of study treatment in the induction or maintenance period; subsequently, patients entered the follow-up period, in which they were followed up every 9 weeks until death or end of the study.

An interactive web response system (IWRS) was used for randomization. A computer-generated randomization schedule was prepared for the IWRS by an unblinded statistician. Patients were randomized in blocks stratified by country, sex (female vs. male), disease status (recurrence vs. metastatic), and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1). Patients and investigators (including local and central outcome assessors) were blinded to treatment group. Blinding and concealment of permuted block size will be maintained until completion of this ongoing study, to avoid bias.

Key protocol amendments made after the study start date are detailed below or listed in the ESM Methods. The study was monitored by an independent data safety monitoring board.

Participants

Full eligibility criteria are listed in the ESM Methods. Briefly, eligible individuals were male or female, aged ≥ 18 years, with histologically or cytologically confirmed stage IV or recurrent NSCLC. Patients were required to have one or more measurable lesions (per Response Evaluation Criteria In Solid Tumours [RECIST] criteria version 1.1); an ECOG performance status of 0 or 1; adequate hematologic, hepatic, and renal functions; and negative epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement test results. Key exclusion criteria included NSCLC with predominantly squamous histology; previous systemic therapy, surgery, or radiotherapy for NSCLC; therapeutic use of parenteral anticoagulants or thrombolytic agents; untreated CNS metastases or CNS metastasis with bleeding risk; hemoptysis; uncontrolled hypertension, diabetes, or cardiac disease; a history of vascular disease; or pregnancy or lactation.

Endpoints

The primary efficacy endpoint was objective response rate (ORR) based on best overall response (BOR), per RECIST criteria version 1.1, achieved during the 6-cycle induction period and confirmed, if necessary, by subsequent assessment up to Cycle 3 of the maintenance period. Central review results were used for the primary analysis and local review results were used for a sensitivity analysis.

Secondary efficacy endpoints included response duration, time to progression (TTP), and PFS, each based on central review results, and OS. Response duration was defined as the time from initial response to progressive disease (PD), recurrence, or death from any cause in patients achieving a CR or PR; during the study, the planned analysis was updated to add death to the description and to add a requirement for CR or PR to be confirmed through subsequent assessment.

Safety evaluations included the incidence and severity of treatment-emergent adverse events (TEAEs) and serious TEAEs. TEAEs of special interest (TEAESIs) were captured using standardized Medical Dictionary for Regulatory Activities queries, thus evaluated across system organ classes, and included hypersensitivity/infusion-related reactions, gastrointestinal perforations and fistulae, wound healing complications, hypertension, posterior reversible encephalopathy syndrome, proteinuria, arterial or venous thromboembolism, hemorrhages, congestive heart failure, or ovarian failure/fertility. The full list of prespecified safety endpoints is available in the ESM Methods. Pharmacokinetic evaluation comprised assessment of trough serum concentrations of CT-P16 (Ctrough). Immunogenicity was assessed in terms of the incidence of both antidrug antibodies (ADAs), antibodies that bind to the biologic agent (in this study, bevacizumab) in human serum, and neutralizing antibodies (NAbs), ADAs that bind to the biologic agent and neutralize its biologic activity [30].

Assessments

RECIST criteria version 1.1 were used for tumor evaluation. Computed tomography (CT) scans were conducted at screening, at the end of Cycles 2, 4, and 6 during the induction period, at the end of every third cycle during the maintenance period, and at EOT. Brain CT or magnetic resonance imaging, and bone scans, were conducted at screening and at later timepoints if brain or bone metastases were present at screening or if new lesions were suspected, respectively. Images for tumor response were assessed via both central review (by a central independent reviewer) and local review (by investigators).

Blood samples were collected predose for pharmacokinetic analyses on Day 1 of each cycle and at the end of Cycle 6 during the induction period, at the end of every third cycle during the maintenance period, and at EOT. Serum CT-P16 and EU-bevacizumab concentrations were measured using a validated electrochemiluminescent assay with a lower limit of quantification of 50 ng/mL.

Adverse events (AEs) were monitored throughout and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Clinical laboratory tests and physical examinations were performed at screening, on Day 1 of each cycle, and at EOT.

Blood samples were collected for immunogenicity assessments on Day 1 of Cycle 1 and at the end of Cycles 2, 4, and 6 during the induction period, at the end of every third cycle during the maintenance period, and at EOT. The presence of ADAs and NAbs was detected using validated electrochemiluminescent assays. Blood samples were first screened for ADAs with a positive control concentration range of 50–2000 ng/mL, and if found to be positive, underwent further testing in a confirmatory assay. Samples with confirmed positive ADA results were further screened for NAbs using three positive controls (low: 125 ng/mL; titer: 500 ng/mL; high: 10,000 ng/mL).

Statistical Analysis

A total of 305 patients per treatment group was estimated to provide 80% power to demonstrate similarity in efficacy between CT-P16 and EU-bevacizumab based on an expected ORR of 38%. This calculation was based on two sets of statistical assumptions, to meet the requirements of both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA): an equivalence margin of −12.5 to +12.5% using a 95% confidence interval (CI; two one-sided alpha of 0.025) for the risk difference (RD) in ORR (EMA assumption; predefined in the original protocol), and an equivalence margin of 0.7368–1.3572 using a 90% CI (two one-sided alpha of 0.05) for the risk ratio (RR) in ORR (FDA assumption; included as a protocol amendment). Therefore, 678 patients (n = 339 per group) were required to allow for an anticipated dropout rate of 10%.

The primary analysis of the primary efficacy endpoint (ORR based on BOR during the induction period) was performed using a logistic regression model for RD and a log-binomial regression model for RR. Covariates comprised region (Europe, Middle East, and Africa vs. America vs. Asia), sex (male vs. female), disease status at baseline (recurrent vs. metastatic), and ECOG performance status at baseline (0 vs. 1). Treatment groups (CT-P16 vs. EU-bevacizumab) were considered as a fixed effect. Equivalence in terms of efficacy would be achieved if the 95% CI for the RD for ORR was bounded by the interval −12.5 to +12.5% (EMA assumption) and if the 90% CI for the RR for ORR was entirely within the predefined equivalence margin of 0.7368–1.3572 (FDA assumption). Patients with missing values for ORR were considered non-responders. For secondary efficacy variables, continuous data were summarized using descriptive statistics, and categorical data were summarized using numbers and percentages. Analysis sets are defined in the ESM Methods. All statistical analyses were conducted using Statistical Analysis System (SAS®) software version 9.4 or higher (SAS Institute Inc., Cary, NC, USA).

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