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Rituximab biosimilars are a cornerstone of treatment of advanced-stage follicular lymphoma (FL). This double-blind, parallel-group, phase 3 trial randomized (1:1) adults (≥18 years) with stage III to IV indolent B-cell lymphoma, including grades 1 to 3a FL, to receive CT-P10 or rituximab (375 mg/m2 IV), with cyclophosphamide, vincristine, and prednisone, every 3 weeks for 8 cycles (induction period). Patients achieving complete response (CR), unconfirmed CR, or partial response (PR) received CT-P10 or rituximab maintenance for 2 years (375 mg/m2, every 8 weeks). Primary end points were previously reported, proving noninferiority of efficacy and pharmacokinetic equivalence of CT-P10 to rituximab. Secondary end points included overall response rate (PR+CR) during the induction period per 2007 International Working Group (IWG) criteria, survival analyses, and overall safety. Between 28 July 2014 and 29 December 2015, 140 patients were randomized (70 per group). Median follow-up was 39.9 months (interquartile range, 36.7-43.5). Per 1999 IWG criteria, 4-year Kaplan-Meier estimates (95% confidence interval [CI]) for CT-P10 and rituximab were 61% (47% to 73%) and 55% (36% to 70%) for progression-free survival (hazard ratio, 1.33 [95% CI, 0.67-2.63]; P=.409), respectively, and 88% (77% to 94%) and 93% (83% to 97%) for overall survival (5.29 [0.84-33.53]; P=.077). Overall, 90% (CT-P10) and 86% (rituximab) of patients experienced treatment-emergent adverse events. Long-term safety profiles were similar between groups. Findings confirm favorable outcomes for CT-P10–treated patients with advanced-stage FL and demonstrate comparable long-term efficacy and overall safety between CT-P10 and rituximab. This trial was registered at www.clinicaltrials.gov as #NCT02162771.

Introduction : CT-P10 is an approved biosimilar to the innovator rituximab by both US FDA and EMA based on a review of comprehensive data package inclusive of foundational and extensive analytical characterization, nonclinical and clinical data. In patients with newly diagnosed advanced stage follicular lymphoma (AFL), equivalence of pharmacokinetics and noninferiority of efficacy was demonstrated in the primary analysis (Kim WS et al. Lancet Hematol. 2017), and progression-free survival (PFS) and overall survival (OS) at a median follow-up of 22.6 months showed the therapeutic similarity between the CT-P10 and Rituxan (RTX) (Kim WS et al. Blood 2018;132:1616). Here, we report the updated data at a median follow-up of 40 months regarding time-to-event endpoints and safety in this CT-P10 3.3 study. Methods: This phase III, randomized, and double-blind study in patients with previously untreated AFL (NCT02162771) was completed within the planned study period. Patients received R-CVP induction therapy (every 3 weeks for 8 cycles) in the Core Study Period and rituximab monotherapy (every 2 months for 12 cycles) in the Maintenance Study Period. Computerized Tomography scans were performed at baseline, month 3 and 6 during the Core Study Period, and then every 6 months for 2 years during the Maintenance Study Period. After 2 years, patients were followed every 6 months for tumor evaluation up to 3 years from the last patient's first infusion date. Kaplan-Meier (KM) method was used to estimate the time-to-event endpoints. Results: In total, 140 patients with AFL were enrolled (CT-P10-CVP; N=70, R-CVP; N=70) with a median age of 58 years and 55.0% of female. The majority of patients completed the induction therapy (62 patients [88.6%] in each group, respectively). Among them, 122 patients (62 [88.6%] patients in CT-P10 and 60 [85.7%] patients in RTX) entered the Maintenance Period and 84 patients (46 [65.7%] patients in CT-P10 and 38 [54.3%] patients in RTX) completed the maintenance therapy. To date, investigator assessed PFS, time-to-progression (TTP) and OS, medians had not been reached in either group due to insufficient number of events. The median follow-up durations of each group were 40 months (25th-75th percentile, 37 to 44) in CT-P10 and 39 months (25th-75th percentile, 36 to 43) in RTX. A total of 42 patients (21 [30.0%] patients in each group, respectively) experienced disease progression and 12 patients reported death during the study. Of these 12 patients, 5 patients (3 [4.3%] patients in CT-P10 and 2 [2.9%] patients in RTX) died due to lymphoma and the other 7 patients (5 [7.1%] patients in CT-P10 and 2 [2.9%] patients in RTX) died due to adverse events or other reasons. There were no significant differences between the 2 groups in PFS (Cox proportional Hazard Ratio [HR]: 1.33; 95% Confidence Interval [CI]: 0.67-2.63; 4-year PFS: CT-P10 60.9% [95% CI: 46.5%-72.5%], RTX 54.7% [95% CI: 36.1%-70.0%]; Figure 1). The TTP revealed the trends similar to PFS. The KM curves showed no significant differences between the 2 groups in TTP (Cox proportional HR: 1.17; 95% CI: 0.58-2.37; 4-year TTP: CT-P10 64.2% [95% CI: 49.4%-75.7%], RTX 55.8% [95% CI: 36.8%-71.1%]; Figure 2). Even with a limited number of events, OS was comparable between the 2 groups (Log rank p-value: 0.287; 4-year OS: CT-P10 88.0% [95% CI: 77.5%-93.8%], RTX 93.3% [95% CI: 83.2%-97.4%]). Overall safety profiles of CT-P10 were consistent with those of RTX (Table 1). No new safety signals were identified during the study and a similar number of patients in each group experienced at least 1 treatment-emergent adverse event, infusion-related reaction, or infection considered to be related to the study drug. One patient from each group reported hepatitis B virus activation related to the study drug. The proportion of patients with positive anti-drug antibody was also similar in both groups (4.3% [3/70] vs 5.7% [4/70] in CT-P10 and RTX) and 2 patients (2.9%) in each group showed the positive neutralizing antibody results. Conclusion: Long-term efficacy results in patients with AFL showed comparable PFS, TTP and OS between the 2 groups, indicating therapeutic similarity of CT-P10 to originator RTX. In addition, CT-P10 was consistently well tolerated and showed comparable safety profiles, including immunogenicity, over the entire study period without any unexpected toxicities compared to RTX. Disclosures Buske: Amgen: Research Funding; Hexal: Honoraria, Speakers Bureau; Bayer: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion Healthcare: Consultancy; Celltrion, Inc.: Consultancy. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca/Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Takeda: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; Incyte: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene: Research Funding; Bayer: Research Funding. Sancho:ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; SANOFI: Honoraria; SERVIER: Honoraria; CELLTRION: Consultancy; Kern-Pharma: Honoraria; Sandoz: Consultancy. Kim:Novartis: Research Funding; Donga: Research Funding; Celltrion: Research Funding; J&J: Research Funding; Kyowa-Kirin: Research Funding; Mundipharma: Research Funding; Roche: Research Funding. Ogura:Celltrion: Honoraria; Celgene: Honoraria; MeijiSeika Pharma: Honoraria; Mundi Pharma: Honoraria; Teva Takeda: Honoraria; Verastem: Honoraria. Lee:Celltrion: Employment. Kim:Celltrion: Employment. Ahn:Celltrion: Employment.

Background: CT-P10 is a biosimilar candidate to the reference rituximab product, EU-approved MabThera® and US-licensed Rituxan®. CT-P10 has an identical amino acid sequence and highly similar physicochemical and in vitro functional properties to its reference drug. In patients with rheumatoid arthritis, CT-P10 has demonstrated compelling similarity in pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity (Yoo DH, et al. Arthritis Rheum. 2013;65(10):1736). Objective: The goal of this study was to demonstrate PK similarity of CT-P10 to rituximab, each administered in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed Advanced Follicular Lymphoma (AFL) (NCT02162771) (Kim WS et al. Blood. 2015;126(23): 5111). The results of PK, PD, safety and immunogenicity up to Core Cycle 4 (12 weeks) are presented here from this ongoing study. Methods: Patients with AFL were randomized 1:1 to receive infusion (375mg/m2) of either CT-P10 or rituximab, at a 3-week interval, in combination with CVP. PK analysis was conducted in terms of AUCtau and Cmax at steady state, Core Cycle 4, as primary PK endpoints. PK parameter values considered as outliers determined by robust regression outlier testing were excluded from the pharmacokinetic primary analysis. Results: In total, 121 patients were randomly assigned to receive either CT-P10 (n=59) or rituximab (n=62) in combination with CVP. Result of CT-P10 PK at Core Cycle 4 was similar to that of rituximab. The ratios (90% CI) of geometric least square means (CT-P10 to rituximab treatment group) were 102.3% (94.1%-111.2%) for AUCtau and 100.7% (93.8%-108.0%) for CmaxSS at Core Cycle 4. The 90% CIs of ratio of geometric LS means for both AUCtau and CmaxSS were entirely contained within the equivalence margin of 80% to 125% (Table 1 and Figure 1). Mean serum concentrations of the study drug were highly similar for the 2 treatment groups at each time point (Core Cycle 1 to 4). The B-cell kinetics was similar up to Core Cycle 4 in the 2 treatment groups. Median number of B-cells decreased to below the lower limit of quantification (LLoQ) (20 cells/μL) 1 hour after the end of infusion at Core Cycle 1 and remained below the LLoQ at each subsequent cycle, up to and including Core Cycle 4. The proportion of patients with a positive anti-drug antibody up to Core Cycle 4 at post-treatment visits was similar between the 2 treatment groups; 3/59 (5.1%) patients and 2/62 (3.2%) patients in the CT-P10 and rituximab groups, respectively. In addition, CT-P10 was well tolerated and the safety profile of CT-P10 up to Core Cycle 4 was similar to that of rituximab. The number of patients who experienced at least 1 treatment emergent adverse event (TEAE) was 43 (72.9%) patients and 41 (66.1%) patients in CT-P10 and rituximab treatment groups, respectively. The proportion of patients who experienced at least 1 treatment emergent serious adverse event considered by the investigator to be related to the study treatment was similar between the 2 treatment groups; 2/59 (3.4%) patients and 2/62 (3.2%) patients in the CT-P10 and rituximab groups, respectively. The frequencies of adverse events special interest (AESI) were similar between the 2 treatment groups (Table 2). Conclusion: This study demonstrated similarity of PK in terms of AUCtau and CmaxSS between CT-P10 and rituximab in AFL patients. The B-cell kinetics and immunogenicity were comparable between the two treatment groups. CT-P10 was well tolerated with a safety profile comparable to that of rituximab up to and including Core Cycle 4 (12 weeks). Table 1 Statistical Analysis of Rituximab Pharmacokinetic Primary Endpoints for Core Cycle 4 at Steady State: Pharmacokinetic Population Table 1. Statistical Analysis of Rituximab Pharmacokinetic Primary Endpoints for Core Cycle 4 at Steady State: Pharmacokinetic Population Figure 1 Mean (±SD) Serum Concentration of Rituximab Versus Time for Cycle 4 at Steady State (Linear Scale): Pharmacokinetic Population Figure 1. Mean (±SD) Serum Concentration of Rituximab Versus Time for Cycle 4 at Steady State (Linear Scale): Pharmacokinetic Population Table 2 The Incidence Rates of Adverse Events Special Interest: Safety Population Table 2. The Incidence Rates of Adverse Events Special Interest: Safety Population Disclosures Coiffier: Celltrion, Inc.: Consultancy, Honoraria. Sancho:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Celltrion, Inc: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding. Kim:Celltrion, Inc.: Research Funding. Nagarkar:Celltrion, Inc.: Research Funding. Zhavrid:Celltrion, Inc.: Research Funding. Hernandez Rivas:Celltrion, Inc.: Research Funding. Prokharau:Celltrion, Inc.: Research Funding. Zodelava:Celltrion, Inc.: Research Funding. Osmanov:Celltrion, Inc.: Research Funding. Ogura:SymBio Pharmaceuticals: Consultancy, Honoraria; Celltrion, Inc.: Consultancy, Honoraria. Buske:Celltrion, Inc.: Consultancy, Honoraria. Kwak:Celltrion, Inc.: Consultancy. Kim:Celltrion, Inc.: Consultancy, Honoraria.