Background: Studies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lymphoma. Methods: In this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients (≥18 years) with stage II–IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m2 intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period of CT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804. Findings: Between Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 to rituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1·8%; 90% CI −6·43 to 10·20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event. Interpretation: CT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma. Funding: Celltrion, Inc.
Bibliographical noteFunding Information:
MO has received research funding from Symbio, and personal fees from Celltrion, Celgene, AstraZeneca, Takeda, Mundipharma, and Meiji Seika Pharma. JS has received grants from Celltrion, Chugai-Roche, Eisai, Takeda, Celgene, Sumitomo Dainippon, Taiho Pharmaceutical, Pfizer, Symbio Pharmaceutical, Astellas, and Toyama Chemical; personal fees from Chugai-Roche, Eisai, Takeda, Celgene, Bristol-Myers Squibb, AbbVie, and Sumitomo Dainippon; and consultancy or advisory fees from Celgene, AbbVie, and Zenyaku Kogyo. WJ has received research funding from Celltrion and research and personal fees from Sandoz Novartis and Roche. MT has received grants from Roche and AbbVie; and personal fees from Roche, Celgene, Takeda, Gilead, Janssen, Bristol-Myers Squibb, MorphoSys, Incyte, and AbbVie. LP has received travel expenses from Celltrion. BC has received personal fees from Celltrion, Mundipharma, Celgene, and Novartis. SJL, SYL, and YJB are employees of Celltrion. LWK is a consultant for Celltrion Inc. and has received travel expenses and personal fees from Celltrion and Celltrion Healthcare. JMS, S-GC, HN, GT, JSK, AL, JM, NI, ALM, OS, EZ, EYR, CB, and W-SK declare no competing interests.
We thank all study investigators, staff, and patients who contributed to this study. The study was sponsored by Celltrion, Inc. Medical writing support, including development of a draft outline and subsequent drafts in consultation with the authors, assembling tables and figures, collating author comments, copyediting, fact checking, and referencing, was provided by Rick Flemming, PhD, CMPP, and Alice Wareham, PhD, at Aspire Scientific Limited (Bollington, UK), and funded by Celltrion, Inc.
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