Rituximab biosimilars, GP2013 and CT-P10, shown to be comparable to reference rituximab

In the August 2017 issue of The Lancet Haematology, two studies on two different rituximab biosimilars were published. Both studies were conducted in patients with newly diagnosed advanced-stage follicular lymphoma, and both studies compared the biosimilar with rituximab (R) in combination with CVP. Biosimilars are molecules which mimic a reference drug which is no longer under patent, with the potential benefit being that they may have a lower cost than the reference drug.

The first study was by Wojciech Jurczak from the Department of Hematology at Jagiellonian University, Krawkow, Poland, and colleagues and compared rituximab with the biosimilar GP2013 in an ongoing, multinational, double-blind, randomized, phase III trial which enrolled 629 patients.

Key highlights from Jurczak et al.

• GP2013 (375mg/m²) plus CVP vs. rituximab (375mg/m²) plus CVP, for eight 21-day cycles, in responders this was followed by up to two years of maintenance monotherapy (375mg/m² every three months)
• GP2013+CVP = 312 pts, R+CVP = 315 pts, similar patient disposition between groups
• Median follow-up = 11.6 months
  • ORR: GP2013+CVP = 87% vs. R+CVP = 88%
  • CR: GP2013+CVP = 15% vs. R+CVP = 13%
• Efficacy at data cut-off, median follow up = 23.8 months
  • PFS: GP2013+CVP = 70% vs. R+CVP = 76%
  • OS: GP2013+CVP = 93% vs. R+CVP = 91%
  • Median PFS and OS not met
• GP2013+CVP had a similar pharmacokinetic profile to R+CVP
• Safety profile was also similar between GP2013+CVP and R+CVP
  • AEs: GP2013+CVP = 93% vs. R+CVP = 91%
  • SAEs: GP2013+CVP = 23% vs. R+CVP = 20%
  • Most common grade 3/4 AE was neutropenia: GP2013+CVP = 18% vs. R+CVP = 21%

In the second study by Won Seog Kim from Sungkyunkwan University School of Medicine, Seoul, South Korea, and colleagues, the biosimilar used was CT-P10 in an ongoing, double-blind, randomized, active-controlled, phase III trial which enrolled 140 patients. Both GP2013 (Riximyo®/Rixathon®)  and CT-P10 (Truxima®) have been given ‘positive opinions’ by the European Medicines Agency recently, as previously reported.

Key highlights from Kim et al.

• CT-P10 (375mg/m²) plus CVP vs. rituximab (375mg/m²) plus CVP, for eight 21-day cycles in responders this was followed by up to two years of maintenance monotherapy (375mg/m² every two months)
• ITT population: CT-P10+CVP = 70 pts, R+CVP = 70 pts, similar patient disposition between groups at baseline
• Efficacy population: CT-P10+CVP = 66 pts, R+CVP = 68 pts
  • Median follow-up = 24 weeks (induction period)
  • ORR: CT-P10+CVP = 97% vs. R+CVP = 92.6%
  • CR: CT-P10+CVP = 30% vs. R+CVP = 22%
  • CRu: CT-P10+CVP = 9% vs. R+CVP = 12%
• CT-P10+CVP was shown to have a similar pharmacokinetic profile to R+CVP
• Safety profile was comparable between CT-P10+CVP and R+CVP
  • Treatment-related AEs: CT-P10+CVP = 53% vs. R+CVP = 49%
  • Treatment-related SAEs: CT-P10+CVP = 9% vs. R+CVP = 6%
  • Treatment-related neutropenia: CT-P10+CVP = 21% vs. R+CVP = 7%

Both of these studies showed that each biosimilar had comparable efficacy data when compared with reference rituximab, and this extended to the pharmacokinetic profile and most of the safety data. In a Comment article in the same issue of The Lancet Haematology, Shinichi Makita and Kensei Tobinai make the points that ORR is not a ‘robust endpoint’ for efficacy in follicular lymphoma, and that CVP is now less commonly used in follicular lymphoma, with bendamustine or CHOP being more likely to be combined with rituximab. Additionally, the data reported here is early, and more mature data would be beneficial to ensure comparability after the maintenance period. Finally, the Comment article concluded by stating that these two studies help support the further incorporation of rituximab biosimilars into daily practice.

Abstracts:

• GP2013 is a rituximab biosimilar developed to stringent development guidelines, including non-clinical and preclinical investigations and clinical trials in rheumatoid arthritis and follicular lymphoma. We aimed to compare the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of GP2013 plus cyclophosphamide, vincristine, and prednisone (GP2013-CVP) with rituximab-CVP (R-CVP) in patients with follicular lymphoma. Methods. In this phase 3, multinational, double-blind, randomised, controlled trial, adults (aged 18 years or older) with previously untreated, advanced stage (Ann Arbor stage III or IV) follicular lymphoma of WHO histological grades 1, 2, or 3a were randomly assigned (1:1) using interactive response technology to eight cycles of GP2013-CVP or R-CVP (combination phase), followed by monotherapy maintenance in responders for a 2-year period. Randomisation was stratified by Follicular Lymphoma International Prognostic Index risk group and geographic region. The primary endpoint was comparability in overall response, with equivalence concluded if the entire 95% CI was within a margin of −12% to 12%. The primary endpoint was analysed using the per-protocol set, which included all patients who received at least one (partial or complete) dose of investigational treatment and who did not have any major protocol deviations. The trial is registered with ClinicalTrials.gov, number NCT01419665, and is ongoing. Findings. Between Dec 1, 2011, and Jan 15, 2015, 858 patients were screened for eligibility. 314 patients were randomly assigned to GP2013, of whom 312 were given GP2013, and 315 were assigned to reference rituximab. Median follow-up was 11·6 months (IQR 5·8–18·2) for the primary analysis. The primary endpoint, equivalence of overall response, was met (271 [87%] of 311 patients with GP2013 and 274 [88%] of 313 patients with reference rituximab achieved an overall response; difference −0·40% [95% CI −5·94 to 5·14]). Occurrence of adverse events and serious adverse events was similar between the treatment groups (289 [93%] of 312 patients in the GP2013-CVP group had an adverse event and 71 [23%] of 312 patients had a serious adverse event; 288 [91%] of 315 patients in the R-CVP group had an adverse event and 63 [20%] had a serious adverse event). The most common adverse event was neutropenia (80 [26%] of 312 patients in the GP2013-CVP group and 93 [30%] of 315 patients in the R-CVP group in the combination phase and 23 [10%] of 231 patients in the GP2013-CVP group and 13 [6%] of 231 patients in the R-CVP group in the maintenance phase). The most common grade 3 or 4 adverse event during the combination and maintenance phase was neutropenia (55 [18%] of 312 patients in the GP2013-CVP group and 65 [21%] of 315 patients in the R-CVP group in the combination phase and 17 [7%] of 231 patients in the GP2013-CVP group and nine [4%] of 231 patients in the R-CVP group in the maintenance phase). The occurrence of anti-drug antibodies was similar in the treatment groups (five [2%] of 268 patients in the GP2013-CVP; three [1%] in the R-CVP group). Interpretation. Our results show that GP2013 represents a viable rituximab biosimilar candidate for patients with previously untreated advanced follicular lymphoma. The introduction of biosimilars provides additional therapeutic options with potential to increase access to effective and life-saving biological therapies such as rituximab.
• Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. Methods. In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III–IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0–2 vs 3–5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and CmaxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the −7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum concentration–time curve at steady state (AUCτ) and maximum serum concentration at steady state (CmaxSS) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Findings. Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI −4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05–111·17) for AUCτ and 100·67% (93·84–108·00) for CmaxSS, with all CIs within the bioequivalence margin of 80–125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation. In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma.

References:

1. Jurczak W. et al. Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study. The Lancet Haematology. 2017 Aug; 4(8): e350-e361. DOI: 1016/S2352-3026(17)30106-0. [Epub ahead of print 2017 Jul 14].
2. Kim W.S. et al. Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial. The Lancet Haematology. 2017 Aug; 4(8): e362-e373. DOI: 1016/S2352-3026(17)30120-5. [Epub ahead of print 2017 Jul 14].
3. Makita S. and Tobinai K. Rituximab biosimilars: introduction into clinical practice. The Lancet Haematology. 2017 Aug; 4(8): e342-e343. DOI: 1016/S2352-3026(17)30124-2. [Epub ahead of print 2017 Jul 14].