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
Randomisierte, doppelblinde, multizentrische Phase-III-Studie zur Wirksamkeit von CT-P16 im Vergleich zum EU-Originator bei metastasiertem oder refraktärem nicht-kleinzelligen Lungenkarzinom (nsNSCLC) Vergleich mit dem...
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
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
Verschraegen C et al.
BioDrugs. 2022; 36(6):749–760
Abstract
Background: CT-P16 is a candidate bevacizumab biosimilar.
Objective: This double-blind, multicenter, parallel-group, phase III study aimed to establish equivalent efficacy between CT-P16 and European Union-approved reference bevacizumab (EU-bevacizumab) in patients with metastatic or recurrent non-squamous non-small cell lung cancer (nsNSCLC).
Patients and Methods: Patients with stage IV or recurrent nsNSCLC were randomized (1:1) to receive CT-P16 or EU-bevacizumab (15 mg/kg every 3 weeks; ≤ 6 cycles) with paclitaxel (200 mg/m 2 ) and carboplatin (area under the curve 6.0; both for 4–6 cycles), as induction therapy. Patients with controlled disease after induction therapy continued with CT-P16 or EU-bevacizumab maintenance therapy. The primary endpoint was objective response rate (ORR) during the induction period. Time-to-event analyses, pharmacokinetics, safety, and immunogenicity were also evaluated. Results obtained after 1 year of follow-up are presented.
Results: Overall, 689 patients were randomized (CT-P16, N = 342; EU-bevacizumab, N = 347). ORR was 42.40 % (95% confidence interval [CI] 37.16–47.64) and 42.07% (95% CI 36.88–47.27) for CT-P16 and EU-bevacizumab, respectively. The risk difference (0.40 [95% CI − 7.02 to 7.83]) and risk ratio (1.0136 [90% CI 0.8767–1.1719]) for ORR fell within predefined equivalence margins (− 12.5 to + 12.5%, and 0.7368 to 1.3572, respectively), demonstrating equivalence between CT-P16 and EU-bevacizumab. Median response duration, time to progression, progression-free survival, and overall survival were comparable between treatment groups. Safety profiles were similar: 96.2% (CT-P16) and 93.0% (EU-bevacizumab) of patients experienced treatment-emergent adverse events. Pharmacokinetics and immunogenicity were comparable between groups.
Conclusions: Equivalent efficacy and similar pharmacokinetics, safety, and immunogenicity support bioequivalence of CT-P16 and EU-bevacizumab in patients with nsNSCLC.
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A Randomized, Double-Blind Trial Comparing the Pharmacokinetics of CT-P16, a Candidate Bevacizumab Biosimilar, with its Reference Product in Healthy Adult Males
Randomisierte doppelblinde Phase-I-Studie zur Pharmakokinetik, Sicherheit und Immunogenität von CT-P16 Vergleich mit dem Bevacizumab-Originator (EU- oder US-Originator) Bei gesunden männlichen Erwachsenen waren die Pharmakokinetik, das Sich...
A Randomized, Double-Blind Trial Comparing the Pharmacokinetics of CT-P16, a Candidate Bevacizumab Biosimilar, with its Reference Product in Healthy Adult Males
A Randomized, Double-Blind Trial Comparing the Pharmacokinetics of CT-P16, a Candidate Bevacizumab Biosimilar, with its Reference Product in Healthy Adult Males
Cho SH et al.
BioDrugs. 2019; 33(2):173–181
Abstract
Background: CT-P16 is a candidate biosimilar of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor that is used in the treatment of a range of advanced solid cancers.
Objective: The objective of this study was to demonstrate the pharmacokinetic equivalence of CT-P16 and European Union (EU)-approved bevacizumab (EU-bevacizumab) and US-licensed bevacizumab (US-bevacizumab) reference products.
Methods: In this double-blind, parallel-group phase I trial (ClinicalTrials.gov identifier NCT03247673), healthy adult males were randomized (1:1:1) to receive a single dose of CT-P16 5 mg/kg, EU-bevacizumab 5 mg/kg, or US-bevacizumab 5 mg/kg. Primary study endpoints were area under the concentration–time curve (AUC) from time zero to infinity (AUC∞), AUC from time zero to the last quantifiable concentration (AUClast), and maximum serum concentration (Cmax). Pharmacokinetic equivalence was shown if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratios of the AUC∞, AUClast, and Cmax were within the predefined bioequivalence margin of 80–125 %. Safety and immunogenicity were also evaluated.
Results: A total of 144 subjects were randomized: 47 to CT-P16, 49 to EU-bevacizumab, and 48 to US-bevacizumab. The 90 % CIs for the GM ratios of AUC∞, AUClast, and Cmax for CT-P16/EU-bevacizumab, CT-P16/US-bevacizumab, and EU-bevacizumab/US-bevacizumab comparisons were all within the bioequivalence margin. Mean serum concentration–time profiles, secondary pharmacokinetic parameters, and safety and immunogenicity profiles were comparable across all three treatment groups.
Conclusion: CT-P16 demonstrated pharmacokinetic equivalence to EU-bevacizumab and US-bevacizumab. Safety and immunogenicity profiles were similar for CT-P16, EU-bevacizumab, and US-bevacizumab. These data support the further clinical evaluation of CT-P16 as a bevacizumab biosimilar.
185P - Long Term Efficacy of Trastuzumab Biosimilar CT-P6 in Patients with HER2 Positive Early Breast Cancer: 6-year Survival Analysis of Phase III Study Results
Multinationale Phase-III-Studie zu Trastuzumab-Biosimilar bei frühem Brustkrebs, 6-Jahres-Follow-up Vergleich zum Trastuzumab-Originator CT-P6 weist auch in der Langzeitbeobachtung eine zum Referenz-Trastuzumab vergleichbare Wirksamkeit au...
185P - Long Term Efficacy of Trastuzumab Biosimilar CT-P6 in Patients with HER2 Positive Early Breast Cancer: 6-year Survival Analysis of Phase III Study Results
185P - Long Term Efficacy of Trastuzumab Biosimilar CT-P6 in Patients with HER2 Positive Early Breast Cancer: 6-year Survival Analysis of Phase III Study Results
Stebbing J et al.
Poster Presentation 185P; ESMO Breast Cancer 2022
Abstract
Background: CT-P6 is now approved in over 85 countries including US and EU as a biosimilar of reference trastuzumab (RTZ). The equivalence between CT-P6 and RTZ in clinical efficacy and safety has been demonstrated in studies including an international phase III randomized study (CT-P6 3.2). Here we report results for long-term efficacy of CT-P6 from a follow-up study of patients who were enrolled in the phase III study (CT-P6 3.2).
Methods: A total of 216 patients, 39.3% of the 549 patients randomized in CT-P6 3.2, were enrolled in an extension study for analysis of long-term survival data and followed up to 6 years from the last patient enrolled in CT-P6 3.2 study. The Kaplan-Meier method was used to estimate survival rates of time to event (TTE) endpoints, which included disease free survival (DFS) and overall survival (OS).
Results: The median follow-up duration was 76.4 month for ITT-E (enrolled patients in extension study) and 42.6 month for ITT (all randomized patients in CT-P6 3.2). Overall, the rates of DFS and OS were similar between CT-P6 and RTZ in both ITT and ITT-E sets. The number of DFS events (47 [18.2%] in CT-P6 and 42 [16.1%] in RTZ) and OS events (22 [8.1%] in CT-P6 and 25 [9.0%] in RTZ) were comparable in ITT set. The hazard ratios for DFS and OS for in the ITT set were 1.18 (95% CI: 0.77 – 1.80) and 0.95 (0.53 – 1.68), respectively. The estimated 6-year survival rates for DFS (0.78 [95% CI: 0.71 – 0.83] in the CT-P6 arm and 0.81 [95% CI: 0.75 – 0.86] in the RTZ arm), and OS (0.89 [95% CI: 0.84 – 0.93] in CT-P6 and 0.87 [95% CI: 0.81 – 0.91] in RTZ) were comparable in all ITT analyses. The median DFS and OS have not been reached due to insufficient number of events.
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Long-term efficacy and safety of CT-P6 versus trastuzumab in patients with HER2-positive early breast cancer: final results from a randomized phase III trial
Multinationale Phase-III-Studie zu Trastuzumab-Biosimilar bei frühem Brustkrebs, 3-Jahres-Follow-up Vergleich zum Trastuzumab-Originator CT-P6 weist eine zum Referenz-Trastuzumab vergleichbare Wirksamkeit, Pharmakokinetik, Immunogenität und Si...
Long-term efficacy and safety of CT-P6 versus trastuzumab in patients with HER2-positive early breast cancer: final results from a randomized phase III trial
Long-term efficacy and safety of CT-P6 versus trastuzumab in patients with HER2-positive early breast cancer: final results from a randomized phase III trial
Stebbing J et al.
Breast Cancer Res Treat. 2021;188(3):631-640
Abstract
Purpose: Equivalent efficacy was demonstrated for the biosimilar CT-P6 and trastuzumab following neoadjuvant therapy for patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer. Following adjuvant treatment, efficacy and safety were comparable between treatments. We report updated safety and efficacy data after up to 3 years’ follow-up.
Methods: Following neoadjuvant chemotherapy with CT-P6/trastuzumab, patients underwent surgery and continued receiving adjuvant CT-P6/trastuzumab. The primary endpoint (previously reported) was pathological complete response. Time-to-event analyses (disease-free survival [DFS], progression-free survival [PFS], and overall survival [OS]), study drug-related and cardiac adverse events, and immunogenicity were assessed during post-treatment follow-up.
Results: Most patients entered the follow-up period (CT-P6: 259 [95.6%]; trastuzumab: 269 [96.8%]). After a median follow-up of 38.7 (CT-P6) and 39.6 (trastuzumab) months, medians were not reached for time-to-event parameters; estimated hazard ratios (HRs) and 3-year survival rates were similar between groups. Estimated HRs (95% confidence intervals) for CT-P6 versus trastuzumab were 1.23 (0.78–1.93) for DFS, 1.31 (0.86–2.01) for PFS, and 1.10 (0.57–2.13) for OS (intention-to-treat population). Safety findings were comparable between groups for the overall study and follow-up period, including study drug-related cardiac disorders (CT-P6: 22 [8.1%] patients; trastuzumab: 24 [8.6%] patients [overall]) and decreases in left ventricular ejection fraction. Immunogenicity was similar between groups.
Conclusion: The similarity of the time-to-event analyses between CT-P6 and trastuzumab supports the equivalence in terms of efficacy established for the primary endpoint. CT-P6 was well tolerated, with comparable safety and immunogenicity to trastuzumab.
Efficacy and safety of CT-P6 versus reference trastuzumab in HER2-positive early breast cancer: updated results of a randomised phase 3 trial
Multinationale Phase-III-Studie Trastuzumab-Biosimilar bei frühem Brustkrebs, Post hoc-Analyse Adjuvante Darreichung, Vergleich zum Trastuzumab-Originator CT-P6 weist eine zum Referenz-Trastuzumab vergleichbare Wirksamkeit, Pharmakokinetik und Sicherheit auf.
Efficacy and safety of CT-P6 versus reference trastuzumab in HER2-positive early breast cancer: updated results of a randomised phase 3 trial
Efficacy and safety of CT-P6 versus reference trastuzumab in HER2-positive early breast cancer: updated results of a randomised phase 3 trial
Esteva FJ et al.
Cancer Chemother Pharmacol. 2019; 84(4):839-847
Abstract
Purpose: Neoadjuvant CT-P6, a trastuzumab biosimilar, demonstrated equivalent efficacy to reference trastuzumab in a phase 3 trial of HER2-positive early-stage breast cancer (EBC) (NCT02162667). We report post hoc analyses evaluating pathological complete response (pCR) and breast pCR alongside additional efficacy and safety measures.
Methods: Following neoadjuvant treatment and surgery, patients received adjuvant CT-P6 or trastuzumab (6 mg/kg) every 3 weeks for ≤ 1 year.
Results: In total, 271 and 278 patients received CT-P6 and trastuzumab, respectively. pCR and breast pCR rates were comparable between treatment groups regardless of age, region, or clinical stage. Overall, 47.6% (CT-P6) and 52.2% (trastuzumab) of patients experienced study drug-related treatment-emergent adverse events (TEAEs), including 17 patients reporting heart failure (CT-P6: 10; trastuzumab: 7). Two CT-P6 and three trastuzumab patients discontinued adjuvant treatment due to TEAEs.
Conclusion: Adjuvant CT-P6 demonstrated comparable efficacy and safety to trastuzumab at 1 year in patients with HER2-positive EBC, supporting CT-P6 and trastuzumab comparability.
CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial
Multinationale Phase-III-Studie zu Trastuzumab-Biosimilar bei frühem Brustkrebs, Primäranalyse Neoadjuvante Darreichung, Vergleich zum Trastuzumab-Originator CT-P6 weist eine zum Referenz-Trastuzumab vergleichbare Wirksamkeit und Sicherheit auf.
CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial
CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial
Stebbing J et al.
Lancet Oncol. 2017;18(7):917-928
Abstract
Background: CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer.
Methods: In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I–IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2–8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1–4) and FEC (fluorouracil [500 mg/m2], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m2]; day 1 of cycles 5–8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3–6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was −0.15 to 0.15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting.
Findings: Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46.8%; 95% CI 40.4–53.2] of 248 patients) and reference trastuzumab (129 [50·4%; 44.1–56.7] of 256 patients). The 95% CI of the estimated treatment outcome difference (−0.04 [95% CI −0.12 to 0.05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%).
Interpretation: CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer.
Trastuzumab biosimilars vs trastuzumab originator in the treatment of HER2-positive breast cancer: a systematic review and network meta-analysis
Review und Metaanalyse Vergleich von verschiedenen Trastuzumab-Biosimilars zum Trastuzumab-Originator Eine Meta-Analyse von Netzwerkdaten belegt die Nicht-Unterlegenheit von CT-P6 gegenüber dem Trastuzumab-Originator.
Trastuzumab biosimilars vs trastuzumab originator in the treatment of HER2-positive breast cancer: a systematic review and network meta-analysis
Trastuzumab biosimilars vs trastuzumab originator in the treatment of HER2-positive breast cancer: a systematic review and network meta-analysis
Tong L et al.
Immunopharmacol Immunotoxicol. 2022; 22:1-7
Abstract
Aim: Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer related death in women. Trastuzumab originator (Herceptin) is a monoclonal antibody used as a standard treatment for breast and metastatic gastric cancer when the cancer cells over-express human epidermal growth factor receptor type 2 (HER2). As the patent of Trastuzumab has now expired, biosimilars are moving into the market. It is still controversial to chose which trastuzumab biosimilar has the best treatment of HER2-positive breast cancer patients. We conducted this network meta-analysis to explore the best trastuzumab biosimilar in the treatment of HER2-positive breast cancer patients.
Methods: PubMed, Cochrane library databases, China National Knowledge infrastructure (CNKI) and WanFang database up to November 2021 were systematically searched. The following search terms were used: 'trastuzumab originator', and 'trastuzumab biosimilar'. No language restriction was imposed. The reference lists of all retrieved articles were also reviewed to identify additional articles missed by using these search terms.
Results: We got 10 studies to conduct network meta-analysis to evaluate efficacy and serious adverse reactions among various trastuzumab biosimilars and trastuzumab originator. The overall response rate (ORR) and pathological complete response (pCR) of SB3 were worse than trastuzumab originator significantly, while the ORR and pCR of other trastuzumab biosimilars had not yet reached statistical differences compared with each other. The cumulative ranking curve (SUCRA) probability indicated that the ORR from best to worst was CT-P6, Herceptin, HLX02, PF-05280014, R-TPR-016, BCD-022, MYL-1401O, SB3, and the pCR from best to worst was PF-05280014, CT-P6, Herceptin, ABP-980, SB3. The serious adverse events (SAEs) of CT-P6 were more than Herceptin and MYL-1401O significantly, while the SAEs of other trastuzumab biosimilars had not statistical differences. The SUCRA probability indicated that the SAEs from best to worst was MYL-1401O, Herceptin, PF-05280014, SB3, HLX02, BCD-22, CT-P6.
Conclusion: There was no statistical difference in both ORR and pCR of various trastuzumab biosimilars and Herceptin except SB3. The ORR and pCR of SB3 were worse than Herceptin. Both CT-P6 and PF-05280014 are better in the overall curative effect, but CT-P6 had the highest serious adverse reactions when compared with others. The PF-05280014 might be a better trastuzumab biosimilar in the treatment of HER2-positive breast cancer patients.
Mechanism of action of the trastuzumab biosimilar CT-P6
In-vitro-Untersuchung des Wirkmechanismus von CT-P6 an Brustkrebszellen mit Her2-Überexpression und Magenkrebszellen Vergleich zum Trastuzumab-Originator Untersuchungen an Modellen von Brustkrebszellen mit Her2-Überexpression sowie von Magenkrebszellen belegen den vergleichbaren Wirkmechanismus von CT-P6 gegenüber dem Trastuzumab-Originator.
Mechanism of action of the trastuzumab biosimilar CT-P6
Mechanism of action of the trastuzumab biosimilar CT-P6
Jeong SA et al.
Expert Opin Biol Ther. 2019; 19(10):1085-1095
Abstract
Objectives: Therapeutic monoclonal antibody biosimilars are expected to help reduce the sizeable economic burden of targeted treatments. Trastuzumab (Herceptin®), a recombinant humanized monoclonal antibody that binds to the extracellular domain of HER2, is approved for use in HER2-overexpressing breast cancer (in both the adjuvant and metastatic settings) and HER2-positive gastric cancer. CT-P6 (Herzuma®) is a biosimilar of trastuzumab, designed to bind with high affinity and specificity to the same HER2 epitope as the reference product. We investigated whether CT-P6 exerts its effects through the same mechanism of action as trastuzumab.
Methods: The mechanism of action of CT-P6 and trastuzumab, both as monotherapy and in combination with paclitaxel or pertuzumab, was compared in HER2-overexpressing breast cancer and gastric cancer cell models.
Results: We confirmed that CT-P6 functions in a manner similar to trastuzumab by binding to the HER2 receptor, which is central to the effects of trastuzumab in all indications.
Conclusions: Collectively, the results of this study show that the mechanisms of action of CT-P6 and trastuzumab are similar in HER2-positive breast cancer and gastric cancer models and, therefore, CT-P6 can be expected to perform similarly in the clinical setting.
Efficacy and Safety of CT-P10 Versus Rituximab in Untreated Low-Tumor-Burden Follicular Lymphoma: Final Results of a Randomized Phase III Study
Phase-III-Studie zu Rituximab-Biosimilar bei follikulärem Lymphom, Finalanalyse Vergleich zum US-amerikanischen Rituximab-Originator CT-P10 weist eine zum US-amerikanischen -Rituximab-Originator vergleichbare Wirksamkeit, Pharmakokinetik, Immunogenität und ...
Efficacy and Safety of CT-P10 Versus Rituximab in Untreated Low-Tumor-Burden Follicular Lymphoma: Final Results of a Randomized Phase III Study
Efficacy and Safety of CT-P10 Versus Rituximab in Untreated Low-Tumor-Burden Follicular Lymphoma: Final Results of a Randomized Phase III Study
Kwak LW et al.
Clin Lymphoma Myeloma Leuk. 2022;22(2):89-97
Abstract
Introduction: This double-blind, parallel-group, active-controlled phase III trial (NCT02260804) assessed CT-P10 and rituximab safety and efficacy in patients with previously untreated low-tumor-burden follicular lymphoma (LTBFL), including after a single switch from rituximab to CT-P10.
Patients and Methods: LTBFL patients were randomized (1:1) to receive CT-P10 or rituximab (375 mg/m2 intravenously; day 1 of 4 7-day cycles). Patients achieving disease control entered a 2-year maintenance period. CT-P10 or rituximab were administered every 8 weeks (6 cycles) in year 1; all patients could receive CT-P10 (every 8 weeks; 6 cycles) in year 2. Secondary endpoints (reported here) were overall response rate (ORR) during the study period, progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Safety and immunogenicity were evaluated.
Results: Between November 9, 2015 and January 4, 2018, 258 patients were randomized (130 for CT-P10; 128 for rituximab). ORR was similar between groups over the study period (CT-P10: 88%; rituximab: 87%). After 29.2 months’ median follow-up, median PFS, TTP, and OS were not estimable; 24-month Kaplan-Meier estimates suggested similarity between groups. Overall, 114 (CT-P10: 88%), and 104 (rituximab: 81%) patients experienced treatment-emergent adverse events. The single switch was well tolerated.
Conclusion: These updated data support therapeutic similarity of CT-P10 and rituximab and support the use of CT-P10 monotherapy for previously untreated LTBFL.
Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 in comparison with rituximab in patients with previously untreated low-tumour-burden follicular lymphoma: a randomised, double-blind, parallel-group, phase 3 trial
Phase-III-Studie zu Rituximab-Biosimilar bei follikulärem Lymphom, Primäranalyse Vergleich zum US-amerikanischen Rituximab-Originator CT-P10 weist eine zum US-amerikanischen...
Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 in comparison with rituximab in patients with previously untreated low-tumour-burden follicular lymphoma: a randomised, double-blind, parallel-group, phase 3 trial
Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 in comparison with rituximab in patients with previously untreated low-tumour-burden follicular lymphoma: a randomised, double-blind, parallel-group, phase 3 trial
Michinori O et al.
Lancet Haematol. 2018;5(11):e543-e553
Abstract
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.
Long-term efficacy and safety of CT-P10 or rituximab in untreated advanced follicular lymphoma: a randomized phase 3 study
Globale Phase-III-Studie zu Rituximab-Biosimilar bei fortgeschrittenem follikulärem Lymphom, Follow-up-Analyse Vergleich zum US-amerikanischen Rituximab-Originator CT-P10 weist eine zum US-amerikanischen Rituximab-Originator vergleichbare Wirksamkeit, Pharmakokinetik, Immunogen...
Long-term efficacy and safety of CT-P10 or rituximab in untreated advanced follicular lymphoma: a randomized phase 3 study
Long-term efficacy and safety of CT-P10 or rituximab in untreated advanced follicular lymphoma: a randomized phase 3 study
Buske C et al.
Blood Adv. 2021 14;5(17):3354-3361
Abstract
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.
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
Globale Phase-III-Studie zu Rituximab-Biosimilar bei fortgeschrittenem follikulärem Lymphom, Primär-Analyse Vergleich zum US-amerikanischen Rituximab-Originator CT-...
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
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
Kim WS et al.
Lancet Haematol. 2017;4(8):e362-e373
Abstract
Background: 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.
Budget Impact Analysis of the Introduction of Rituximab and Trastuzumab Intravenous Biosimilars to EU-5 Markets
Analyse zum Einsparpotenzial von Rituximab- und Trastuzumab-Biosimilars gegenüber den Originatoren Trastuzumab- und Rituximab-Biosimilars in subkutaner Formulierung können im Vergleich zu intravenös verabreichten Produkten Verwaltungskosten und in intravenöser Formulierung Arzneimittelkos...
Budget Impact Analysis of the Introduction of Rituximab and Trastuzumab Intravenous Biosimilars to EU-5 Markets
Budget Impact Analysis of the Introduction of Rituximab and Trastuzumab Intravenous Biosimilars to EU-5 Markets
Jang M et al.
BioDrugs. 2021;35(1):89-101
Abstract
Background: Biologic treatments impose a large financial burden on healthcare payers. Subcutaneous formulations of trastuzumab and rituximab offer administration cost savings relative to the intravenous products through reduced preparation and infusion times. However, intravenous biosimilars have the potential to offset administration costs through lower drug costs.
Objective: The objective was to develop a budget impact model (BIM) from a payer’s perspective for the EU-5 countries (UK, France, Germany, Spain, Italy) to demonstrate the economic impact of using intravenous trastuzumab and rituximab biosimilars.
Methods: An incidence-based BIM was developed to estimate the net budget impact utilising epidemiology data from the literature, market research data on the use of relevant treatments in all approved indications, and corresponding costs. The budget impact was estimated for 5 years following introduction of the biosimilars.
Results: Analysis using the base-case results indicated that adoption of the biosimilars trastuzumab and rituximab would result in net cost savings. At year 5, the net budget saving ranged from €4.05 million to 303.86 million for rituximab and from €19 million to 172 million for trastuzumab. The cost saving could potentially extend treatment to 291–15,671 more patients with rituximab and 622–3688 more patients with trastuzumab.
Conclusion: This budget impact analysis emphasised that increased use of intravenous rituximab and trastuzumab biosimilars may result in cost savings from the payer’s perspective across the EU-5 countries
Understanding the Role of Comparative Clinical Studies in the Development of Oncology Biosimilars
Review Die Zulassung von Biosimilars beruht auf der klinisch nachgewiesenen Gleichwertigkeit zum Originator-Präparat, die in der Regel nicht für jede einzelne Indikation nachgewiesen werden muss. Um potenziell klinisch bedeutsame Unterschiede zu erkennen, sollten deshalb vergleichende klinische Studien...
Understanding the Role of Comparative Clinical Studies in the Development of Oncology Biosimilars
Understanding the Role of Comparative Clinical Studies in the Development of Oncology Biosimilars
Stebbing J et al.
J Clin Oncol. 2020 1;38(10):1070-1080
Abstract
Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.