• Tais F Galvao, Annemeri Livinalli, Luciane C Lopes, Ivan R Zimmermann, and Marcus Tolentino Silva.
• School of Pharmaceutical Sciences, Universidade Estadual de Campinas, Campinas, Brazil.
• Cochrane Db Syst Rev. 2024 Nov 28; 11 (11): CD013539CD013539.

BackgroundBiosimilars are products containing an approved biological medicine. They are similar, but not identical, to an originator medicine. In cancer, biosimilars have been developed from the monoclonal antibodies, bevacizumab, rituximab, and trastuzumab. They have become available for the treatment of lung, colorectal, non-Hodkin's lymphoma, and breast cancers. As these biological products are not identical, synthesis of evidence of the clinical effects of biosimilars compared to their originators is needed to understand their comparative effectiveness and harms.ObjectivesTo evaluate the benefits and harms of biosimilar monoclonal antibodies versus their originator drugs for adults with cancer.Search MethodsWe searched bibliographic (CENTRAL, MEDLINE, Embase, Web of Science) and clinical trials databases to February 2024.Selection CriteriaWe included head-to-head randomised controlled trials conducted in adults with cancer treated with biosimilar or originator monoclonal antibodies.Data Collection And AnalysisWe followed standard Cochrane methodology. Primary outcomes were progression-free survival, duration of response, overall survival, breast cancer's pathological complete response, serious adverse events, and health-related quality of life. If survival estimates were adjusted or provided as rates, we did not combine them. We used Cochrane's RoB 1 tool to assess the risk of bias and GRADE to evaluate the certainty of evidence of critical and important outcomes according to the relevance determined by consumers.Main ResultsWe included 55 studies with 22,046 adults (23 of bevacizumab, 10,639 participants with colorectal or lung cancer; 17 of rituximab, 4412 participants with non-Hodgkin's lymphoma; and 15 of trastuzumab, 6995 participants with breast cancer). Studies were conducted in all continents, most were multicentre, and all were funded by the drug manufacturer. Participants' ages ranged from 47 (mean) to 62 (median) years and the proportion of women from 18% to 100%. Fifteen studies were conducted as non-inferiority and 40 as equivalence. The overall risk of bias was low; main biases were in the incomplete outcome data and selective reporting domains. Bevacizumab biosimilar versus bevacizumab originator in lung or colorectal cancer Progression-free survival is likely similar between bevacizumab biosimilar and the originator (per 1000: 380 in both groups at 12 months, hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 5 studies, 2660 participants; moderate-certainty evidence). There were no differences in lung or colorectal cancer subgroups. Bevacizumab biosimilar is likely similar to the originator in duration of response (per 1000: 219 participants who achieved response progressed with biosimilar versus 210 with originator at 12 months; HR 1.05, 95% CI 0.81 to 1.37; 1 study, 762 participants; moderate-certainty evidence) and overall survival (per 1000: 592 with biosimilar versus 610 with originator at 12 months; HR 1.06, 95% CI 0.94 to 1.19; 5 studies, 2783 participants; moderate-certainty evidence). There were no differences in cancer type subgroups. Bevacizumab biosimilar is likely similar to the originator in serious adverse events (per 1000: 303 with biosimilar versus 309 with originator; risk ratio (RR) 0.98, 95% CI 0.93 to 1.03; 23 studies, 10,619 participants; moderate-certainty evidence). Bevacizumab biosimilar may be similar to originator in health-related quality of life as scores were comparable in the one study that assessed this outcome in metastatic colorectal cancer (low-certainty evidence). This critical outcome was not assessed in other biosimilars comparisons. Bevacizumab biosimilar is likely similar to originator in objective response (per 1000: 481 with biosimilar versus 501 with originator; RR 0.96, 95% CI 0.93 to 1.00; 23 studies, 10,054 participants; moderate-certainty evidence) and mortality (per 1000: 287 with biosimilar versus 279 with originator; RR 1.03, 95% CI 0.97 to 1.09; 19 studies, 9231 participants; moderate-certainty evidence). There were no differences in lung or colorectal cancers. Rituximab biosimilar versus rituximab originator in non-Hodgkin's lymphoma Rituximab biosimilar is likely similar to originator in progression-free survival (7 studies, 2456 participants), duration of response (2 studies, 522 participants), and overall survival (7 studies, 2353 participants; data not pooled as survival estimates were adjusted for different factors or reported as rates) (all moderate-certainty evidence). Rituximab biosimilar is likely similar to originator in the risk of serious adverse events (per 1000: 210 with biosimilar versus 204 with originator; RR 1.03, 95% CI 0.94 to 1.14; 15 studies, 4197 participants; moderate-certainty evidence) and objective response (per 1000: 807 with biosimilar versus 799 with originator; RR 1.01, 95% CI 0.98 to 1.04; 16 studies, 3922 participants; moderate-certainty evidence). No study reported quality of life. Rituximab biosimilar is similar to originator in mortality (per 1000: 52 with biosimilar versus 53 with originator; RR 0.97, 95% CI 0.70 to 1.35; 8 studies, 2557 participants; high-certainty evidence). Trastuzumab biosimilar versus trastuzumab originator in breast cancer Trastuzumab biosimilar is likely similar to originator in progression-free survival (4 studies, 2221 participants), duration of response (3 studies, 1488 participants), and overall survival (6 studies, 2221 participants), which were not pooled due to adjustment for different factors or provided as rates. No study reported quality of life. Trastuzumab biosimilar may be similar to originator in pathological complete response (per 1000: 459 with biosimilar versus 433 with originator; RR 1.06, 95% CI 0.95 to 1.17; 7 studies, 3403 participants; low-certainty evidence), is likely similar in serious adverse events (per 1000: 129 in both groups; RR 1.00, 95% CI 0.85 to 1.17; 13 studies, 6183 participants; moderate-certainty evidence), and slightly increases objective response (per 1000: 801 with biosimilar versus 777 with originator; RR 1.03, 95% CI 1.01 to 1.05; 13 studies, 5509 participants; moderate-certainty evidence).Authors' ConclusionsTreatment with bevacizumab, rituximab, and trastuzumab biosimilars are likely similar to their originator drugs in terms of their impact on progression-free survival, duration of response, overall survival, serious adverse events, objective response, and mortality. Limited evidence showed similarity in pathological complete response for trastuzumab and quality of life for bevacizumab compared with originators, which was not assessed in the other comparisons. The overall certainty of evidence was moderate and imprecision was the main reason for downgrading our certainty in the findings.Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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