Biosimilar monoclonal antibodies for cancer treatment in adults.

Biosimilars 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. To evaluate the benefits and harms of biosimilar monoclonal antibodies versus their originator drugs for adults with cancer. We searched bibliographic (CENTRAL, MEDLINE, Embase, Web of Science) and clinical trials databases to February 2024. We included head-to-head randomised controlled trials conducted in adults with cancer treated with biosimilar or originator monoclonal antibodies. We 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. We 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). Treatment 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.

Galvao TF ，Livinalli A ，Lopes LC ，Zimmermann IR ，Silva MT ... -  《Cochrane Database of Systematic Reviews》

Anti-vascular endothelial growth factor biosimilars for neovascular age-related macular degeneration.

Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss and disability worldwide. Although intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is an effective treatment option that helps to prevent vision loss or to improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems. A biosimilar is a biological product that has been developed to be nearly identical to a previously approved biological product. The use of biosimilars may help reduce costs and so may increase patient access to effective biologic medicines with similar levels of safety to the drugs on which they are based. To assess the benefits and harms of anti-VEGF biosimilar agents compared with their corresponding anti-VEGF agents (i.e. the reference products) that have obtained regulatory approval for intravitreal injections in people with neovascular AMD. We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries together with reference checking and contact with study authors to identify studies that are included in the review. The latest search date was 2 June 2023. We included randomized controlled trials (RCTs) that compared approved anti-VEGF biosimilars with their reference products for treating the eyes of adult participants (≥ 50 years) who had an active primary or recurrent choroidal neovascularization lesion secondary to neovascular AMD. Our outcomes were: best-corrected visual acuity (BCVA), central subfield thickness (CST), vision-related quality of life, serious ocular and non-ocular adverse events (AE), treatment-emergent adverse events (TEAEs), anti-drug antibodies (ADAs), and serum concentrations of biosimilars and reference drugs. We assessed the risk of bias (RoB) for seven outcomes reported in a summary of findings table by using the Cochrane RoB 2 tool. We synthesized results for each outcome using meta-analysis, where possible, by calculating risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. Where this was not possible due to the nature of the data, we summarized the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes. We included nine parallel-group multi-center RCTs that enrolled a total of 3814 participants (3814 participating eyes), with sample sizes that ranged from 160 to 705 participants per study. The mean age of the participants in these studies ranged from 67 to 76 years, and the proportion of women ranged from 26.5% to 58.7%. Ranibizumab (Lucentis) was the reference product in seven studies, and aflibercept (Eyelea) was the reference product in two others. All the included studies had been supported by industry. The follow-up periods ranged from 12 to 52 weeks (median 48 weeks). Five studies (56%) were conducted in multi-country settings across Europe, North America and Asia, two studies in India, and one each in Japan and the Republic of Korea. We judged all the included studies to have met high methodological standards. With regard to efficacy, our meta-analyses demonstrated that anti-VEGF biosimilars for neovascular AMD resulted in little to no difference compared with the reference products for BCVA change at 8 to 12 weeks (MD -0.55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% CI -1.17 to 0.07; 8 studies, 3603 participants; high-certainty evidence) and the proportion of participants who lost fewer than 15 letters in BCVA at 24 to 48 weeks (RR 0.99, 95% CI 0.98 to 1.01; 7 studies, 2658 participants; moderate-certainty evidence). Almost all participants (96.6% in the biosimilar group and 97.0% in the reference product group) lost fewer than 15 letters in BCVA. The evidence from two studies suggested that there was no evidence of difference between biosimilars and reference products in vision-related quality of life measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) summary scores at 24 to 48 weeks (MD 0.82, 95% CI -0.70 to 2.35; 2 studies, 894 participants; moderate-certainty evidence). With regard to the safety profile, meta-analyses also revealed little to no difference between anti-VEGF biosimilars and the reference products for the proportion of participants who experienced serious ocular AEs (RR 1.24, 95% CI 0.68 to 2.26; 7 studies, 3292 participants; moderate-certainty evidence), and for TEAEs leading to investigational product discontinuation or death (RR 0.96, 95% CI 0.63 to 1.46; 8 studies, 3497 participants; moderate-certainty evidence). Overall, 1.4% of participants in the biosimilar group and 1.2% in the reference product group experienced serious ocular adverse events. The most frequently documented serious ocular AEs were retinal hemorrhage and endophthalmitis. Although the evidence is of low certainty due to imprecision, meta-analysis suggested that anti-VEGF biosimilars led to no difference compared with the reference products for cumulative incidence of ADAs (RR 0.84, 95% CI 0.58 to 1.22; 8 studies, 3066 participants; low-certainty evidence) or mean maximum serum concentrations (MD 0.42 ng/mL, 95% CI -0.22 to 1.05; subgroup of 3 studies, 100 participants; low-certainty evidence). We judged the overall risk of bias to be low for all studies. In our review, low to high certainty evidence suggests that there is little to no difference, to date, between the anti-VEGF biosimilars approved for treating neovascular AMD and their reference products in terms of benefits and harms. While anti-VEGF biosimilars may be a viable alternative to reference products, current evidence for their use is based on a limited number of studies - particularly for comparison with aflibercept - with sparse long-term safety data, and infrequent assessment of quality of life outcomes. Our effect estimates and conclusions may be modified once findings have been reported from studies that are currently ongoing, and studies of biosimilar agents that are currently in development. Cochrane Eyes and Vision US Project is supported by grant UG1EY020522, National Eye Institute, National Institutes of Health. Takeshi Hasegawa and Hisashi Noma were supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239). Protocol available via doi.org/10.1002/14651858.CD015804.

Sunaga T ，Maeda M ，Saulle R ，Ng SM ，Sato MT ，Hasegawa T ，Mason AN ，Noma H ，Ota E ... -  《Cochrane Database of Systematic Reviews》

Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early-stage Hodgkin's lymphoma.

Early-stage Hodgkin's lymphoma in adults is commonly treated with combined modality treatment of chemotherapy followed by radiotherapy. The role of radiotherapy has been questioned due to potential long-term adverse effects. To assess the effects of chemotherapy compared to chemotherapy plus radiotherapy in adults with early-stage Hodgkin's lymphoma. We updated all previous searches for randomised controlled trials (RCTs) on the databases Cochrane Central Register of Controlled Trial, MEDLINE and Embase, in trial registries and in relevant conference proceedings until November 2023. We included RCTs comparing chemotherapy alone with chemotherapy plus radiotherapy in adults with early-stage Hodgkin's lymphoma and excluded trials with more than 20% of participants with advanced Hodgkin's lymphoma. We considered immunotherapy in addition to chemotherapy eligible if both were applied similarly in the comparator groups, but did not identify such trials. For our comparisons, we separated RCTs with the same number of chemotherapy cycles in both arms and RCTs with a different number of cycles, when the chemotherapy regimens were the same. We separated RCTs which compared participants with a favourable, mixed or unfavourable risk profile. Two review authors independently screened search results, extracted data and assessed the quality of included trials. A third review author resolved discrepancies. We analysed time-to-event outcomes (overall survival, progression-free survival) as hazard ratios (HR) and binary outcomes (adverse events) as risk ratios (RR). We assessed the certainty of evidence using the GRADE approach. We included nine comparisons of eight RCTs involving 3840 participants in this updated review. Same number of chemotherapy cycles in both trial arms Favourable disease For overall survival in individuals with favourable Hodgkin's lymphoma, the evidence is uncertain and inconclusive (HR 0.92, 95% confidence interval (CI) 0.11 to 7.92; 2 RCTs, 1245 participants; very low-certainty evidence due to study limitations, inconsistency and imprecision). Additional radiotherapy to chemotherapy is likely to improve progression-free survival (HR 0.36, 95% CI 0.20 to 0.68; 2 RCTs, 1245 participants; moderate-certainty evidence due to study limitations). The evidence was uncertain and inconclusive for second-cancer-related mortality (RR 0.93, 95% CI 0.01 to 74.24; 2 RCTs, 1245 participants; very low-certainty evidence due to study limitations, inconsistency and substantial imprecision) and suggests little to no difference in cardiac disease-related mortality (RR 0.89, 95% CI 0.06 to 14.16; 1 RCT, 667 participants; low-certainty evidence due to substantial imprecision). There were no data on infection-related mortality or infertility. Mixed population For a population of mixed risk profile, the evidence on overall survival is uncertain and inconclusive (HR 0.79, 95% CI 0.13 to 4.80; 2 RCTs, 572 participants; very low-certainty evidence due to study limitations, inconsistency and imprecision). It indicates that additional radiotherapy may lead to an improvement in progression-free survival (HR 0.71, 95% CI 0.43 to 1.17; 2 RCTs, 572 participants; low-certainty evidence due to study limitations and imprecision). The evidence is uncertain and inconclusive for infection-related mortality (RR 1.35, 95% CI 0.17 to 10.87; 2 RCTs, 572 participants) and second-cancer-related mortality (RR 0.52, 95% CI 0.09 to 2.98; 2 RCTs, 572 participants) (both very low-certainty evidence due to study limitations and substantial imprecision), but suggests that additional radiotherapy may increase cardiac disease-related mortality (RR 3.03, 95% CI 0.12 to 73.92; 1 RCT, 420 participants; low-certainty evidence due to substantial imprecision). There were no data on infertility. Unfavourable disease For individuals with unfavourable disease, the evidence on overall survival is uncertain and inconclusive (HR 0.69, 95% CI 0.20 to 2.44; 2 RCTs, 688 participants; very low-certainty evidence due to study limitations and substantial imprecision), but additional radiotherapy probably improves progression-free survival (HR 0.55, 95% CI 0.19 to 1.60; 1 RCT, 651 participants; moderate-certainty evidence due to imprecision). The evidence was uncertain and inconclusive for cardiac disease-related mortality (RR 2.85, 95% CI 0.12 to 65.74; 1 RCT, 37 participants; very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infection-related mortality, second-cancer related mortality or infertility. Different number of chemotherapy cycles in both trial arms Favourable disease The evidence for overall survival in individuals with favourable disease treated with different numbers of chemotherapy cycles in both arms is uncertain and inclusive (HR 0.36, 95% CI 0.04 to 3.38; 1 RCT, 357 participants; very low-certainty evidence due to study limitations and substantial imprecision), yet it suggests a likely improvement in progression-free survival with additional radiotherapy (HR 0.08, 95% CI 0.02 to 0.32; 1 RCT, 357 participants; moderate-certainty evidence due to study limitations). For second-cancer-related mortality, the evidence is uncertain and inconclusive (RR 0.21, 95% CI 0.01 to 4.34; 1 RCT, 465 participants; very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infection-related mortality and infertility and data for cardiac disease-related mortality were not estimable (no events in either group). Unfavourable disease For individuals with an unfavourable risk profile, additional radiotherapy may decrease overall survival slightly (HR 1.66, 95% CI 0.95 to 2.90; 2 RCTs, 698 participants; low-certainty evidence due to study limitations and imprecision), but may slightly improve progression-free survival (HR 0.84, 95% CI 0.53 to 1.33; 2 RCTs, 698 participants; low-certainty evidence due to study limitations and imprecision). The evidence is uncertain and inconclusive for infection-related mortality (RR 6.90, 95% CI 0.36 to 132.34; 1 RCT, 276 participants), second-cancer-related mortality (RR 2.19, 95% CI 0.77 to 6.19; 2 RCTs, 870 participants) and cardiac disease-related mortality (RR 1.60, 95% CI 0.31 to 8.22; 2 RCTs, 870 participants) (all very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infertility. The chemotherapy regimens in the trials differed and data for regimens commonly used today were limited. Additional radiotherapy may slightly improve progression-free survival. The available data for overall survival and adverse events were of low and very low certainty, and we were unable to draw conclusions about the effects of additional radiotherapy on these outcomes. No studies evaluated infertility. High-quality, longer-term follow-up data are required and data on fertility are needed.

Goldkuhle M ，Kreuzberger N ，von Tresckow B ，Eichenauer DA ，Specht L ，Monsef I ，Skoetz N ... -  《Cochrane Database of Systematic Reviews》

Electronic cigarettes for smoking cessation.

Electronic cigarettes (ECs) are handheld electronic vaping devices that produce an aerosol by heating an e-liquid. People who smoke, healthcare providers, and regulators want to know if ECs can help people quit smoking, and if they are safe to use for this purpose. This is a review update conducted as part of a living systematic review. To examine the safety, tolerability, and effectiveness of using EC to help people who smoke tobacco achieve long-term smoking abstinence, in comparison to non-nicotine EC, other smoking cessation treatments, and no treatment. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 February 2024 and the Cochrane Tobacco Addiction Group's Specialized Register to 1 February 2023, reference-checked, and contacted study authors. We included trials randomizing people who smoke to an EC or control condition. We included uncontrolled intervention studies in which all participants received an EC intervention. Studies had to report an eligible outcome. We followed standard Cochrane methods for screening and data extraction. We used the risk of bias tool (RoB 1) and GRADE to assess the certainty of evidence. Critical outcomes were abstinence from smoking after at least six months, adverse events (AEs), and serious adverse events (SAEs). Important outcomes were biomarkers, toxicants/carcinogens, and longer-term EC use. We used a fixed-effect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in pairwise and network meta-analyses (NMA). We included 90 completed studies (two new to this update), representing 29,044 participants, of which 49 were randomized controlled trials (RCTs). Of the included studies, we rated 10 (all but one contributing to our main comparisons) at low risk of bias overall, 61 at high risk overall (including all non-randomized studies), and the remainder at unclear risk. Nicotine EC results in increased quit rates compared to nicotine replacement therapy (NRT) (high-certainty evidence) (RR 1.59, 95% CI 1.30 to 1.93; I2 = 0%; 7 studies, 2544 participants). In absolute terms, this might translate to an additional four quitters per 100 (95% CI 2 to 6 more). The rate of occurrence of AEs is probably similar between groups (moderate-certainty evidence (limited by imprecision)) (RR 1.03, 95% CI 0.91 to 1.17; I2 = 0%; 5 studies, 2052 participants). SAEs were rare, and there is insufficient evidence to determine whether rates differ between groups due to very serious imprecision (RR 1.20, 95% CI 0.90 to 1.60; I2 = 32%; 6 studies, 2761 participants; low-certainty evidence). Nicotine EC probably results in increased quit rates compared to non-nicotine EC (moderate-certainty evidence, limited by imprecision) (RR 1.46, 95% CI 1.09 to 1.96; I2 = 4%; 6 studies, 1613 participants). In absolute terms, this might lead to an additional three quitters per 100 (95% CI 1 to 7 more). There is probably little to no difference in the rate of AEs between these groups (moderate-certainty evidence) (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 5 studies, 840 participants). There is insufficient evidence to determine whether rates of SAEs differ between groups, due to very serious imprecision (RR 1.00, 95% CI 0.56 to 1.79; I2 = 0%; 9 studies, 1412 participants; low-certainty evidence). Compared to behavioural support only/no support, quit rates may be higher for participants randomized to nicotine EC (low-certainty evidence due to issues with risk of bias) (RR 1.96, 95% CI 1.66 to 2.32; I2 = 0%; 11 studies, 6819 participants). In absolute terms, this represents an additional four quitters per 100 (95% CI 3 to 5 more). There was some evidence that (non-serious) AEs may be more common in people randomized to nicotine EC (RR 1.18, 95% CI 1.10 to 1.27; I2 = 6%; low-certainty evidence; 6 studies, 2351 participants) and, again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 0.93, 95% CI 0.68 to 1.28; I2 = 0%; 12 studies, 4561 participants; very low-certainty evidence). Results from the NMA were consistent with those from pairwise meta-analyses for all critical outcomes. There was inconsistency in the AE network, which was explained by a single outlying study contributing the only direct evidence for one of the nodes. Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued EC use. Very few studies reported data on other outcomes or comparisons; hence, evidence for these is limited, with CIs often encompassing both clinically significant harm and benefit. There is high-certainty evidence that ECs with nicotine increase quit rates compared to NRT and moderate-certainty evidence that they increase quit rates compared to ECs without nicotine. Evidence comparing nicotine EC with usual care or no treatment also suggests benefit, but is less certain due to risk of bias inherent in the study design. Confidence intervals were, for the most part, wide for data on AEs, SAEs, and other safety markers, with no evidence for a difference in AEs between nicotine and non-nicotine ECs nor between nicotine ECs and NRT, but low-certainty evidence for increased AEs compared with behavioural support/no support. Overall incidence of SAEs was low across all study arms. We did not detect evidence of serious harm from nicotine EC, but longer, larger studies are needed to fully evaluate EC safety. Our included studies tested regulated nicotine-containing EC; illicit products and/or products containing other active substances (e.g. tetrahydrocannabinol (THC)) may have different harm profiles. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, this is a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

Lindson N ，Butler AR ，McRobbie H ，Bullen C ，Hajek P ，Wu AD ，Begh R ，Theodoulou A ，Notley C ，Rigotti NA ，Turner T ，Livingstone-Banks J ，Morris T ，Hartmann-Boyce J ... -  《Cochrane Database of Systematic Reviews》

Electronic cigarettes for smoking cessation.

Lindson N ，Butler AR ，McRobbie H ，Bullen C ，Hajek P ，Begh R ，Theodoulou A ，Notley C ，Rigotti NA ，Turner T ，Livingstone-Banks J ，Morris T ，Hartmann-Boyce J ... -  《Cochrane Database of Systematic Reviews》