Efficacy and safety of osimertinib plus bevacizumab versus osimertinib alone for advanced non-small-cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials.

To systematically evaluate the efficacy and safety of osimertinib plus bevacizumab in treating advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Up to May 26, 2024, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, Chinese Biomedical Literature, China Science and Technology Journal, and Wanfang were searched, and the randomized controlled clinical trials (RCTs) of osimertinib plus bevacizumab in the treatment of advanced EGFR-mutant NSCLC were included. Two researchers independently screened the literature, assessed the quality of the included literature, and extracted the literature data. Revman5.4 software was used for meta-analysis. A total of 824 patients were included in 10 RCTs. The results of meta-analysis showed that compared with the control group (osimertinib alone), the experimental group (osimertinib plus bevacizumab) had a higher objective response rate (ORR) (relative risk [RR] = 1.23, 95% confidence interval [CI] = 1.03-1.47, P = .02), and the experimental group could significantly reduce the expression levels of carcinoembryonic antigen (mean difference [SMD] = 0.82, 95% CI = 0.30-1.35, P = .002), vascular endothelial growth factor (SMD = 0.43, 95% CI = 0.13-0.73, P = .005), neuron-specific enolase (SMD = 0.88, 95% CI = 0.60-1.17, P < .00001), cytokeratin 19 fragments (SMD = 1.33, 95% CI = 0.34-2.33, P = .009), and carbohydrate antigen 125 (SMD = 0.46, 95% CI = 0.15-0.77, P = .004) in serum. However, the experimental group did not significantly improve the disease control rate (DCR) (RR = 1.17, 95% CI = 1.00-1.36, P = .05), 1- and 2-year progression-free survival (PFS) rates (RR = 1.15, 95% CI = 1.00-1.33, P = .05; RR = 1.02, 95% CI = 0.74-1.40, P = .92), 1- and 2-year overall survival (OS) rates (RR = 1.11, 95% CI = 0.92-1.36, P = .28; RR = 0.99, 95% CI = 0.84-1.18, P = .95). Interestingly, the results of subgroup analysis showed that the experimental group significantly improved ORR, DCR, 1-year PFS, and OS rates in the Chinese population and patients under 65 years old (P < .05). In addition, when the dose of bevacizumab was 7.5 mg/kg q3w in the experimental group, ORR, DCR, 1-year PFS, and OS rates were significantly better than those in the control group (P < .05). In terms of adverse events of drugs, the incidence of proteinuria, hypertension, oral mucositis, bleeding, nausea, and vomiting in the experimental group was higher than that in the control group (P < .05). For patients with advanced EGFR-mutant NSCLC, osimertinib plus bevacizumab has some clinical benefit compared with osimertinib alone. Still, it does not provide additional long-term survival benefits and has higher toxicity. More well-designed, multicenter RCTs are needed to identify the subgroups of patients most likely to benefit from this combination regimen and to validate the optimal dose of this combination regimen.

Yao L ，Zhang C ，Li D ，Xu L ，Yang X ... -  《-》

Comparison of efficacy and safety of PD-1/PD-L1 combination therapy in first-line treatment of advanced NSCLC: an updated systematic review and network meta-analysis.

The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens. The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history. Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38-0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26-0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25-0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31-0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28-0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits. For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone.

Yang Y ，Chen W ，Dong L ，Duan L ，Gao P ... -  《-》

Sequencing of systemic therapy in unresectable hepatocellular carcinoma: A systematic review and Bayesian network meta-analysis of randomized clinical trials.

For patients with advanced or unresectable hepatocellular carcinoma (HCC), safe and effective therapies are urgently needed to improve their long-term prognosis. Although the guidelines recommend first-line treatments such as sorafenib, lenvatinib, and atezolizumab in combination with bevacizumab (T+A) and second-line treatments such as regorafenib, the efficacy comparison between drugs is lacking, that is, a treatment is not recommended as the optimal or alternative choice for a specific patient population. Therefore, we will conduct a high-quality network meta-analysis based on Phase III randomized controlled trials (RCTs) to systematically evaluate and compare overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and serious adverse events (SAE) of different treatment protocols in the context of first-line and second-line therapies, which are critical for clinical decision making and prognostic improvement in advanced HCC patients. The studies of interest were Phase III RCTs evaluating the efficacy or safety of first- or second-line therapies in patients with unresectable or advanced HCC. Literature published in English from the four databases of PubMed, Embase, Cochrane Library, and Web of Science was comprehensively searched from the inception to May 23, 2022. Outcomes of interest included OS, PFS, ORR, and SAE. A league table was developed to show the results of the comparison between different treatments. A histogram of cumulative probability was drawn to discuss the ranking probability of treatments based on different outcomes. The effectiveness and safety of various treatments were comprehensively considered and the two-dimensional diagram was plotted to guide clinical practice. The Gemtc package in R Studio was used for network meta-analysis in a Bayesian framework. The results showed that HAIC-FO was superior to T+A regimen, regardless of OS, PFS or ORR. TACE combined with lenvatinib performed better than T+A in PFS, and ORR. In addition to the T+A regimen, Sintilimab combined with IBI305 and camrelizumab combined with apatinib were also associated with longer OS, PFS, and ORR, and their SAE incidence was not higher than that of T+A, especially for camrelizumab combined with apatinib, its safety was better than that of T+A regimen. There were no new treatments or combinations that were more effective than regorafenib. It was important to note that for PFS, the efficacy of apatinib and cabozantinib was not statistically different from that of regorafenib, so these two treatments could be used as alternative treatment options in cases where regorafenib was not tolerated or treatment failed. We conducted a network meta-analysis to evaluate the efficacy and safety of multiple treatment modalities by integrating the results of direct and indirect comparisons. This study included high-quality multicenter Phase III RCTs, collated and summarized all treatments involved in advanced or unresectable HCC in first-line and second-line settings, and compared with T+A and regorafenib, respectively, and ranked based on efficacy and safety to support clinical decision making.

Wang Q ，Yu J ，Sun X ，Li J ，Cao S ，Han Y ，Wang H ，Yang Z ，Li J ，Hu C ，Zhang Y ，Jin L ... -  《-》

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》

Falls prevention interventions for community-dwelling older adults: systematic review and meta-analysis of benefits, harms, and patient values and preferences.

About 20-30% of older adults (≥ 65 years old) experience one or more falls each year, and falls are associated with substantial burden to the health care system, individuals, and families from resulting injuries, fractures, and reduced functioning and quality of life. Many interventions for preventing falls have been studied, and their effectiveness, factors relevant to their implementation, and patient preferences may determine which interventions to use in primary care. The aim of this set of reviews was to inform recommendations by the Canadian Task Force on Preventive Health Care (task force) on fall prevention interventions. We undertook three systematic reviews to address questions about the following: (i) the benefits and harms of interventions, (ii) how patients weigh the potential outcomes (outcome valuation), and (iii) patient preferences for different types of interventions, and their attributes, shown to offer benefit (intervention preferences). We searched four databases for benefits and harms (MEDLINE, Embase, AgeLine, CENTRAL, to August 25, 2023) and three for outcome valuation and intervention preferences (MEDLINE, PsycINFO, CINAHL, to June 9, 2023). For benefits and harms, we relied heavily on a previous review for studies published until 2016. We also searched trial registries, references of included studies, and recent reviews. Two reviewers independently screened studies. The population of interest was community-dwelling adults ≥ 65 years old. We did not limit eligibility by participant fall history. The task force rated several outcomes, decided on their eligibility, and provided input on the effect thresholds to apply for each outcome (fallers, falls, injurious fallers, fractures, hip fractures, functional status, health-related quality of life, long-term care admissions, adverse effects, serious adverse effects). For benefits and harms, we included a broad range of non-pharmacological interventions relevant to primary care. Although usual care was the main comparator of interest, we included studies comparing interventions head-to-head and conducted a network meta-analysis (NMAs) for each outcome, enabling analysis of interventions lacking direct comparisons to usual care. For benefits and harms, we included randomized controlled trials with a minimum 3-month follow-up and reporting on one of our fall outcomes (fallers, falls, injurious fallers); for the other questions, we preferred quantitative data but considered qualitative findings to fill gaps in evidence. No date limits were applied for benefits and harms, whereas for outcome valuation and intervention preferences we included studies published in 2000 or later. All data were extracted by one trained reviewer and verified for accuracy and completeness. For benefits and harms, we relied on the previous review team's risk-of-bias assessments for benefit outcomes, but otherwise, two reviewers independently assessed the risk of bias (within and across study). For the other questions, one reviewer verified another's assessments. Consensus was used, with adjudication by a lead author when necessary. A coding framework, modified from the ProFANE taxonomy, classified interventions and their attributes (e.g., supervision, delivery format, duration/intensity). For benefit outcomes, we employed random-effects NMA using a frequentist approach and a consistency model. Transitivity and coherence were assessed using meta-regressions and global and local coherence tests, as well as through graphical display and descriptive data on the composition of the nodes with respect to major pre-planned effect modifiers. We assessed heterogeneity using prediction intervals. For intervention-related adverse effects, we pooled proportions except for vitamin D for which we considered data in the control groups and undertook random-effects pairwise meta-analysis using a relative risk (any adverse effects) or risk difference (serious adverse effects). For outcome valuation, we pooled disutilities (representing the impact of a negative event, e.g. fall, on one's usual quality of life, with 0 = no impact and 1 = death and ~ 0.05 indicating important disutility) from the EQ-5D utility measurement using the inverse variance method and a random-effects model and explored heterogeneity. When studies only reported other data, we compared the findings with our main analysis. For intervention preferences, we used a coding schema identifying whether there were strong, clear, no, or variable preferences within, and then across, studies. We assessed the certainty of evidence for each outcome using CINeMA for benefit outcomes and GRADE for all other outcomes. A total of 290 studies were included across the reviews, with two studies included in multiple questions. For benefits and harms, we included 219 trials reporting on 167,864 participants and created 59 interventions (nodes). Transitivity and coherence were assessed as adequate. Across eight NMAs, the number of contributing trials ranged between 19 and 173, and the number of interventions ranged from 19 to 57. Approximately, half of the interventions in each network had at least low certainty for benefit. The fallers outcome had the highest number of interventions with moderate certainty for benefit (18/57). For the non-fall outcomes (fractures, hip fracture, long-term care [LTC] admission, functional status, health-related quality of life), many interventions had very low certainty evidence, often from lack of data. We prioritized findings from 21 interventions where there was moderate certainty for at least some benefit. Fourteen of these had a focus on exercise, the majority being supervised (for > 2 sessions) and of long duration (> 3 months), and with balance/resistance and group Tai Chi interventions generally having the most outcomes with at least low certainty for benefit. None of the interventions having moderate certainty evidence focused on walking. Whole-body vibration or home-hazard assessment (HHA) plus exercise provided to everyone showed moderate certainty for some benefit. No multifactorial intervention alone showed moderate certainty for any benefit. Six interventions only had very-low certainty evidence for the benefit outcomes. Two interventions had moderate certainty of harmful effects for at least one benefit outcome, though the populations across studies were at high risk for falls. Vitamin D and most single-component exercise interventions are probably associated with minimal adverse effects. Some uncertainty exists about possible adverse effects from other interventions. For outcome valuation, we included 44 studies of which 34 reported EQ-5D disutilities. Admission to long-term care had the highest disutility (1.0), but the evidence was rated as low certainty. Both fall-related hip (moderate certainty) and non-hip (low certainty) fracture may result in substantial disutility (0.53 and 0.57) in the first 3 months after injury. Disutility for both hip and non-hip fractures is probably lower 12 months after injury (0.16 and 0.19, with high and moderate certainty, respectively) compared to within the first 3 months. No study measured the disutility of an injurious fall. Fractures are probably more important than either falls (0.09 over 12 months) or functional status (0.12). Functional status may be somewhat more important than falls. For intervention preferences, 29 studies (9 qualitative) reported on 17 comparisons among single-component interventions showing benefit. Exercise interventions focusing on balance and/or resistance training appear to be clearly preferred over Tai Chi and other forms of exercise (e.g., yoga, aerobic). For exercise programs in general, there is probably variability among people in whether they prefer group or individual delivery, though there was high certainty that individual was preferred over group delivery of balance/resistance programs. Balance/resistance exercise may be preferred over education, though the evidence was low certainty. There was low certainty for a slight preference for education over cognitive-behavioral therapy, and group education may be preferred over individual education. To prevent falls among community-dwelling older adults, evidence is most certain for benefit, at least over 1-2 years, from supervised, long-duration balance/resistance and group Tai Chi interventions, whole-body vibration, high-intensity/dose education or cognitive-behavioral therapy, and interventions of comprehensive multifactorial assessment with targeted treatment plus HHA, HHA plus exercise, or education provided to everyone. Adding other interventions to exercise does not appear to substantially increase benefits. Overall, effects appear most applicable to those with elevated fall risk. Choice among effective interventions that are available may best depend on individual patient preferences, though when implementing new balance/resistance programs delivering individual over group sessions when feasible may be most acceptable. Data on more patient-important outcomes including fall-related fractures and adverse effects would be beneficial, as would studies focusing on equity-deserving populations and on programs delivered virtually. Not registered.

Pillay J ，Gaudet LA ，Saba S ，Vandermeer B ，Ashiq AR ，Wingert A ，Hartling L ... -  《Systematic Reviews》