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First-line targ veted therapies of advanced hepatocellular carcinoma: A Bayesian network analysis of randomized controlled trials.

ABSTRACT: PURPOSE:A variety of targeted drug were developed and proved effective and safe in clinical trials. Our study aims to compare the efficacies and safety of different targeted drugs in advanced hepatocellular carcinoma (HCC) for first-line treatment using a Bayesian network meta-analysis approach. METHODS:PubMed, Embase, and Cochrane library were searched for randomized controlled trials (RCTs) of advanced HCC patients that treated with different targeted drugs. Time to progress (TTP), overall survival (OS) and progress-free survival (PFS) were calculated as hazard ratios (HRs). Objective response rate (ORR) and the proportion of Grade 3-5 adverse events (G3-5AE) were expressed as odds ratios (ORs). We pooled study-specific HRs and ORs using Bayesian network meta-analyses, and ranked first-line drugs by the surface under the cumulative ranking curve (SUCRA). RESULTS:A total of 22 RCTs with 9288 patients were enrolled. Brivanib, linifanib, lenvatinib and sorafenib showed a significant improvement on TTP compared to placebo (HR range, 0.45-0.72). Sunitinib (HR = 1.99) and nintedanib (HR = 2.17) showed a significant decline on TTP compared to lenvatinib. Vandetanib (HR = 0.44) and sorafenib (HR = 0.73) showed a significant improvement on OS compared to placebo. There was no significant difference in PFS, ORR and G3-5AE across different drugs. According to cluster rank analysis, vandetanib was the drug with both more effective (OS) and more secure (G3-5AE) compared to Sor followed by nintedanib. CONCLUSIONS:This network meta-analysis shows that vandetanib, linifanib, lenvatinib and nintedanib potentially may be the best substitution of sorafenib against advanced HCC as first-line targeted drugs. Vandetanib seems to be the best choise with low quality of evidence. For better survival, novel targeted treatment options for HCC are sorely needed.

SUBMITTER: Ding W

PROVIDER: S-EPMC7058293 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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First-line targ veted therapies of advanced hepatocellular carcinoma: A Bayesian network analysis of randomized controlled trials.

Ding Wei W Tan Yulin Y Qian Yan Y Xue Wenbo W Wang Yibo Y Jiang Peng P Xu Xuezhong X

PloS one 20200305 3

<h4>Purpose</h4>A variety of targeted drug were developed and proved effective and safe in clinical trials. Our study aims to compare the efficacies and safety of different targeted drugs in advanced hepatocellular carcinoma (HCC) for first-line treatment using a Bayesian network meta-analysis approach.<h4>Methods</h4>PubMed, Embase, and Cochrane library were searched for randomized controlled trials (RCTs) of advanced HCC patients that treated with different targeted drugs. Time to progress (TT ...[more]

PMID: 32134981

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Project description:IntroductionAtezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies.MethodsA Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences.ResultsATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases.ConclusionOur simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.

Project description:BackgroundSorafenib has consistently served as the control arm in multiple randomized clinical trials (RCTs) evaluating novel therapies for advanced hepatocellular carcinoma (HCC) for more than a decade. Analyzing trends in clinical outcomes of patients treated with sorafenib for the same indication over time offers the opportunity for unique insight into the evolution of clinical trial conduct and potential non-drug factors impacting outcomes.MethodsWe identified RCTs in patients with treatment-naïve advanced HCC where sorafenib was compared to another systemic therapy or placebo. We extracted trial-level demographic, clinicopathologic, and outcome data (overall survival [OS], progression-free survival [PFS], objective response rate [ORR], and duration of therapy). Sample-weighted linear regression was used to identify temporal trends with significance set at p ≤ 0.05.ResultsSixteen RCTs (9 phase III and 7 phase II) enrolling 4,086 patients treated with sorafenib were included in the analysis. Included trials enrolled patients from 2005 to 2019. OS has significantly improved by 4.5 months from 2005 to 2019 (p = 0.048) over time. Thirteen studies provided data on PFS using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, with no significant change over time (p = 0.69). ORR assessed by RECIST 1.1 has significantly improved by 6.0% over time (p = 0.003). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p = 0.0037). There was no significant change in patient demographics were identified over time to explain the OS findings.ConclusionThe median OS of patients with advanced HCC treated with sorafenib has improved significantly over 15 years. At the same time, the median duration of therapy with sorafenib has decreased. The reason for these findings was not explained by changing demographics of patients enrolled in these trials and has implications for ongoing clinical trials.

Project description:BackgroundSeveral systemic agents have been approved for use in advanced hepatocellular carcinoma (aHCC). However, it is unclear which treatment is superior in either the first- or second-line settings due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings.MethodsRandomized clinical trials evaluating systemic agents in first and second line settings in aHCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and the annual ASCO and ESMO conferences from 2017 to 2020. Studies in English reporting clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were included. The primary outcomes of interest were pooled hazard ratios (HR) of OS and pooled odds ratios (OR) of ORR in first line studies and pooled HR of PFS and OR of ORR for second line studies. Additionally, OS for second line agents were reported in the qualitative analysis.ResultsOverall, first line studies comprised 8335 patients (13 studies) and second line studies comprised 4612 patients (11 studies). In the first line setting, atezolizumab plus bevacizumab was associated with the highest OS benefit over sorafenib (HR 0.58, 95% CI, 0.42-0.80; P-score 0.993). Additionally, lenvatinib was associated with the greatest ORR benefit (OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) in the first line setting. In the second line setting, cabozantinib was associated with the highest PFS benefit over placebo (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest ORR benefit (OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266).ConclusionAtezolizumab plus bevacizumab appears to have superior efficacy among first line agents whereas cabozantinib appears to be superior in the second line setting. Further studies are warranted to determine whether the type of prior therapy received affects the efficacy of subsequent second line therapy.

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First-line targ veted therapies of advanced hepatocellular carcinoma: A Bayesian network analysis of randomized controlled trials.

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First-line targ veted therapies of advanced hepatocellular carcinoma: A Bayesian network analysis of randomized controlled trials.

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