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Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma.

ABSTRACT: Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46-0.98 for nivolumab, HR = 0.70, 95% CI = 0.54-0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59-0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46-0.92 for nivolumab, HR = 0.77, 95% CI = 0.61-0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65-0.94 for durvalumab, HR = 0.75, 95% CI = 0.61-0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3-4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3-4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

SUBMITTER: Chen HL

PROVIDER: S-EPMC7761843 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma.

Chen Hsiao-Ling HL Tu Yu-Kang YK Chang Hsiu-Mei HM Lee Tai-Huang TH Wu Kuan-Li KL Tsai Yu-Chen YC Lee Mei-Hsuan MH Yang Chih-Jen CJ Hung Jen-Yu JY Chong Inn-Wen IW

Cancers 20201203 12

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary ...[more]

PMID: 33287455

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Project description:BackgroundOur goal was to organize the data from randomized controlled trials that evaluated first-line chemotherapy for chemo-naïve extensive disease small-cell lung cancer (ED-SCLC).MethodsThe protocol following PRISMA methodology was submitted as PROSPERO 154049. We included individually randomized trials comparing two or more chemotherapy regimens as the first-line treatment for chemo-naïve ED-SCLC regardless of the age, sex, performance status, co-morbidities, and organ functions written in the English language since 2000. Molecular targeted agents and immune checkpoint inhibitors were considered chemotherapy along with cytotoxic medications. We pooled the logarithm of hazard ratio (HR) and its standard error using the frequentist weighted least squares approach random-model network meta-analysis.ResultsA total of 46 eligible trials that involved 11,987 patients were included. The primary endpoint, HR of overall survival (OS, HRos) of the selected comparisons was as follows: carboplatin+amrubicin (HRos 0.56, 95% confidence interval (CI) 0.33-0.96), carboplatin+etoposide+atezolizumab (HRos 0.70, 95% CI 0.53-0.92), and carboplatin+irinotecan (HRos 0.73, 95% CI 0.58-0.91) were compared with carboplatin+etoposide. The carboplatin+etoposide+atezolizumab regimen was compared with carboplatin+irinotecan (HRos 0.97, 95% CI 0.68-1.37) and cisplatin+irinotecan regimen (HRos 0.87, 95% CI 0.58-1.31). "Selective carboplatin or cisplatin (CBDCA/CDDP)"+etoposide+durvalumab was compared with CBDCA/CDDP+etoposide (HRos 0.73, 95% CI 0.59-0.91). Platinum+etoposide+durvalumab was compared with platinum+irinotecan (HRos 0.88, 95% CI 0.67-1.15). Cumulative meta-analysis suggested that platinum+irinotecan was associated with better OS than platinum+etoposide as of 2010 through 40 out of 46 trials in our review that used platinum+etoposide as a reference regimen.ConclusionPatients treated with carboplatin+amrubicin, carboplatin+etoposide+atezolizumab, CBDCA/CDDP+etoposide+durvalumab, and platinum+irinotecan showed better HRos than those treated with platinum+etoposide, one of the standard regimens.

Project description:IntroductionMany randomized controlled trials have indicated that immuno-chemotherapy could generate clinical benefits, though the cost of immuno-chemotherapy was so prohibitive and the options were varied. This investigation aimed at evaluating effectiveness, safety, and cost-effectiveness for immuno-chemotherapy as a first-line therapeutic option for ES-SCLC patients.MethodsMultiple scientific literature repositories were searched for clinical studies where immuno-chemotherapy was regarded as the first-line treatment for ES-SCLC, which were published in English between Jan 1, 2000, and Nov 30, 2021. This study conducted a network meta-analysis (NMA) and cost-effectiveness analysis (CEA) based upon US-resident payer perspectives. Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were evaluated through NMA. In addition, costings, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-benefit ratio (ICER) were estimated by CEA.ResultsWe identified 200 relevant search records, of which four randomized controlled trials (RCTs) (2,793 patients) were included. NMA demonstrated that the effect of atezolizumab plus chemotherapy was ranked at a more elevated position in comparison to other immuno-chemotherapy options and chemotherapy alone, within the general population. The influence of atezolizumab plus chemotherapy and durvalumab plus chemotherapy was ranked higher within populations experiencing non-brain metastases (NBMs) andbrain metastases (BMs), respectively. The CEA revealed that the ICERs of immuno-chemotherapy over chemotherapyalone were higher than the willingness-to-pay (WTP) threshold of $150,000/QALY in any population. However, treatment with atezolizumab plus chemotherapy and durvalumab plus chemotherapy were more favorable health advantages than other immuno-chemotherapy regimens and chemotherapy alone, and the results were 1.02 QALYs and 0.89 QALYs within overall populations and populations with BMs, respectively.ConclusionThe NMA and cost-effectiveness investigation demonstrated that atezolizumab plus chemotherapy could be an optimal first-line therapeutic option for ES-SCLC when compared with other immuno-chemotherapy regimens. Durvalumab plus chemotherapy is likely to be the most favorable first-line therapeutic option for ES-SCLC with BMs.

Project description:ObjectiveIn recent years, the introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of extensive-stage small cell lung carcinoma (ES-SCLC), but the optimal combination of ICI and standard chemotherapy strategy is yet to be established. The aim of this network meta-analysis (NMA) was to identify which first-line combination strategy is optimal for patients with ES-SCLC.MethodsPubMed, Embase, Cochrane Library, and the proceedings of international conferences, including American Society of Clinical Oncology and European Society for Medical Oncology meetings, were searched for randomized controlled trials (RCTs) published through October 31, 2022. The collected primary outcomes were overall survival (OS), progression-free survival (PFS), and grade 3-5 treatment-related adverse events (TRAEs).ResultsOur NMA study included six phase 3 and three phase 2 RCTs including 4037 patients and 10 first-line regimens. Regarding effectiveness, the addition of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors to standard chemotherapy provided greater efficacy than chemotherapy alone. However, cytotoxic T lymphocyte-associated antigen-4 inhibitors were not associated with satisfactory prognoses. Serplulimab plus carboplatin-etoposide (vs. standard chemotherapy, hazard ratio [HR] = 0.63; 95% CI = 0.49-0.82) and nivolumab plus platinum-etoposide (HR = 0.65; 95% confidence interval [CI] = 0.46-0.91) displayed the greatest benefit regarding OS. In terms of PFS, serplulimab plus carboplatin-etoposide yielded the best benefit of all treatments (HR = 0.48; 95% CI = 0.39-0.6). The combination of ICIs and chemotherapy caused more toxicity in general, but durvalumab plus platinum-etoposide (odds ratio [OR] = 0.98; 95% CI = 0.68-1.4), atezolizumab plus carboplatin-etoposide (OR = 1.04; 95% CI = 0.68-1.6), and adebrelimab plus platinum-etoposide (OR = 1.02; 95% CI = 0.52-2) displayed similar safety as standard chemotherapy. Subgroup analysis by race illustrated that serplulimab plus carboplatin-etoposide was associated with the best OS in Asian patients. And in non-Asian patients, the combination of PD-1/PD-L1 inhibitors and chemotherapy (pembrolizumab plus platinum-etoposide, durvalumab plus platinum-etoposide, and durvalumab and tremelimumab plus platinum-etoposide) displayed superiority to standard chemotherapy.ConclusionsThe results of our NMA study suggested that serplulimab plus carboplatin-etoposide and nivolumab plus platinum-etoposide are associated with the best OS as first-line treatments for patients with ES-SCLC. Serplulimab plus carboplatin-etoposide was associated with the best PFS. In Asian patients, serplulimab plus carboplatin-etoposide had the best OS.Systematic review registrationThis study is registered with PROSPERO, number CRD42022345850.

Project description:BackgroundThe prognosis of patients with extensive-stage small cell lung cancer (SCLC) is poor. Adding an immune checkpoint inhibitor (ICI) to chemotherapy may exert a synergistic effect and improve survival outcomes. However, for treatment-naive extensive-stage SCLC patients, the efficacy of immunotherapy in combination with cytotoxic chemotherapy remains controversial.ObjectiveTo evaluate the benefits and risks of the combination of immunotherapy and chemotherapy and to assess the comparative effectiveness of different first-line treatment strategies for extensive-stage SCLC.MethodsPubMed, Web of Science, EMBASE, and Cochrane Library were searched for randomized clinical trials studying different immunotherapeutics for patients with previously untreated extensive-stage SCLC up to Feb 16, 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were objective response rate (ORR), disease control rate (DCR), and adverse events.ResultsWe identified 141 published records, and 4 studies (comprising 2202 patients) were included in the analysis. Immunotherapy (including ipilimumab, atezolizumab, and durvalumab) plus chemotherapy was associated with better OS (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.75-0.93; risk ratio (RR) 0.90, 95% CI 0.81-1.00) and PFS (HR: 0.81, 95% CI 0.74-0.88; RR 0.96, 95% CI 0.93-0.99) than placebo plus chemotherapy. The addition of immunotherapy to chemotherapy showed similar improvement in ORR, DCR, and adverse events versus placebo plus chemotherapy. On the surface under the cumulative ranking (SUCRA) analysis, the anti-PD-L1 agent, atezolizumab, had the highest likelihood of achieving improved OS (93.4%) and PFS (95.0%).ConclusionIn the first-line setting, combining immunotherapy with chemotherapy is better than standard chemotherapy in terms of OS and PFS. Across the eligible studies, PD-L1 inhibitors might be preferred. Further explorations of more ICIs in the first-line treatment for extensive-stage SCLC patients should be needed.

Project description:BackgroundExtensive-stage small cell lung cancer (ES-SCLC) is a highly invasive and fatal disease with limited therapeutic options and poor prognosis. Our study aims to systematically evaluate the efficacy and safety of immune checkpoint inhibitors combined with chemotherapy (ICIs+ChT) vs. chemotherapy alone (ChT) in the first-line treatment of ES-SCLC.MethodsA literature search was performed for randomized controlled trials (RCTs) related to "ICIs+ChT" vs. "ChT" in the first-line treatment of ES-SCLC in PubMed, Cochrane Library, Embase, CNKI, and other databases. RevMan 5.4 software was used to perform meta-analyses with hazard ratio (HR) and relative risk (RR). SAS 9.4 software was applied to conduct a mixed-effect model meta-analysis of the survival outcomes and draw survival curves.ResultsA total of 2,638 patients with ES-SCLC from 6 RCTs were included, of which 1,341 patients received "ICIs+ChT" and 1,297 received ChT. Based on the meta-analysis results provided by the mixed-effect model, patients receiving the "ICIs+ChT" regimen had a significantly longer overall survival (OS, HR = 0.800, 95% CI = 0.731-0.876, P < 0.001) and progression-free survival (PFS, HR = 0.815, 95% CI = 0.757-0.878, P <0.001) in comparison to those receiving ChT only. Compared with ChT, "ICIs+ChT" did neither improve the objective response rate (ORR, RR = 1.06, 95% CI = 1.00-1.12, P = 0.06) nor did it improve the disease control rate (DCR, RR = 0.97, 95% CI = 0.92-1.03, P = 0.35). Although the incidence of grade 3 to 5 treatment-related adverse events (trAEs) in the "ICIs+ChT" subgroup did not increase (RR = 1.16, 95% CI = 0.97-1.39, P = 0.11), the incidence of grade 3 to 5 immune-related adverse events (irAEs) increased significantly (RR = 4.29, 95% CI = 1.73-10.61, P < 0.00001).ConclusionICIs+ChT regimen could significantly prolong OS and PFS in patients with ES-SCLC compared with ChT alone. Although the incidence of irAEs in "ICIs+ChT" is higher than that in the "ChT" subgroup, the incidence of trAEs is similar within the two subgroups. ICIs combined with chemotherapy demonstrated a good choice as first-line treatment for ES-SCLC.Systematic review registrationPROSPERO, identifier: CRD42022348496.

Dataset Information

Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma.

Publications

Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma.

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