First-Line Checkpoint Inhibitors for Wild-Type Advanced Non-Small-Cell Cancer: A Pair-Wise And Network Meta-Analysis

Wang, Xiaojian; Lin, Jia-Zhou; Yu, Sile; Wu, Sihan; Luo, Hui; Du, Ze-Sen; Li, Xu‐Yuan

doi:10.2217/imt-2018-0107

Cited by 7 publications

(6 citation statements)

References 47 publications

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“…Despite these strengths, there have been several controversies. Three studies associated with NMA had been conducted to figure out the best PD-1/L1 inhibitor for advanced NSCLC patients in the first-line settings (51)(52)(53). Our results were generally consistent with the previous studies, which had all indicated the combination of pembrolizumab to be better than other combined therapies or chemotherapies for patients with relatively high expression of PD-L1.…”

Section: Discussionsupporting

confidence: 89%

Compare the efficacy and safety of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors for advanced non-small cell lung cancer: a Bayesian analysis

Liang

Sui

et al. 2020

Transl Lung Cancer Res

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Background: Inhibitors of programmed cell death-1 (PD-1) and its ligand (PD-L1) have represented a novel approach for the management of advanced non-small cell lung cancer (NSCLC). In this study, we aimed to estimate five anti-PD-1/L1 agents (nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab) using network meta-analyses (NMAs) and the Bayesian method to provide suggestions for advanced NSCLC treatments.Methods: We searched PubMed, Web of Science, Embase, and the Wiley Online Library for eligible studies published up to March 2020. Both pairwise analyses and NMAs were conducted with clinical outcomes, including overall survival (OS), progression-free survival (PFS), objective response rate, and the incidences of adverse events. Results were presented in several patient populations according to treatment lines and PD-L1 status.Results: Nineteen randomized clinical trials (RCTs) involving 11,456 patients were included in our study.PD-1/L1 inhibitors showed significant benefits over chemotherapies in OS regardless of tumor PD-L1 status [first-line settings: OS =0.85, 95% CI (0.77, 0.94), I 2 =37%; second-or further-line settings: OS =0.77, 95% CI (0.71, 0.84), I 2 =37%]. The combined regimen of pembrolizumab and chemotherapy stood out to be the most effective and safest for patients in the first-line settings. Pembrolizumab monotherapy was showed to be the best especially for patients with PD-L1 ≥50%. In the subsequent-line settings, nivolumab ranked the best in improving the survival of patients, and durvalumab had the greatest effect in tumor shrinkage.Atezolizumab, followed by nivolumab, ranked the safest in reducing adverse events, whereas durvalumab was showed with the largest side effects among the five inhibitors. Conclusions:The combination of pembrolizumab with chemotherapy is suitable for advanced NSCLC patients who have not received any systematic treatments before, and pembrolizumab monotherapy should also be considered, especially for patients with highly-expressed PD-L1 (≥50%). Nivolumab is the best option for patients with advanced NSCLC whose tumors have progressed following chemotherapies or combined modalities of treatments including chemotherapy. However, our results need to be further validated in future head-to-head clinical trials.

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Section: Discussionsupporting

confidence: 89%

Compare the efficacy and safety of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors for advanced non-small cell lung cancer: a Bayesian analysis

Liang

Sui

et al. 2020

Transl Lung Cancer Res

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“…Wang et al (63) confirmed that 1st line immunotherapy, either nivolumab, pembrolizumab or atezolizumab considering monotherapy or combined chemo-immunotherapy, had better efficacy than chemotherapy in reducing disease progression (HR 0.69, 95% CI 0.56-0.86; p = 0.001) and mortality (HR 0.74, 95% CI 0.63-0.87; p < 0.001), and that grade 3-5 adverse events were less pronounced with immunotherapy monotherapy (RR 0.42, 95% CI 0.35-0.51; p < 0.001) but were worse with combined chemo-immunotherapy (RR 1.15, 95% CI 1.04-1.27; p = 0.008). Using pembrolizumab alone (P-score 0.65) as the reference comparator, only pembrolizumab plus platinum doublet (HR 0.87, 95% CI 0.79-0.95; P-score 0.95) showed any significant superiority while combination including nivolumab or atezolizumab did not (HR 0.93-1.13).…”

Section: Which Is the Best Treatment Duration?mentioning

confidence: 99%

Immunotherapy: From Advanced NSCLC to Early Stages, an Evolving Concept

et al. 2020

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Immunotherapy in lung cancer treatment is a long history paved with failures and some successes. During the last decade, the discovery of checkpoints inhibitors led to major advances in treating advanced and metastatic non-small cell lung cancer (NSCLC). Impressive data from early phase I-II studies were subsequently confirmed in large prospective randomized trials and meta-analyses (High-level of evidence). Three anti-programmed death-1 (PD1) (pembrolizumab, nivolumab) or antiPD-ligand(L)1 (atezolizumab) antibodies showed clinically significant improved survival compared to second-line docetaxel. Then, first-line pembrolizumab monotherapy demonstrated its superiority over platinum-doublet in high PD-L1 NSCLC. The addition of pembrolizumab or atezolizumab to chemotherapy derived the same results regardless of the PD-L1 status. On the opposite, antiCTLA4 (Cytotoxic T-Lymphocyte Associated 4) results are currently disappointing in unselected patients while recent development suggest that the combination of antiPD1 and antiCTLA4 (nivolumab-ipilimumab) positively impact on overall survival. Some secondary analyses also showed that immunotherapy has a positive impact on quality of life and that the clinical improvement can be done at an acceptable incremental cost per QALY. A lot of questions remain unresolved: which is the best treatment duration and is it the same for all patients, how to choose the patients that will have the highest benefit of immunotherapy, how to identify the patients who will have rapid progression, how to improve the current data (new targets, new combinations)…

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“…One issue deserved attention for the patients with lower-level, negative, or unknown PD-L1 status: whether they should be excluding the possible benefit from ICIs. A subgroup analysis in a meta-analysis showed that patients with PD-L1 expression of <1% also derived benefit from ICIs ( 50 ). Furthermore, PD-L1 status has low sensibility (72%) and specificity (58%), thus PD-L1 status alone is not an appropriate biomarker to optimize immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Comparative Efficacy and Safety of Anti-PD-1/PD-L1 for the Treatment of Non-Small Cell Lung Cancer: A Network Meta-Analysis of 13 Randomized Controlled Studies

et al. 2022

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ObjectiveThe present network meta-analysis (NMA) was conducted to summarize the direct and indirect evidence of common programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors including avelumab, atezolizumab, cemiplimab, nivolumab, and pembrolizumab for the treatment of non-small cell lung cancer (NSCLC) patients and further to determine the optimal therapeutic regimen.MethodsWe performed a systematic literature search to identify all potentially eligible studies in PubMed, Embase, and the Cochrane Library until August 7, 2021. The primary outcome was overall survival (OS), and the second outcome was treatment-related adverse events (TRAEs). We used random-effects model to conduct direct and network meta-analyses, which were performed by using RevMan 5.3 and R version 3.6.1, respectively.ResultsDirect meta-analysis suggested that atezolizumab, cemiplimab, nivolumab, or pembrolizumab significantly improved OS compared with chemotherapy (CT), and NMA further established that atezolizumab [hazard ratio (HR), 0.77; 95% CrI, 0.62–0.96], nivolumab (HR, 0.75; 95% CrI, 0.62–0.93), or pembrolizumab (HR, 0.71; 95% Credible interval (Crl), 0.57–0.89) significantly and cemiplimab (HR, 0.68; 95% CrI, 0.46–1.02) numerically improved OS compared with CT. Meanwhile, NMA also indicated that cemiplimab was numerically superior to other PD-1/PD-L1 agents. Moreover, avelumab, atezolizumab, cemiplimab, nivolumab, and pembrolizumab were found to have fewer TRAEs compared with CT in direct meta-analysis, which were supported by the results from the NMA. Meanwhile, surface under the cumulative ranking curve (SUCRA) and ranking probability suggested that cemiplimab provided the most favorable balance between efficacy and safety, with the first ranking for the OS.ConclusionsBased on available evidence, cemiplimab may have the most favorable risk–benefit ratio for NSCLC patients compared with other common therapeutic management. However, future research with a large-scale, high-quality, and mature follow-up is needed to further determine which agents should be preferentially selected for NSCLC patients due to the limitations of our NMA and variations of eligible studies in treatment line and PD-L1 status.

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First-Line Checkpoint Inhibitors for Wild-Type Advanced Non-Small-Cell Cancer: A Pair-Wise And Network Meta-Analysis

Cited by 7 publications

References 47 publications

Compare the efficacy and safety of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors for advanced non-small cell lung cancer: a Bayesian analysis

Compare the efficacy and safety of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors for advanced non-small cell lung cancer: a Bayesian analysis

Immunotherapy: From Advanced NSCLC to Early Stages, an Evolving Concept

Comparative Efficacy and Safety of Anti-PD-1/PD-L1 for the Treatment of Non-Small Cell Lung Cancer: A Network Meta-Analysis of 13 Randomized Controlled Studies

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