Comparative effectiveness of immune-checkpoint inhibitors for previously treated advanced non-small cell lung cancer - A systematic review and network meta-analysis of 3024 participants.

Role of PD-L1 expression to guide immunotherapies in previously treated advanced NSCLC remains unclear and there is a lack of data comparing immune checkpoint inhibitors (ICIs) with each other. This network meta-analysis (NMA) aims to compare survival with ICIs to docetaxel and perform indirect comparisons between ICIs in the PD-L1 unselected population and by PD-L1 expression levels. PubMed was searched and study screening was performed by two independent reviewers. NMA of survival outcomes in the PD-L1 unselected population and by PD-L1 expression levels <1%, >=1%,>=5%,>=10%, and >=50% was performed. Head-to-head indirect comparisons were constructed and treatment rankings were provided. Potential survival benefits by PD-L1 expression level as compared to a PD-L1 unselected population were estimated. 5 trials with 3024 total patients were included for meta-analysis. Overall, ICIs improved survival across PD-L1 expression levels compared to docetaxel, although there was only weak evidence of benefit for individual ICI nivolumab or atezolizumab in PD-L1<1%. PD-L1 subgroups suggested positive dose-response relationship between PD-L1 expression levels with survival benefits. In addition, there were also survival benefits due to selecting for PD-L1 in the PD-L1>=10% and >=50% subgroups as compared to the PD-L1 unselected population. Indirect comparisons of ICIs showed little evidence of differences between nivolumab, pembrolizumab and atezolizumab. ICIs improve survival in previously treated advanced NSCLC patients across PD-L1 expression levels compared to docetaxel. There is a positive dose-response relationship between PD-L1 expression and survival benefits, and little evidence of survival differences between nivolumab, pembrolizumab and atezolizumab.

Tan PS ，Aguiar P Jr ，Haaland B ，Lopes G ... -  《-》

Comparative Efficacy of Second- and Subsequent-line Treatments for Metastatic NSCLC: A Fractional Polynomials Network Meta-analysis of Cancer Immunotherapies.

Extended onset of treatment effect and longer-term survival with anti-programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immunotherapies, atezolizumab, nivolumab, and pembrolizumab, have changed the landscape of second- or subsequent-line (2L+) treatments for adults with non-small-cell lung cancer (NSCLC). This systematic literature review included phase I to IV randomized, controlled trials of 2L+ NSCLC therapies from MEDLINE, Embase, and secondary sources. Studies of treatments approved in the European Union or United States had to be in English with ≥ 10 patients per arm. A fractional polynomials network meta-analysis (NMA) was conducted because traditional NMA of hazard ratios does not account for delayed onset of clinical effect or long-term survival observed in PD-L1/PD-1 inhibitor trials. Adjusted analyses accounted for treatment switching in the atezolizumab OAK trial. Expected survival time reflected area under the curve over the time horizon. Expected overall survival (OS) was ranked by median ranking with 95% credible intervals and by surface under the cumulative ranking curve. Of 25,115 screened records, 28 studies were included in the quantitative analyses of OS and progression-free survival. PD-L1/PD-1 inhibitors had comparable expected 5-year OS; all performed better than other treatment options. In unadjusted analyses, surface under the cumulative ranking curve ranked nivolumab first (87.9%), followed by atezolizumab (85.8%) and pembrolizumab (82.8%). Analyses adjusted for patients switching from docetaxel to immunotherapy ranked atezolizumab first (89.6%), followed by nivolumab (86.5%) and pembrolizumab (81.9%). This NMA applied an appropriate approach for indirect comparisons, including cancer immunotherapies, and supported robustness of PD-L1/PD-1 immunotherapies for 2L+ treatment of NSCLC.

Schulz C ，Gandara D ，Berardo CG ，Rosenthal R ，Foo J ，Morel C ，Ballinger M ，Watkins C ，Chu P ... -  《-》

Immune checkpoint inhibitors, alone or in combination with chemotherapy, as first-line treatment for advanced non-small cell lung cancer. A systematic review and network meta-analysis.

This network meta-analysis (NMA), based on 12 phase-III studies with 9,236 metastatic NSCLC patients, aims to compare the efficacy of treatments including at least one immune-checkpoint inhibitor (ICI) with or without chemotherapy, as frontline therapy for advanced NSCLC patients. The NMA includes direct randomized evidence on treatments of interest along with indirect evidence from randomized studies with chemotherapy as the common comparator. Studies were identified by searching PubMed, and the abstracts of most recent main oncology congresses. The primary endpoint, Hazard-Ratio (HR) of Progression-free Survival (PFS), was estimated by a frequentist-approach NMA. Results are presented in the overall cohort (all-comers or PD-L1-positive) irrespective of histology, and by histology, PD-L1 expression level and sex. According to the primary PFS-NMA in the overall cohort, the combination of chemotherapy, first with pembrolizumab, second with atezolizumab exhibit significantly higher benefit than any other treatment examined. This superior PFS benefit is found for both squamous and non-squamous patients. Similarly for OS, the combination of pembrolizumab/chemotherapy, and atezolizumab/bevacizumab/chemotherapy-(ABC), followed by pembrolizumab-monotherapy and atezolizumab/chemotherapy, are the best treatments in the overall cohort, driven by the non-squamous histology. In the PD-L1-high patients again the combination of chemotherapy with atezolizumab or pembrolizumab, exhibit significant PFS benefit, followed by pembrolizumab-monotherapy. PFS benefit of these ICI/chemotherapy combinations are also found in PD-L1-negative and PD-L1-intermediate patients(1%≤PD-L1 < 50%). Of note, ABC is evaluated only for OS in non-squamous patients while the pembrolizumab-monotherapy PFS benefit and the atezolizumab/chemotherapy OS benefit are probably under-estimated since most of the data stems from non-significant interim analyses of ongoing studies [KN042;IM131/132/150]. In conclusion, the addition of chemotherapy to ICIs enhanced their treatment efficacy as first-line treatment for advanced NSCLC patients. The combination of chemotherapy with either pembrolizumab or atezolizumab show consistently higher efficacy than chemotherapy-alone or any other ICI-combination or monotherapy, particularly in non-squamous patients.

Dafni U ，Tsourti Z ，Vervita K ，Peters S ... -  《-》

Predictors for clinical benefit of immune checkpoint inhibitors in advanced non-small-cell lung cancer: a meta-analysis.

El-Osta H ，Jafri S 《-》

Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer: A Meta-analysis and Individual Patient-Level Analysis.

Yu Y ，Zeng D ，Ou Q ，Liu S ，Li A ，Chen Y ，Lin D ，Gao Q ，Zhou H ，Liao W ，Yao H ... -  《JAMA Network Open》