The sound and surprise: overlapping meta-analyses on the topic of safety and efficacy of PD-1 and PD-L1 inhibitors in the treatment of non-small cell lung cancer.

PURPOSE: To analyze the characteristics of overlapping meta-analyses based on randomized controlled trials (RCTs) which reported PD-1/PD-L1 inhibitors in non-small cell cancer (NSCLC). METHODS: Meta-analyses were identified from English and Chinese databases until January 1, 2022. Differences in characteristics of overlapping meta-analyses that conducted in China and other countries were compared to assess their publication propensity. The corrected covered area (CCA) and coverage of relevant RCTs were analyzed for subtopics according to detailed intervention types. The waste and redundancy of evidence were assessed in the case of PD-1/PD-L1 inhibitor monotherapy for second-line treatment for NSCLC. RESULTS: Fifty-nine meta-analyses published in English and 17 meta-analyses published in Chinese reporting 26 RCTs were identified. Fifty-three (69.74%) meta-analyses were conducted in China. The overlapping meta-analyses in China were more likely to be from hospitals, supported by government funding, integrate first and second-line therapies. Five of the six subtopics had overlapping meta-analyses according to specific types of interventions. The CCA of overlapping meta-analyses ranged from 33.33 to 63.19%, and the coverage of relevant RCTs ranged from 63.64 to 100%. All the conclusions of overlapping meta-analyses have been consistent in the subtopic of PD-1/PD-L1 inhibitor monotherapy for second-line treatment since 2017. CONCLUSION: Overlapping meta-analyses of PD-1/PD-L1 inhibitors in NSCLC hints that meta-analyses under this topic probably exist serious redundancy. Future research should focus on prospective registration of protocols for systematic reviews/meta-analyses, scientific designed PICO, and cumulative meta-analysis to reduce redundant and wasted studies. Journals should strengthen the requirement for reviewing previously published evidence in manuscript review.

Value assessment of PD-1/PD-L1 inhibitors in the treatment of oesophageal and gastrointestinal cancers.

Background: Evidence of efficacy and safety of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in oesophageal cancer (EC), gastric cancer (GC) and colorectal cancer (CRC) was inconsistent, obscuring their clinical application and decision-making. The aim of this study was to comprehensively evaluate the value of PD-1/PD-L1 inhibitors in EC, GC and CRC to select valuable PD-1/PD-L1 inhibitors, and to assess the association between the value and cost of PD-1/PD-L1 inhibitors. Methods: A comprehensive search of trials of PD-1/PD-L1 inhibitors in EC, GC and CRC was performed in Chinese and English medical databases with a cut-off date of 1 July 2022. Two authors independently applied the ASCO-VF and ESMO-MCBS to assess the value of PD-1/PD-L1 inhibitors. A receiver operating characteristic (ROC) curve was generated to establish the predictive value of the ASCO-VF score to meet the threshold of the ESMO-MCBS grade. Spearman's correlation was used to calculate the relationship between the cost and value of drugs. Results: Twenty-three randomized controlled trials were identified: ten (43.48%) in EC, five (21.74%) in CRC, and eight (34.78%) in GC or gastroesophageal junction cancer (GEJC). For advanced diseases, ASCO-VF scores ranged from -12.5 to 69, with a mean score of 26.5 (95% CI 18.4-34.6). Six (42.9%) therapeutic regimens met the ESMO-MCBS benefit threshold grade. The area under the ROC curve was 1.0 (p = 0.002). ASCO-VF scores and incremental monthly cost were negatively correlated (Spearman's ρ = -0.465, p = 0.034). ESMO-MCBS grades and incremental monthly cost were negatively correlated (Spearman's ρ = -0.211, p = 0.489). Conclusion: PD-1/PD-L1 inhibitors did not meet valuable threshold in GC/GEJC. Pembrolizumab met valuable threshold in advanced microsatellite instability-high CRC. The value of camrelizumab and toripalimab may be more worth paying in EC.

Safety and Efficacy of Programmed Cell Death 1 and Programmed Death Ligand-1 Inhibitors in the Treatment of Cancer: An Overview of Systematic Reviews.

Background: An influx of systematic reviews (SRs) of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in cancer treatment with or without meta-analysis and with different methodological quality and inconsistent results have been published, confusing clinical decision making. The aim of this study was to comprehensively evaluate and summarize the current evidence of PD-(L)1 inhibitors in the treatment of cancer. Methods: A comprehensive search of SRs, which included meta-analyses of PD-(L)1 inhibitors on cancer, was performed on eight databases with a cutoff date of 1 January 2022. Two authors independently identified SRs, extracted data, assessed the report quality according to the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, evaluated the methodological quality by the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2), and appraised the quality of evidence by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Results: A total of 172 SRs with meta-analysis met the inclusion criteria. The report quality of included SRs was quite good, with 128 (74.42%) SRs of high quality and 44 (25.58%) of moderate quality. The methodological quality was alarming, as only one (0.58%) SR had high quality, five (2.91%) SRs had low quality, and the other 166 (96.51%) SRs had critically low quality. For GRADE, 38 (3.77%) outcomes had high-quality evidence, 288 (28.57%) moderate, 545 (54.07%) low, and 137 (13.59%) critically low-quality evidence. Current evidence indicated that treatment with PD-(L)1 inhibitors were significantly effective in non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, malignant melanoma, renal cell carcinoma, and urothelial carcinoma, breast cancer, and head and neck squamous cell carcinoma with PD-L1 expression level≥1%, whereas the evidence in gastroesophageal and colorectal tumors is still controversial. Monotherapy with PD-(L)1 inhibitors was associated with a lower frequency of any grade and high-grade adverse events (AEs). The incidence of any grade and high-grade AEs caused by PD-(L)1 inhibitors in combination with other therapies was no lower than the controls. However, PD-(L)1 inhibitors were associated with a higher frequency of any grade and high-grade immune-related AEs. Conclusions: PD-(L)1 inhibitors appeared to be effective and safe for cancer treatment, except for gastrointestinal tumors; however, the quality of the evidence is not convincing. Future studies should improve methodological quality and focus on the sequential trial analysis of subgroups and safety. Systematic Review Registration: http://www.crd.york.ac.uk/prospero, identifier CRD42020194260.