Dataset Information

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis.

ABSTRACT:

Background

Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC.

Methods

Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta.

Results

Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10?weeks (interquartile range, 6-19.5?weeks) and varied depending on the organ system involved.

Conclusions

The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.

SUBMITTER: Sun X

PROVIDER: S-EPMC6558759 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis.

Sun Xiaoying X Roudi Raheleh R Dai Ting T Chen Shangya S Fan Bin B Li Hongjin H Zhou Yaqiong Y Zhou Min M Zhu Bo B Yin Chengqian C Li Bin B Li Xin X

BMC cancer 20190610 1

<h4>Background</h4>Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and natur ...[more]

PMID: 31182061

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Project description:Purpose:We performed this systematic review and meta-analysis to assess the incidence of fatal adverse events that were associated with the use of programmed cell death ligand 1 (PD-L1) inhibitors, to describe them and to statistically depict factors that were associated with these events. Method:PubMed, Embase, and Cochrane Library were completely searched based on the following terms or relevant Medical Subject Heading ones: "atezolizumab", "durvalumab", "avelumab", and "cemiplimab". Results:A total of 26 eligible studies were identified, incorporating 6,896 unique participants. The overall incidence was 1.24% (95% CI: 0.93-1.65%). The incidence and odds were higher in patients with non-squamous non-small cell lung cancer (NSCLC) than those with urothelial carcinoma [(2.25 vs. 0.85, p = 0.04), (odds ratio [OR]: 2.69; 95% CI: 1.04-6.97, p = 0.04)], higher in the middle-aged group than the young group [(1.74 vs. 0.89, p = 0.01), (OR: 2.13; 95% CI: 1.26-3.61, p = 0.01)], and higher in the trial phase I than the trial phase II [(1.76 vs. 0.60, p = 0.01), (OR: 0.31; 95% CI: 0.13-0.75, p = 0.01)]. Notably, the trial phase I had a higher incidence than trial phase II or III following regulating for cancer types and average age (OR: 0.28; 95% CI: 0.11-0.71, p = 0.01, OR: 0.48; 95% CI: 0.24-0.95, p = 0.04, respectively). In terms of organ-specific fatal adverse events, interstitial lung disease (ILD) was frequently documented. A variety of respiratory system-related fatal adverse events were recorded, including but not limited to pneumonia and respiratory failure. As for organ-unspecific fatal adverse events, substantial cases of sepsis and neutropenia were recorded. Conclusion:This study firstly provided a comprehensive incidence and the spectrum of fatal adverse events associated with PD-L1 inhibitors, and identified three potential susceptible factors of that, yielding a capability for clinicians to distinguish high-risk populations from relatively low-risk ones, and facilitating to improve the safety of PD-L1 inhibitors broadly used in the clinical setting.

Project description:Despite impressive antitumor efficacy of programmed cell death 1 (PD-1) inhibitors, this inhibition can induce mild to severe autoimmune toxicities, termed immune-related adverse events (irAEs). Yet, predictive pretreatment biomarkers for irAEs development across cancer types remain elusive. We first assessed cellular and molecular factors. To determine factors predicting the risk of irAEs for anti-PD-1 immunotherapy across multiple cancer types, an integrative analysis of cellular and molecular factors from 9104 patients across 21 cancer types and 4865522 postmarketing adverse event reports retrieved from adverse event reporting system was then performed. Accuracy of predictions was quantified as Pearson correlation coefficient determined using leave-one-out cross-validation. Independent validation sets included small cell lung cancer and melanoma cohorts. Out of 4865522 eligible adverse events reports, 10412 cases received anti-PD-1 monotherapy, of which, 2997 (28.78%) exhibited at least one irAE. Among established immunogenomic factors, dendritic cells (DC) abundance showed the strongest correlation with irAEs risk, followed by tumor mutational burden (TMB). Further predictive accuracy was achieved by DC and TMB in combination with CD4+ naive T-cells abundance, and then validated in the small cell lung cancer cohort. Additionally, global screening of multiomics data identified 11 novel predictors of irAEs. Of these, IRF4 showed the highest correlation. Best predictive performance was observed in the IRF4 - TCL1A - SHC-pY317 trivariate model. Associations of IRF4 and TCL1A expression with irAEs development were verified in the melanoma cohort receiving immune checkpoint inhibitors. Collectively, pretreatment cellular and molecular irAEs-associated features as well as their combinations are identified regardless of cancer types. These findings may deepen our knowledge of irAEs pathogenesis and, ultimately, aid in early detection of high-risk patients and management of irAEs.

Project description:ImportanceInitial approval for immune checkpoint inhibitors (ICIs) for treatment of advanced non-small cell lung cancer (NSCLC) was limited to patients with high levels of programmed cell death ligand 1 (PD-L1) expression. However, in the period after approval, it is not known how new evidence supporting efficacy of these treatments in patients with low or negative PD-L1 expression was incorporated into real-world practice.ObjectiveTo evaluate the association between PD-L1 testing and first-line ICI use.Design, setting, and participantsThis retrospective cohort study (January 1, 2011, to December 31, 2018) used a deidentified nationwide electronic health record-derived database reflecting real-world care at more than 280 US community and academic cancer clinics (approximately 800 sites of care). Patients included those with advanced NSCLC without other identifiable variations diagnosed in the period after the US Food and Drug Administration's initial first-line approval of ICIs for patients with high PD-L1 expression (≥50%).ExposureFirst-line ICI treatment.Main outcomes and measuresPatterns of PD-L1 testing and first-line ICI treatment among all patients and patients stratified by tumor histologic type (squamous vs nonsquamous).ResultsA total of 45 631 patients (mean [SD] age, 68.4 [9.6] years; 21 614 [47.4%] female) with advanced NSCLC were included in the study. PD-L1 testing increased from 468 (7.2%) in 2015 to 4202 (73.2%) in 2018. Within a subset of 7785 patients receiving first-line treatment in the period after first-line approval of pembrolizumab, those who received PD-L1 testing had a greater odds of receiving an ICI (odds ratio, 2.11; 95% CI, 1.89-2.36). Among patients with high PD-L1 expression (≥50%), 1541 (83.5%) received first-line ICI treatment; 776 patients (40.3%) with low PD-L1 expression (1%-49%) and 348 (32.3%) with negative PD-L1 expression (0%) also received ICIs. In addition, 755 untested patients (32.8%) were treated with a first-line ICI. The proportion of patients who received ICIs without PD-L1 testing increased during the study period (59 [17%] in quarter 4 of 2016 to 141 [53.8%] in quarter 4 of 2018).Conclusions and relevanceIn this study, use of first-line ICI treatment increased among patients with advanced NSCLC with negative, low, or untested PD-L1 expression status in 2016 through 2018. These findings suggest that national practice was rapidly responsive to new clinical evidence rather than adhering to regulatory guidance in place at the time.

Project description:Introduction: Inhibitors of programmed cell death 1 (PD1) and its ligand (PDL1) have exhibited favorable long-term survival in many types of advanced-stage cancer and current approvals have to date been granted in certain tumour types irrespective of PD-L1 status. Methods: We extracted the following information: study sample size, trial period, cancer types, intervention of treatment, type of PD-L1 antibody, immunohistochemistry (IHC) scoring method, number and percentage of PD-L1 < 1% population, and median follow- up time. PD-L1 expression was defined as percentage of number of PD-L1-stained tumor cells (TPS), area of tumor infiltrated by PD-L1-stained immune cells (IPS), number of PD-L1-stained cells (tumor cells, lymphocytes and macrophages; CPS). Different trials used distinct method to define low PD-L1 expression. The risk of bias of the included trials was assessed by using the Cochrane risk of bias tool for RCTs. Results: Here, a total of 34 trials were included to extract individual patient data (IPD) to evaluate the survival benefit of first line PD1/PDL1 inhibitors vs. standard-of-care (SOC) in patients with PDL1 < 1%. In term of anti-PD-1/PD-L1 monotherapy, OS (HR = 0.90, 0.81-1.01) and PFS (HR = 1.11, 0.97-1.27) between PD-1/PD-L1 inhibitor group and SOC group were comparable. In term of anti-PD-1/PD-L1 combination therapy, PD-1/PD-L1 inhibitor group exhibited longer OS (median 19.5 months vs. 16.3 months; HR = 0.83, 0.79-0.88, p < 0.001) and PFS than those of SOC group (median 8.11 months vs. 6.96 months; HR = 0.82, 0.77-0.87, p < 0.001).Subgroup analysis showed that survival benefit was mainly observed in non-small cell lung cancer (NSCLC) (HROS = 0.74; HRPFS = 0.69; p < 0.001), small-cell lung cancer (SCLC) (HROS = 0.58, p < 0.001; HRPFS = 0.55, p = 0.030), esophageal squamous cell carcinoma (ESCC) (HROS = 0.62, p = 0.005; HRPFS = 0.79, p < 0.001), melanoma (HROS = 0.53, p < 0.001) and nasopharyngeal carcinoma (NPC) (HRPFS = 0.35, p = 0.013). Conclusion: Anti-PD-1/PD-L1 combinational therapy rather than monotherapy exhibit survival benefit in the low PD-L1 population in the first-line setting, and the survival benefit was mainly observed in specific tumor types.

Dataset Information

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis.

Background

Methods

Results

Conclusions

Publications

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis.

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