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Frontiers in Immunology 2019During the past years biologic agents (also termed biologicals or biologics) have become a crucial treatment option in immunological diseases. Numerous articles have...
During the past years biologic agents (also termed biologicals or biologics) have become a crucial treatment option in immunological diseases. Numerous articles have been published on biologicals, which complicates the decision making process on the use of the most appropriate biologic for a given immune-mediated disease. This systematic review is the first of a series of articles assessing the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. To evaluate rituximab's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment, or other biologics. The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. The literature search identified 19,665 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 105 articles were finally included in a narrative synthesis. Rituximab is both safe and effective for the treatment of acquired angioedema with C1-inhibitor deficiency, ANCA-associated vasculitis, autoimmune hemolytic anemia, Behçet's disease, bullous pemphigoid, Castleman's disease, cryoglobulinemia, Goodpasture's disease, IgG4-related disease, immune thrombocytopenia, juvenile idiopathic arthritis, relapsing-remitting multiple sclerosis, myasthenia gravis, nephrotic syndrome, neuromyelitis optica, pemphigus, rheumatoid arthritis, spondyloarthropathy, and systemic sclerosis. Conversely, rituximab failed to show an effect for antiphospholipid syndrome, autoimmune hepatitis, IgA nephropathy, inflammatory myositis, primary-progressive multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis. Finally, mixed results were reported for membranous nephropathy, primary Sjögren's syndrome and Graves' disease, therefore warranting better quality trials with larger patient numbers.
Topics: Animals; Antigens, CD20; B-Lymphocytes; Disease Progression; Humans; Immune System Diseases; Immunotherapy; Lymphocyte Depletion; Rituximab; Treatment Outcome
PubMed: 31555262
DOI: 10.3389/fimmu.2019.01990 -
Annals of Oncology : Official Journal... Aug 2019Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined...
ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach.
BACKGROUND
Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy.
METHODS
To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression.
RESULTS
The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types.
CONCLUSIONS
This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.
Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Biomarkers, Tumor; DNA Mismatch Repair; DNA Mutational Analysis; European Union; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Medical Oncology; Microsatellite Instability; Mutation; Neoplasms; Patient Selection; Practice Guidelines as Topic; Programmed Cell Death 1 Receptor; Societies, Medical
PubMed: 31056702
DOI: 10.1093/annonc/mdz116 -
International Journal of Molecular... Sep 2022Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of... (Review)
Review
Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body's own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016-2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.
Topics: Antineoplastic Agents, Immunological; Apoptosis Regulatory Proteins; B7-H1 Antigen; CTLA-4 Antigen; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Drug-Related Side Effects and Adverse Reactions; Humans; Immune Checkpoint Inhibitors; Ligands; Liver Neoplasms; Lung Neoplasms; Myocarditis; Programmed Cell Death 1 Receptor
PubMed: 36142866
DOI: 10.3390/ijms231810948 -
European Journal of Medical Genetics Oct 2021Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset...
Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset diffuse gastric cancer (DGC) and/or invasive lobular breast cancer (LBC) are the main phenotypes in CDH1-associated HDGC. CTNNA1, encoding for α-E-catenin, and E-cadherin-partner in the adherens junction complex, has been recently classified as a HDGC predisposing gene. Nevertheless, little is known about CTNNA1 tumor spectrum in variant carriers and variant-type associated causality. Herein, we systematically reviewed the literature searching for CTNNA1 germline variants carriers, further categorized them according to HDGC clinical criteria (HDGC vs non-HDGC), collected phenotypes, classified variants molecularly and according to CDH1 ACMG/AMP guidelines and performed genotype-phenotype analysis. We found 41 families carrying CTNNA1 germline variants encompassing in total 105 probands and relatives. All probands from 13 HDGC families presented DGC and their average age of onset was 40 ± 17 years; 10/13 (77%) HDGC families carried a pathogenic (P) variant. Most probands from 28 non-HDGC families developed unspecified-BC, as well as most of their relatives; 4/28 (14%) carried a P variant, 16/28 (57%) carried a likely pathogenic (LP) variant, 7/28 (25%) carried variants of unknown significance (VUS) and 1/28 (4%) carried a likely benign variant. Regardless of clinical criteria, 97% (32/33) of probands and relatives from P variant-carrier families had DGC/unspecified-GC. In LP variant-carrier families, 82% (28/34) of probands and relatives had unspecified-BC. Only 2/105 individuals had LBC. A cluster of frameshift and nonsense variants was found in CTNNA1 last exon of non-HDGC families and classified as VUS. In conclusion, current available data confirms an association of CTNNA1 P variants with early-onset DGC, but not with LBC. We demonstrate that in ascertained cohorts, CTNNA1 P variants explain <2% of HDGC families and support the use of ACMG/AMP CDH1 specific variant curation guidelines, while no specific guidelines are developed for CTNNA1 variant classification. Moreover, we demonstrated that truncating variants at the CTNNA1 NMD-incompetent last exon have limited deleteriousness, and that CTNNA1 LP variants have lower actionability than CDH1 LP variants. Current knowledge supports considering only CTNNA1 P variants as clinically actionable in HDGC carrying families.
Topics: Antigens, CD; Cadherins; Gene Frequency; Genetic Predisposition to Disease; Germ-Line Mutation; Heterozygote; Humans; Pedigree; Phenotype; Stomach Neoplasms; alpha Catenin
PubMed: 34425242
DOI: 10.1016/j.ejmg.2021.104316 -
Blood Advances Oct 2023Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell... (Meta-Analysis)
Meta-Analysis
Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein-coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific; B-Cell Maturation Antigen; Immunotherapy; T-Lymphocytes; CD3 Complex
PubMed: 37467036
DOI: 10.1182/bloodadvances.2023010539 -
Frontiers in Immunology 2021B cells can contribute to immune-mediated disorders. Targeting CD20 has proved to be efficacious in several B cell-mediated immunopathologies, as illustrated by the use...
BACKGROUND
B cells can contribute to immune-mediated disorders. Targeting CD20 has proved to be efficacious in several B cell-mediated immunopathologies, as illustrated by the use of rituximab, the first anti-CD20 monoclonal antibody (mAb). Following rituximab, second- and third-generation anti-CD20 mAbs have been developed and tried in immune-mediated diseases, including obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab. However, their safety and efficacy has not been systematically reviewed.
OBJECTIVE
To evaluate safety and efficacy of obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics.
METHODS
The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 22 July 2021 concentrating on immune-mediated disorders.
RESULTS
The literature search identified 2220 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 27 articles were finally included in a narrative synthesis.
CONCLUSIONS
Obinutuzumab has shown promising results in a case series of patients with phospholipase A receptor-associated membranous nephropathy and mixed results in systemic lupus erythematosus. Ocrelizumab has been approved for the use in patients with relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. Ocrelizumab was also tested in patients with rheumatoid arthritis, demonstrating promising results, and in systemic lupus erythematosus, revealing mixed results; however, in these conditions, its use was associated with increased risk of serious infections. Ofatumumab received approval for treating patients with relapsing-remitting multiple sclerosis. Moreover, ofatumumab showed promising results in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, rheumatoid arthritis, and systemic lupus erythematosus, as well as mixed results in phospholipase A receptor-associated membranous nephropathy. Ublituximab was assessed in relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorder, with promising results, however, the included number of patients was too small to conclude. Veltuzumab was tested in patients with immune thrombocytopenia resulting in improved platelet counts.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD4201913421.
Topics: Antigens, CD20; Arthritis, Rheumatoid; Biological Products; Glomerulonephritis, Membranous; Humans; Immune System Diseases; Lupus Erythematosus, Systemic; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Phospholipases; Rituximab
PubMed: 35185862
DOI: 10.3389/fimmu.2021.788830 -
The Lancet. Oncology Sep 2021Numerous ongoing trials are testing anti-PD-1-based or anti-PD-L1-based cancer treatment combinations. Understanding the toxicity profiles of treatment-related adverse... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Numerous ongoing trials are testing anti-PD-1-based or anti-PD-L1-based cancer treatment combinations. Understanding the toxicity profiles of treatment-related adverse events is essential. The aim of this study was to comprehensively investigate the incidences and profiles of treatment-related adverse events across different combination therapies.
METHODS
We did a systematic review and meta-analysis comparing different chemotherapy, targeted therapy, immunotherapy, and radiotherapy combinations with PD-1 or PD-L1 inhibitors. We searched Pubmed, Embase, and Cochrane databases for articles published in English between Jan 1, 2000, and May 21, 2020, investigating globally approved PD-1 or PD-L1 inhibitor-based combination therapies. Only prospective trials reporting overall incidence or tabulated data of treatment-related adverse events were included. Trials investigating sequential therapies, comprising three or more classes of therapies, and enrolling less than ten patients were excluded. The primary outcomes were overall incidences and profiles for all-grade and grade 3 or higher treatment-related adverse events by random-effect models. Heterogeneity between studies was assessed with I statistics. The summary measures for main outcomes are incidences (95% CI). The 95% CI were calculated together with the incidence through a random-effects model with a logit transformation. The protocol is registered with PROSPERO (CRD42020189617).
FINDINGS
We identified 2540 records, of which 161 studies (17 197 patients) met the inclusion criteria. The overall incidence of treatment-related adverse events in the chemotherapy combination was 97·7% (95% CI 96·4-98·5; I=75%) for all-grade adverse events and 68·3% (60·7-75·0; I=93%) for grade 3 or higher adverse events; in the targeted therapy combination was 94·5% (90·7-96·8; I=86%) for all-grade adverse events and 47·3% (37·3-57·5; I=93%) for grade 3 or higher adverse events; in the immunotherapy combination was 86·8% (80·9-91·1; I=94%) for all-grade adverse events and 35·9% (29·5-42·9; I=92%) for grade 3 or higher adverse events; and in the radiotherapy combination was 89·4% (69·0-96·9; I=74%) for all-grade adverse events and 12·4% (4·4-30·6; I=73%) for grade 3 or higher adverse events. For these four combination therapies, the most common all-grade adverse events were anaemia (45.4% [95% CI 32·4-59·1]), fatigue (34·3% [27·5-41·9]), fatigue (26·4% [19·2-35·2]), and dysphagia (30·0% [18·7-44·5]), respectively, and the most common grade 3 or higher adverse events were neutropenia (19·6% [13·5-27·7]), hypertension (9·3% [5·7-14·9]), lipase increased (7·2% [5·2-9·9]), and lymphopenia (10·3% [4·5-21·8]). All included randomised controlled trials had a low risk of bias.
INTERPRETATION
Our study provides comprehensive data on treatment-related adverse events of different PD-1 or PD-L1 inhibitor-based combination therapies. Our results provide an essential reference of toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies for clinicians in routine practice of cancer care.
FUNDING
National Key Research and Development Programme, National Natural Science Foundation of China key program, National Natural Science Foundation of China general program, Chinese Academy of Medical Sciences Initiative for Innovative Medicine, Beijing Municipal Science and Technology Commission, Non-profit Central Research Institute Fund.
Topics: B7-H1 Antigen; Clinical Trials as Topic; Combined Modality Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Immune Checkpoint Inhibitors; Incidence; Programmed Cell Death 1 Receptor
PubMed: 34391508
DOI: 10.1016/S1470-2045(21)00333-8 -
JAMA Otolaryngology-- Head & Neck... Oct 2021The emerging approach of neoadjuvant immunotherapy for solid cancers has set the ground for the integration of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1)... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The emerging approach of neoadjuvant immunotherapy for solid cancers has set the ground for the integration of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors into the neoadjuvant setting of head and neck squamous cell carcinoma (HNSCC) treatment.
OBJECTIVE
To assess the reported efficacy and safety of neoadjuvant immunotherapy for resectable HNSCC.
DATA SOURCES AND STUDY SELECTION
Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched for published and ongoing cohort studies and randomized clinical trials that evaluate neoadjuvant immunotherapy for resectable HNSCC. The search results generated studies from 2015 to July 2021.
DATA EXTRACTION AND SYNTHESIS
Two investigators (R.M. and L.K.) independently identified and extracted articles for potential inclusion. Random and fixed models were used to achieve pooled odds ratios. All results are presented with 95% CIs. Data quality was assessed by means of the Cochrane Collaboration's risk of bias tool.
MAIN OUTCOMES AND MEASURES
The primary outcomes were reported efficacy, evaluated by major pathological response and pathological complete response in the primary tumors and lymph nodes separately, and safety, assessed by preoperative grade 3 to 4 treatment-related adverse events and surgical delay rate.
RESULTS
A total of 344 patients from 10 studies were included. In 8 studies, neoadjuvant immunotherapy only was administered, and the other 2 studies combined immunotherapy with neoadjuvant chemotherapy and/or radiotherapy. The overall major pathological response rate in the primary tumor sites from studies reporting on neoadjuvant immunotherapy only was 9.7% (95% CI, 3.1%-18.9%) and the pathological complete response rate was 2.9% (95% CI, 0%-9.5%). Preoperative grade 3 to 4 treatment-related adverse events were reported at a rate of 8.4% (95% CI, 0.2%-23.2%) and surgical delay at a rate of 0% (95% CI, 0%-0.9%). There was a favorable association of neoadjuvant immunotherapy with all outcome measures. The subgroup analyses did not find one specific anti-PD-1/PD-L1 agent to be superior to another, and the favorable association was demonstrated by either immunotherapy alone or in combination with anti-CTLA-4.
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis, neoadjuvant anti-PD-1/PD-L1 immunotherapy for resectable HNSCC was well tolerated and may confer therapeutic advantages implied by histopathological response. Long-term outcomes are awaited.
Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoadjuvant Therapy; Programmed Cell Death 1 Receptor
PubMed: 34473219
DOI: 10.1001/jamaoto.2021.2191 -
JAMA Pediatrics Aug 2022Neonatal early-onset sepsis (EOS) is a severe disease, particularly in preterm infants. Timely diagnosis can be challenging owing to unspecific presentation and... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Neonatal early-onset sepsis (EOS) is a severe disease, particularly in preterm infants. Timely diagnosis can be challenging owing to unspecific presentation and questionable performance of the common markers of infection. Presepsin was recently proven to be a promising biomarker for the diagnosis of EOS.
OBJECTIVE
To assess presepsin accuracy for the diagnosis of EOS.
DATA SOURCES
PubMed Medline, EMBASE, Web of Science, and Google Scholar. No publication date restrictions were applied. The literature search was limited to the English language. Articles were checked for duplication.
STUDY SELECTION
Inclusion criteria were studies that (1) included term or preterm newborns (defined as newborns with gestational age ≥37 weeks or <37 weeks, respectively); (2) included a diagnosis of EOS, defined as culture-proven sepsis for primary analysis and as either clinical or culture-proven sepsis for secondary analysis; and (3) assessed presepsin values during the initial workup for suspected EOS. Exclusion criteria were studies that (1) did not include EOS cases; (2) lacked data on presepsin sensitivity and/or specificity; and (3) were case reports, commentaries, or reviews. Two independent reviewers performed the study selection.
DATA EXTRACTION AND SYNTHESIS
Two independent reviewers performed data extraction and quality assessment. Quality assessment was performed using the Quality Assessment for Studies of Diagnostic Accuracy 2 tool, and data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were pooled using a random-effects model.
MAIN OUTCOMES AND MEASURES
The outcomes of interest for both the primary and secondary analyses were presepsin sensitivity, specificity, and diagnostic odds ratio for the diagnosis of EOS.
RESULTS
A total of 12 studies of 245 (4.9%) met inclusion criteria for the primary analysis. Twenty-three studies of 245 (9.4%) met the inclusion criteria for the secondary analysis. In the primary analysis, among 12 studies and 828 newborns of any gestational age, pooled sensitivity and specificity were 0.93 (95% CI, 0.86-0.95) and 0.91 (95% CI, 0.85-0.95), respectively; pooled diagnostic odds ratio was 131.69 (95% CI, 54.93-310.94). Subgroup analysis showed that presepsin specificity was associated with the inclusion of only EOS or all neonatal sepsis. Presepsin accuracy was not associated with gestational age, measurement with chemiluminescence enzyme immunoassay or enzyme-linked immunosorbent assay testing, country where the study was performed, or risk of bias judgment. In the secondary analysis, among 23 studies and 1866 newborns, accuracy was significantly associated with only test type.
CONCLUSIONS AND RELEVANCE
Results of this systematic review and meta-analysis suggest that presepsin was an accurate biomarker of EOS. Clinical trials are warranted to assess its usefulness and safety to reduce early antibiotic exposure, particularly in preterm newborns.
Topics: Biomarkers; Humans; Infant; Infant, Newborn; Infant, Premature; Lipopolysaccharide Receptors; Neonatal Sepsis; Peptide Fragments; Sepsis
PubMed: 35639395
DOI: 10.1001/jamapediatrics.2022.1647 -
Cancer Medicine Feb 2021A combination of programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors and radiotherapy (RT) is increasingly being used to treat... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A combination of programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors and radiotherapy (RT) is increasingly being used to treat non-small-cell lung cancer (NSCLC). However, the safety and efficacy of this approach remains controversial. We performed a systematic review and meta-analysis to summarize the related research.
METHODS
We searched the China Biology Medicine, EMBASE, Cochrane Library, and PubMed databases for all the relevant studies. The Stata software, version 12.0 was used for the meta-analysis.
RESULTS
The study included 20 clinical trials that enrolled 2027 patients with NSCLC. Compared with non-combination therapy, combination therapy using PD-1/PD-L1 inhibitors and RT was associated with prolonged overall survival (OS) (1-year OS: odds ratio [OR] 1.77, 95% confidence interval [CI] 1.35-2.33, p = 0.000; 2-year OS: OR 1.77, 95% CI 1.35-2.33, p = 0.000) and progression-free survival (PFS) (0.5-year PFS: OR 1.83, 95% CI 1.13-2.98, p = 0.014; 1-year PFS: OR 2.09, 95% CI 1.29-3.38, p = 0.003; 2-year PFS: OR 2.47, 95% CI 1.13-5.37, p = 0.023). Combination therapy also improved the objective response rate (OR 2.76, 95% CI 1.06-7.19, p = 0.038) and disease control rate (OR 1.80, 95% CI 1.21-2.68, p = 0.004). This meta-analysis showed that compared with non-combination therapy, combination therapy using PD-1/PD-L1 inhibitors and RT did not increase the serious adverse event rates (≥grade 3); however, this approach increased the rate of grade 1-2 immune-related or radiation pneumonitis. Subgroup analyses revealed that the sequence of PD-1/PD-L1 inhibitors followed RT outperformed in which concurrent PD-1/PD-L1 inhibitor and RT followed PD-1/PD-L1 inhibitor. Combination of stereotactic body RT or stereotactic radiosurgery with PD-1/PD-L1 inhibitors may be more effective than a combination of conventional RT with PD-1/PD-L1 inhibitors in patients with advanced NSCLC.
CONCLUSION
Combination therapy using PD-1/PD-L1 inhibitors and RT may improve OS, PFS, and tumor response rates without an increase in serious adverse events in patients with advanced NSCLC. However, combination therapy was shown to increase the incidence of mild pneumonitis.
Topics: B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Combined Modality Therapy; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Lung Neoplasms; Programmed Cell Death 1 Receptor; Radiosurgery; Randomized Controlled Trials as Topic; Survival Rate
PubMed: 33465302
DOI: 10.1002/cam4.3718