0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Immune checkpoint inhibitors efficacy across solid cancers and the utility of PD-L1 as a biomarker of response: a systematic review and meta-analysis

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Immune checkpoint inhibitors (ICPI) are a tumor agnostic treatment. However, trials of their use have been site specific. Here we summarize the trial data and explore the utility of programmed death-ligand 1 (PD-L1) expression as a biomarker to direct their pan-cancer use.

          Method

          A systematic review of literature, following PRISMA guidelines, was performed. Medline, Embase, Cochrane CENTRAL, NHS Health and Technology, and Web of Science were searched from their conception to June 2022 limited to the English language. The search terms and method were devised by a specialist medical librarian. Studies were limited to adults with solid cancers (excluding melanomas) treated with ICPIs. Only phase III randomized control trials (RCT) were included. The primary outcome was overall survival and secondary outcomes were progression free survival, PD-L1 expression, quality of life outcomes and adverse event data. Where present in eligible clinical trials, hazard ratios (HR), risk ratios (RR), standard error (SE) and 95% confidence intervals (CI) were extracted or calculated. Heterogeneity across studies was described with the use of an I 2 score (Low: 25, 50%: moderate, 75% low heterogeneity). HR pools inverse variance methods were adopted by Random Effects (RE). Means were standardized across any heterogenous scale limits.

          Results

          In total 46,510 participants were included in the meta-analysis. Overall, meta-analysis favored the use of ICPIs with an overall survival (OS) HR of 0.74 (95% CI 0.71 to 0.78). Lung cancers showed the most benefit in OS [HR 0.72 (95% 0.66–0.78)] followed by head and neck cancers [HR 0.75 (95% CI 0.66–0.84)] and gastroesophageal junction cancers [HR 0.75 (95% CI 0.61–0.92)]. ICPIs seem to be efficacious at both primary presentation and recurrence [OS HR 0.73 (95% CI 0.68–0.77)] vs. [OS HR 0.79 (95% CI 0.72 to 0.87)] respectively. Interestingly, subgroup analysis comparing studies in which most cancers demonstrated PD-L1 expression vs. those studies in which a minority of cancer demonstrated PD-L1 expression reported similar effect of ICPI use on OS; oddly the data favored ICPI use in studies with a minority of PD-L1 expression. Specifically, studies with minority PD-L1 expression had an HR 0.73 (95% CI 0.68–0.78) vs. studies with majority PD-L1 expression HR 0.76 (95% CI 0.70–0.84). This was maintained even when studies exploring the same cancer site were directly compared. Subgroup analysis was performed comparing the impact on OS subdivided by the specific ICPI used. Where meta-analysis was performed, Nivolumab led to the greatest impact [HR 0.70 (95% CI 0.64–0.77)] with Avelumab failing to reach significance [HR 0.93 (95% CI 0.80–1.06)]. However, overall heterogenicity was high ( I 2 = 95%). Finally, the use of ICPIs led to an improved side effect profile when compared with standard chemotherapy [RR 0.85 (95% CI 0.73–0.98)].

          Conclusion

          ICPIs improve survival outcomes in all cancer types. These effects are seen in the primary, recurrent, chemotherapy sensitive, chemotherapy resistant disease. These data support their use as a tumor agnostic therapy. Furthermore, they are well tolerated. However, PD-L1 as a biomarker for the targeting of ICPI use seems problematic. Other biomarkers such as mismatch repair or tumor mutational burden should be explored in randomized trials. In addition, there are still limited trials looking at ICPI use outside of lung cancer.

          Related collections

          Most cited references76

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

          The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The blockade of immune checkpoints in cancer immunotherapy.

            Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Welcome to the Tidyverse

                Bookmark

                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                12 May 2023
                2023
                : 10
                : 1192762
                Affiliations
                [1] 1Clinical Medical School, University of Bristol , Bristol, United Kingdom
                [2] 2Division of Cancer Sciences, St Mary’s Hospital, Faculty of Biology, Medicine and Health, University of Manchester , Manchester, United Kingdom
                [3] 3Department of Obstetrics and Gynaecology, St Michaels Hospital , Bristol, United Kingdom
                [4] 4Division of Evolution and Genomic Medicine, St Mary’s Hospital, University of Manchester , Manchester, United Kingdom
                [5] 5The College of Medicine and Veterinary Medicine, University of Edinburgh , Edinburgh, United Kingdom
                [6] 6Department of Gynaecology Oncology, Royal Infirmary of Edinburgh , Edinburgh, United Kingdom
                Author notes

                Edited by: Heping Yang, Cedars-Sinai Medical Center, United States

                Reviewed by: Man Jiang, The Affiliated Hospital of Qingdao University, China; Bing Yang, Cedars-Sinai Medical Center, United States

                *Correspondence: Timothy S. Fitzsimmons, timfitzsimmons2101@ 123456icloud.com

                These authors share first authorship

                Article
                10.3389/fmed.2023.1192762
                10219231
                37250628
                4a6c0bf1-805d-46df-a9ad-9a8af334038e
                Copyright © 2023 Fitzsimmons, Singh, Walker, Newton, Evans, Crosbie and Ryan.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 March 2023
                : 20 April 2023
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 79, Pages: 14, Words: 8802
                Categories
                Medicine
                Original Research
                Custom metadata
                Precision Medicine

                pan-cancer therapy,checkpoint immune blockade antibodies,pdl1,mismatch repair,oncology,immunotherapy

                Comments

                Comment on this article