Immune checkpoint inhibitors in advanced gastroesophageal adenocarcinoma: a series of patient-level meta-analyses in different programmed death-ligand 1 subgroups
{"title":"Immune checkpoint inhibitors in advanced gastroesophageal adenocarcinoma: a series of patient-level meta-analyses in different programmed death-ligand 1 subgroups","authors":"","doi":"10.1016/j.esmoop.2024.103962","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>While the benefit of immune checkpoint inhibitors (ICI) is well established in programmed death-ligand 1 high (PD-L1<sub>high</sub>) advanced gastroesophageal adenocarcinoma (GEAC), there remains significant controversy about their benefit in PD-L1<sub>low</sub> GEAC. To elucidate the benefit of ICI in PD-L1<sub>low</sub> and PD-L1<sub>negative</sub> GEAC, we conducted an analysis leveraging individual patient data (IPD) extracted from Kaplan–Meier (KM) plots of pivotal trials.</div></div><div><h3>Methods</h3><div>KM curves from randomized clinical trials investigating the efficacy of ICI for advanced GEAC were extracted from published articles. IPD were extracted from the reported curves, and, in the case of unreported KM plots, KMSubtraction was used to retrieve survival data. A patient-level meta-analysis was conducted for PD-L1<sub>low</sub> tumors.</div></div><div><h3>Results</h3><div>In the human epidermal growth factor receptor 2 (HER2)-negative setting, pooled PD-L1 combined positive score (CPS) 1-4 subgroup KM plots from KEYNOTE-859, CHECKMATE-649, and RATIONALE-305 showed a modest overall survival (OS) benefit with the addition of an anti-programmed cell death protein 1 (anti-PD-1) agent [hazard ratio (HR) 0.868, <em>P</em> = 0.018]. Similarly, a modest OS benefit was shown by our IPD meta-analysis of PD-L1 CPS 1-9 subgroups from KEYNOTE-859, KEYNOTE-062, and RATIONALE-305 (HR 0.840, <em>P</em> = 0.002.) Conversely, when CPS 5-9 subgroup KM plots from KEYNOTE-859 and RATIONALE-305 were pooled together, no significant OS benefit was found in the ICI-chemotherapy arm (HR 0.867, <em>P</em> = 0.181), although this subgroup was relatively small.</div></div><div><h3>Conclusions</h3><div>In PD-L1<sub>low</sub> HER-2 negative GEAC, the benefit of first-line ICI is modest, yet significant. Further translational work is warranted to better select patients who could benefit from immunotherapy in this setting. Meanwhile, alternative therapeutic options such as zolbetuximab in Claudin18.2-positive disease must be taken into account.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ESMO Open","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2059702924017320","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background
While the benefit of immune checkpoint inhibitors (ICI) is well established in programmed death-ligand 1 high (PD-L1high) advanced gastroesophageal adenocarcinoma (GEAC), there remains significant controversy about their benefit in PD-L1low GEAC. To elucidate the benefit of ICI in PD-L1low and PD-L1negative GEAC, we conducted an analysis leveraging individual patient data (IPD) extracted from Kaplan–Meier (KM) plots of pivotal trials.
Methods
KM curves from randomized clinical trials investigating the efficacy of ICI for advanced GEAC were extracted from published articles. IPD were extracted from the reported curves, and, in the case of unreported KM plots, KMSubtraction was used to retrieve survival data. A patient-level meta-analysis was conducted for PD-L1low tumors.
Results
In the human epidermal growth factor receptor 2 (HER2)-negative setting, pooled PD-L1 combined positive score (CPS) 1-4 subgroup KM plots from KEYNOTE-859, CHECKMATE-649, and RATIONALE-305 showed a modest overall survival (OS) benefit with the addition of an anti-programmed cell death protein 1 (anti-PD-1) agent [hazard ratio (HR) 0.868, P = 0.018]. Similarly, a modest OS benefit was shown by our IPD meta-analysis of PD-L1 CPS 1-9 subgroups from KEYNOTE-859, KEYNOTE-062, and RATIONALE-305 (HR 0.840, P = 0.002.) Conversely, when CPS 5-9 subgroup KM plots from KEYNOTE-859 and RATIONALE-305 were pooled together, no significant OS benefit was found in the ICI-chemotherapy arm (HR 0.867, P = 0.181), although this subgroup was relatively small.
Conclusions
In PD-L1low HER-2 negative GEAC, the benefit of first-line ICI is modest, yet significant. Further translational work is warranted to better select patients who could benefit from immunotherapy in this setting. Meanwhile, alternative therapeutic options such as zolbetuximab in Claudin18.2-positive disease must be taken into account.
期刊介绍:
ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research.
ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO.
Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.