Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Shitara, Kohei; Ajani, Jaffer A.; Moehler, Markus; Garrido, Marcelo; Gallardo, Carlos; Shen, Lin; Yamaguchi, Kensei; Wyrwicz, Lucjan; Skoczylas, Tomasz; Bragagnoli, Arinilda Campos; Liu, Tianshu; Tehfé, Mustapha; Elimova, Elena; Brugés, Ricardo; Zander, Thomas; Azevedo, Sérgio de; Kowalyszyn, Rubén Dario; Pazo-Cid, Roberto; Schenker, Michael; Cleary, James M.; Yañez, Patricio; Feeney, Kynan; Karamouzis, Michalis V.; Poulart, Valerie; Lei, Ming; Xiao, Hong; Kondo, Kaoru; Li, Mingshun; Janjigian, Yelena Y.

doi:10.1038/s41586-022-04508-4

Cited by 200 publications

(187 citation statements)

References 32 publications

(45 reference statements)

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“…We retrieved 6680 potentially relevant trials from PubMed, Embase and the Cochrane Library databases. After removing duplicates and screening titles, abstracts, and full texts, 50 articles met our inclusion criteria and were included in the meta-analysis ( 21 – 70 ). There was a high-risk bias in 11 clinical trials, mainly due to incomplete reported data and other biases in 5 studies.…”

Section: Resultsmentioning

confidence: 99%

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

et al. 2022

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BackgroundPD-1/PD-L1 inhibitors have significantly improved the outcomes of those patients with various malignancies. However, the incidence of adverse events also increased. This meta-analysis aims to systematically evaluate the risk of cardiovascular toxicity in patients treated with PD-1/PD-L1 inhibitors.Materials and methodsWe searched PubMed, Embase, the Cochrane Library databases for all randomized controlled trials (RCTs) comparing all-grade and grade 3-5 cardiovascular toxicity of single-agent PD-1/PD-L1 inhibitors to placebo/chemotherapy, PD-1/PD-L1 inhibitors combined with chemotherapy to chemotherapy, or PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors to single-agent immune checkpoint inhibitors (ICIs) and pooled our data in a meta-analysis stratified by tumor types and PD-1 or PD-L1 inhibitors. The Mantel-Haenszel method calculated the odds ratio (OR) and its corresponding 95% confidence intervals (CIs).ResultsA total of 50 trials were included in the analysis. Single-agent PD-1/PD-L1 inhibitors increased the risk of all-grade cardiotoxicity compared with placebo (OR=2.11, 95%CI 1.02-4.36, P=0.04). Compared with chemotherapy, patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy had a significant higher risk of all-grade (OR=1.53, 95%CI 1.18-1.99, P=0.001) and grade 3-5 cardiotoxicity (OR=1.63, 95%CI 1.11-2.39, P=0.01) cardiotoxicity, especially patients with non-small cell lung cancer (NSCLC) [all-grade cardiotoxicity (OR=1.97, 95%CI 1.14-3.41, P=0.02) and grade 3-5 cardiotoxicity (OR=2.15, 95%CI 1.08-4.27, P=0.03)]. Subgroup analysis showed that PD-1 inhibitors combined with chemotherapy were associated with a higher risk of grade 3-5 cardiotoxicity (OR=2.08, 95%CI 1.18-3.66, P=0.01). Compared with placebo or chemotherapy, single-agent PD-1/PD-L1 inhibitors did not increase the risk of all-grade of myocarditis, arrhythmia and hypertension. However, PD-1/PD-L1 inhibitors combined with chemotherapy increased the risk of all-grade arrhythmia (OR=1.63, 95%CI 1.07-2.46, P=0.02) [PD-L1 inhibitor-containing treatment (OR=1.75, 95%CI 1.09-2.80, P=0.02)], and the risk of all-grade hypertension (OR=1.34, 95%CI 1.02-1.77, P=0.04) and grade 3-5 hypertension (OR=1.54, 95%CI 1.10-2.15, P=0.01).ConclusionsOur results suggest that single-agent PD-1/PD-L1 inhibitors increase the risk of all-grade cardiotoxicity, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of all-grade and grade 3-5 cardiotoxicity, especially in those patients treated with PD-1 inhibitor-containing treatment and those with NSCLC. In addition, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of arrhythmia and hypertension. Therefore, this evidence should be considered when assessing the benefits and risks of PD-1/PD-L1 inhibitors in treating malignancies.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022303115.

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Section: Resultsmentioning

confidence: 99%

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

et al. 2022

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“…For tumors of the esophagus (both squamous cell carcinoma and adenocarcinoma), esophago–gastric junction and stomach, recent studies clarified the pivotal role of the 22C3 (Dako) and 28-8 (Dako) clones [ 35 , 36 , 37 ]. At the immunohistochemical level, the staining pattern should be assessed using the CPS.…”

Section: Introductionmentioning

confidence: 99%

“…At the immunohistochemical level, the staining pattern should be assessed using the CPS. The CPS thresholds for considering a specific case as “positive” (i.e., eligible for immunotherapy) in this context represent a changing landscape, with current evidence suggesting a threshold of five for gastric tumors, also including those of the esophago–gastric junction, and of 10 for esophageal malignancies [ 35 , 36 , 37 ]. Given that this scenario is in constant and rapid evolution, the general suggestion for pathologists assessing PD-L1 in esophageal–gastric specimens is to provide the exact CPS score in the pathology report.…”

Section: Introductionmentioning

confidence: 99%

Atlas of PD-L1 for Pathologists: Indications, Scores, Diagnostic Platforms and Reporting Systems

Marletta

Fusco

Munari

et al. 2022

JPM

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Background. Innovative drugs targeting the PD1/PD-L1 axis have opened promising scenarios in modern cancer therapy. Plenty of assays and scoring systems have been developed for the evaluation of PD-L1 immunohistochemical expression, so far considered the most reliable therapeutic predictive marker. Methods. By gathering the opinion of acknowledged experts in dedicated fields of pathology, we sought to update the currently available evidence on PD-L1 assessment in various types of tumors. Results. Robust data were progressively collected for several anatomic districts and leading international agencies to approve specific protocols: among these, TPS with 22C3, SP142 and SP263 clones in lung cancer; IC with SP142 antibody in breast, lung and urothelial tumors; and CPS with 22C3/SP263 assays in head and neck and urothelial carcinomas. On the other hand, for other malignancies, such as gastroenteric neoplasms, immunotherapy has been only recently introduced, often for particular histotypes, so specific guidelines are still lacking. Conclusions. PD-L1 immunohistochemical scoring is currently the basis for allowing many cancer patients to receive properly targeted therapies. While protocols supported by proven data are already available for many tumors, dedicated studies and clinical trials focusing on harmonization of the topic in other still only partially explored fields are surely yet advisable.

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“…The CheckMate 649 trial evaluated PD-1 inhibitor-based first-line chemotherapy [ 34 , 41 ]. Participants with unresectable tumors, PD-L1 CPS ≥ 5, non-HER2-positive GC, GEJ, or esophageal adenocarcinoma were classified into 3 groups and received nivolumab plus chemotherapy (oxaliplatin plus capecitabine or fluorouracil, leucovorin), nivolumab plus ipilimumab, or chemotherapy alone, respectively.…”

Section: Immune Checkpoint Inhibitors For Gastric Cancermentioning

confidence: 99%

Gastric cancer and genomics: review of literature

2022

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Gastric cancer (GC) is a major health concern in many countries. GC is a heterogeneous disease stratified by histopathological differences. However, these variations are not used to determine GC management. Next-generation sequencing (NGS) technologies have become widely used, and cancer genomic analysis has recently revealed the relationships between various malignant tumors and genomic information. In 2014, studies using whole-exome sequencing (WES) and whole-genome sequencing (WGS) for GC revealed the entire structure of GC genomics. Genomics with NGS has been used to identify new therapeutic targets for GC. Moreover, personalized medicine to provide specific therapy for targets based on multiplex gene panel testing of tumor tissues has become of clinical use. Recently, immune checkpoint inhibitors (ICIs) have been used for GC treatment; however, their response rates are limited. To predict the anti-tumor effects of ICIs for GC and to select patients suitable for ICI treatment, genomics also provides informative data not only of tumors but also of tumor microenvironments, such as tumor-infiltrating lymphocytes. In therapeutic strategies for unresectable or recurrent malignant tumors, the target is not only the primary lesion but also metastatic lesions, and metastatic lesions are often resistant to chemotherapy. Unlike colorectal carcinoma, there is a heterogeneous status of genetic variants between the primary and metastatic lesions in GC. Liquid biopsy analysis is also helpful for predicting the genomic status of both primary and metastatic lesions. Genomics has become an indispensable tool for GC treatment and is expected to be further developed in the future.

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Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Cited by 200 publications

References 32 publications

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

Atlas of PD-L1 for Pathologists: Indications, Scores, Diagnostic Platforms and Reporting Systems

Gastric cancer and genomics: review of literature

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