What do we mean by the group of drugs teemed as "Check point Inhibitors" for which Nobel prize was conferred to the Scientists who discover I such kind of drugs ?? What ate is those drugs??Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011. Currently approved checkpoint inhibitors target the molecules CTLA4, PD-1, and PD-L1.heckpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets.
Checkpoint Inhibitors in Metastatic EGFR-Mutated Non–Small Cell Lung Cancer—A Meta-Analysis
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Journal of Thoracic Oncology, Volume 12, Issue 2, February 2017, Pages 171-172
Download PDFKeywords
NSCLC
EGFR mutation
Immune checkpoint inhibitors
Predictive biomarker
Introduction
Small molecule EGFR tyrosine kinase inhibitors (TKIs) are a highly effective treatment for advanced NSCLC with activating mutations of the EGFR gene. Despite an initial response, most of these patients experience disease progression approximately 10 to 13 months after first-line TKI therapy. Selection of optimal salvage therapy for some of these patients remains an ongoing challenge.
Several mechanisms of acquired resistance to TKI therapy have been reported: new EGFR T790M mutation,1, 2 transformation to a small cell histological type,1 and activation of alternative antiapoptosis signaling pathways.1, 2, 3, 4 Third-generation TKIs are potent oral irreversible inhibitors of sensitizing EGFR mutations and the T790M resistance mutation. Third-generation TKIs can be effective salvage therapy for patients in whom T790M mutation develops and whose disease progresses during treatment with earlier-generation TKIs.5
Novel immunotherapy agents, nivolumab6 and pembrolizumab,7 which are programmed death 1 (PD-1) immune checkpoint inhibitors, are potential alternative salvage treatments. Both prolong overall survival (OS) compared with docetaxel and have been approved by the U.S. Food and Drug Administration as a new standard of care for second-line treatment of advanced NSCLC.
Evidence to support the role of immune checkpoint inhibitors in EGFR-mutated lung cancers is conflicting. Murine models have demonstrated significant response to the treatment with anti–PD-1 antibody in EGFR-mutant but not KRAS-driven lung tumors8; however, in a retrospective analysis of 58 patients with advanced NSCLC treated with PD-1/programmed death ligand 1 (PD-L1) inhibitors, only 4% of patients harboring EGFR mutations or anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements were tumor responders and 23% of patients with EGFR wild-type and ALK-negative or unknown tumors were responders.9 We performed this meta-analysis to better assess the role of immune checkpoint inhibitors in EGFR-mutated advanced NSCLC.
Methods
Eligible randomized trials that compared immune checkpoint inhibitors against chemotherapy in the second-line setting were identified from MEDLINE, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials databases for articles published in English between January 1996 and July 2016 by using the following terms: advanced/metastatic lung neoplasm/cancer/carcinoma, checkpoint inhibitor, cytotoxic T-lymphocyte associated protein 4, PD-1, PD-L1, ipilimumab, nivolumab, pembrolizumab, and randomized/controlled clinical trial. To identify unpublished studies, we also searched abstracts from proceedings of the American Society of Clinical Oncology and European Society for Medical Oncology conferences and proceedings of the World Lung Cancer Conference.
For each included trial, we extracted study and patient characteristics and retrieved the hazard ratio (HR) and 95% confidence interval (CI) for OS of the intention-to-treat population and subgroups defined by EGFR mutation status. Data were extracted independently by two authors (C. L. and J. M.), with discrepancies resolved by consensus.
We used the fixed-effects inverse variance–weighted method to pool results to estimate the size of the benefit of treatment. A test for treatment-mutation interaction was used to assess differences in treatment effect across EGFR-defined subgroups. All statistical tests were two sided.
We identified three ). In total, 1903 patients were randomized to receive an immune checkpoint inhibitor (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n = 144]) or docetaxel (n = 776). EGFR mutation status was known for 1548 patients (81%). Treatment with an immune checkpoint inhibitor, compared with docetaxel, was associated with a 32% reduction in the risk for death in the intention-to-treat population (HR = 0.68, 95% CI: 0.61–0.77, p < 0.0001; heterogeneity p = 0.67). In the EGFR wild-type subgroup (n = 1362), the pooled HR was 0.66 (95% CI: 0.58–0.76, p < 0.0001; heterogeneity p = 0.96). In the EGFR-mutant subgroup (n = 186), the pooled HR was 1.05 (95% CI: 0.70–1.55, p < 0.81; heterogeneity p = 0.80). There was a statistically significant treatment-mutation interaction (p = 0.03) (Fig. 2). Among the EGFR-mutant subgroup, there was no significant statistical heterogeneity in treatment effect: χ2 = 0.46 (p = 0.42) and I2 = 0%.
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