Toxicity with small molecule and immunotherapy combinations in non-small cell lung cancer
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REVIEW
Toxicity with small molecule and immunotherapy combinations in non‑small cell lung cancer H. Adderley1 · F. H. Blackhall1,2,3 · C. R. Lindsay1,2,3 Received: 6 May 2020 / Accepted: 31 August 2020 © The Author(s) 2020
Abstract Treatment stratification in stage IV NSCLC is guided by identification of oncogene driver mutations. Actionable mutations with current licenced therapeutic agents include epidermal growth factor receptor (EGFR), rearrangements of anaplastic lymphoma kinase (ALK), ROS-1 and BRAF V600. Alongside progress with small molecule therapy, developments in immune checkpoint inhibitors (CPIs) have transformed the landscape of stage III and stage IV NSCLC. The success of CPIs has led to evaluation with small molecule therapy in both concurrent and sequential settings. In this review we summarise recent results of combination CPIs and tyrosine kinase inhibitors (TKIs) in stage IV NSCLC, detailing significant toxicity and its potential mechanisms with both concurrent and sequential approaches. As more therapeutic targets are being discovered it is becoming increasingly important for clinicians to correctly sequence therapy for delivery of safe and effective treatment. In addition to stage IV disease we suggest that comprehensive molecular profiling of key NSCLC drivers, particularly in stage III disease, will help to inform optimal treatment sequencing and minimise potential toxicity.
Introduction Molecular aberrations or oncogene driver mutations in non-small cell lung cancer (NSCLC) are frequently used to stratify treatment for patients with stage IV disease. Actionable mutations in the epidermal growth factor receptor (EGFR), rearrangements of anaplastic lymphoma kinase (ALK) ROS-1 and BRAF V600 represent targets with current licenced therapeutic agents that can improve progression-free survival (PFS) and overall survival (OS) [1, 2]. These include EMA- and FDA-approved erlotinib, gefitinib, afatinib and osimertinib for EGFR-mutant cancers. Alectinib, crizotinib, ceritinib, brigatinib and lorlatinib for ALKrearranged cancers, as well as dabrafenib and trametinib for BRAF V600 mutant disease [3–15]. Other oncogene driver mutations or alterations are the subject of ongoing evaluation in clinical trials, with further standard of care breakthroughs * C. R. Lindsay [email protected] 1
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
2
Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK
3
Cancer Research UK Lung Cancer Centre of Excellence, London and Manchester, Manchester, UK
expected for small molecules targeting NTRK, RET, HER2/ MET and KRAS G12C subsets in particular. Indeed, the FDA have recently approved selpercatinib for RET and entrectinib for NTRK mutations [16, 17]. In parallel to this progress, recent developments in immune checkpoint inhibitors (CPIs) have transformed the landscape of stage III and IV NSCLC, conferring significant improvements in PFS and OS in the first and second line settings
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