Raising the bar: the future of EGFR inhibition in non-small lung cancer.
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ABSTRACT:
SUBMITTER: Redig AJ
PROVIDER: S-EPMC5750143 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The targeting of oncogenic 'driver' kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy. In this study, we sought to determine mechanisms of acquired resistance to ROS1 inhibition. To accomplish this, we analyzed tumor samples from a patient who initially responded to the ROS1 inhibitor crizotinib but eventually developed acquired resistance. In addition, we generated a ROS1 inhibition-resistant derivative of the initially sensitive NSCLC cell line HCC78. Previously described mechanisms of acquired resistance to tyrosine kinase inhibitors including target kinase-domain mutation, target copy number gain, epithelial-mesenchymal transition, and conversion to small cell lung cancer histology were found to not underlie resistance in the patient sample or resistant cell line. However, we did observe a switch in the control of growth and survival signaling pathways from ROS1 to EGFR in the resistant cell line. As a result of this switch, ROS1 inhibition-resistant HCC78 cells became sensitive to EGFR inhibition, an effect that was enhanced by co-treatment with a ROS1 inhibitor. Our results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive NSCLC patients.
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Project description:BackgroundAdjuvant platinum-based chemotherapy is standard of care for patients with resected stage IIA/B or IIIA NSCLC. Overall survival is suboptimal due to the high metastatic potential of early-stage NSCLC and there is substantial clinical need for additional efficacious adjuvant treatment options.MethodsPubMed (all time to 4 February 2021) and related conference databases were searched using the key search terms 'NSCLC' AND 'Adjuvant' AND 'EGFR inhibitor' OR respective aliases.ResultsThe literature search identified five adjuvant phase III trials of EGFR inhibitors in early NSCLC. The earlier BR19 and RADIANT trials failed to demonstrate statistically significant improvements in either OS or DFS for gefitinib and erlotinib, respectively, compared with placebo in patients with EGFR mutation-unselected NSCLC. Three subsequent phase III trials, ADAURA, CTONG1104, and IMPACT, were conducted in EGFR-mutant NSCLC. IMPACT showed no statistically significant DFS benefit for adjuvant gefitinib, and although CTONG1104 did report improved DFS for gefitinib (HR = 0.56, p = 0.001), this benefit was not enduring, resulting in comparable 5-year DFS rates. Statistically significant and clinically meaningful DFS benefits were observed in ADAURA for osimertinib compared with placebo in patients with stage IB-IIIA and II-IIIA disease (7th Edition Staging), and these benefits, coupled with a meaningful improvement in 2-year CNS DFS and favorable HRQoL, make osimertinib an important new treatment option for the adjuvant treatment of EGFR exon 19 deletion or exon 21 L858R-mutated stage II-IIIA NSCLC (UICC/AJCC 8th Edition Staging), with final mature OS data eagerly awaited.ConclusionAdjuvant osimertinib used alone or following platinum-based chemotherapy is now recommended in patients with stage II-IIIA EGFR-mutated NSCLC.
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