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Until recently, there were no standard therapeutic options in the setting of acquired resistance to initial EGFR TKIs and, outside clinical trials with investigational drugs, EGFR-mutated NSCLC patients generally received platinum-based or single-agent chemotherapy upon progression. Osimertinib has led to a paradigm shift in the management of lung cancer patients progressing to first- or second-generation TKIs, thus supporting the need in clinical practice for tumor genotyping at the time of disease progression on or after EGFR TKI therapy for biomarker evaluation of EGFR T790M. Osimertinib has also demonstrated activity in patients with CNS and leptomeningeal metastasis, which is particularly relevant, given the possibility to potentially spare these patients from radiotherapy or delay its use, including WBRT, that can ultimately compromise the cognitive function and QoL. Other novel, mutant-selective EGFR TKIs produced by different pharmaceutical companies, including EGF816, naquotinib (ASP8273), avitinib (AC0010) and PF-06747775, are in clinical development (Table 2) and have shown promising activity with manageable safety profile in early phase studies.133–139 More data from ongoing studies are eagerly awaited to confirm these preliminary results. Despite the evolving therapeutic landscape for EGFR-mutated NSCLC patients, there are still several issues to be addressed, such as the optimal therapeutic sequence of different generation EGFR TKIs. Osimertinib is being tested in the first-line setting, compared with standard EGFR TKI therapy, to see whether upfront use of an irreversible inhibitor could be a more effective strategy to improve clinical outcome and delay the resistance. Another possible strategy to prevent or delay the occurrence of resistance could be the upfront combination of EGFR inhibitors with other targeted agents. Indeed, the combination of erlotinib and bevacizumab results in a long PFS in EGFR-mutated NSCLC patients and, in the BELIEF trial, this combination was effective in presence of the T790M mutation, identified in 35% of patients, who attained a PFS of 16 months.16 The assessment of T790M mutation in ctDNA by using highly sensitive blood-based assays has already proven to be feasible in clinical practice and useful to identify those patients who are candidates for osimertinib. Moreover, a combined analysis of EGFR genotyping in matched blood and urine by a highly sensitive and quantitative assay using next-generation sequencing, as performed in the TIGER-X study of rociletinib, could further improve the chance of T790M mutation detection.140 Despite the high efficacy of osimertinib in T790M-mutant NSCLC, similar to other oncogene-addicted tumors, patients may ultimately progress due to acquisition of additional mechanism of resistance by tumor cells under the selective pressure of the EGFR TKI, including the C797S mutation. A novel EGFR inhibitor, EAI045, has shown to be able to overcome T790M and C797S resistance in in vitro and in vivo studies, although its clinical efficacy still needs to be investigated. Profiling of tumors at progression remains crucial in order to unravel the complex and heterogeneous resistance mechanisms to first-, second- and third-generation EGFR TKIs. The detection of new mechanisms of resistance to third-generation EGFR TKIs is feasible through ctDNA genotyping and suggests the need for new therapeutic approaches for these patients. Liquid biopsy, including not only ctDNA but also other tumor sources such as CTCs and exosomes, appears to be the most appealing strategy to study the dynamic evolution of oncogene-addicted tumor cells during treatment with different EGFR TKIs, thereby giving an early warning about possible recurrence and helping to establish novel, potentially targetable molecular alterations.

(To view a larger version of Table 2, click here.)


The authors report no conflicts of interest in this work.

Mariacarmela Santarpia,1 Alessia Liguori,1 Niki Karachaliou,2 Maria Gonzalez-Cao,3 Maria Grazia Daffinà,1 Alessandro D’Aveni,1 Grazia Marabello,1 Giuseppe Altavilla,1 Rafael Rosell3–5

1Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, Messina, Italy; 2Institute of Oncology Rosell (IOR), University Hospital Sagrat Cor,  3Department of Oncology, Institute of Oncology Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, 4Cancer Biology and Precision Medicine Program, Germans Trias i Pujol Research Institute, 5Catalan Institute of Oncology, Germans Trias i Pujol University Hospital, Badalona, Spain 


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<pSource: Lung Cancer: Targets and Therapy
Originally published August 18, 2017.</p