Abstract

BackgroundOsimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients.MethodsThe medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy.ResultsFrom April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥12 mm, or metastases at minor sites.ConclusionAmong patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

Highlights

  • Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the EGFR p.Thr790Met point mutation (T790M) substitution

  • Key message Three alternatives are currently available for the use of first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat EGFR-mutated lung cancer, such as single agents or combinatorial treatment with an anti-Vascular endothelial growth factor (VEGF) antibody or chemotherapy

  • After the failure of initial EGFR-TKI treatment, repeated biopsy is expected to maximize the detection of T790M substitutions, prompting osimertinib therapy

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Summary

Introduction

Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Most patients eventually become resistant to EGFR-TKIs, the EGFR p.Thr790Met point mutation (EGFR T790M) is detected in 30–50% of patients presenting with disease progression after receiving first- or second-generation TKIs [2, 3] These patients can be treated with osimertinib, whereas other patients might be treated with cytotoxic chemotherapy. First-generation EGFR-TKIs have been used in combination with an anti-VEGF antibody or chemotherapy [6,7,8] These clinical trials reported almost the same high efficacy as that of osimertinib, despite slightly increased toxicities. We will be able to identify appropriate patients who require repeated tissue or liquid rebiopsy

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