EGFR C797S as a Resistance Mechanism of Lazertinib in Non-small Cell Lung Cancer with EGFR T790M Mutation

Article information

Cancer Res Treat. 2020;52(4):1288-1290

Publication date (electronic) : 2020 June 22

doi : https://doi.org/10.4143/crt.2020.278

Sehhoon Park, MD ¹, Bo Mi Ku, PhD ², Hyun Ae Jung, MD, PhD ¹, Jong-Mu Sun, MD, PhD ¹, Jin Seok Ahn, MD, PhD ¹, Se-Hoon Lee, MD, PhD ¹, Keunchil Park, MD, PhD ¹, Myung-Ju Ahn, MD, PhD ¹

¹Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence: Myung-Ju Ahn, MD, PhD Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: 82-2-3410-3438 Fax: 82-2-3410-1754 Email: silkahn@skku.edu

Received 2020 April 5; Accepted 2020 June 19.

Abstract

The non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutation eventually acquires resistant to either first or second-generation EGFR tyrosine kinase inhibitor (TKI). As the following option, targeting EGFR T790M with third-generation EGFR TKI is now established as a standard treatment option. In this study, we are reporting the first case of resistance mechanism to the novel third-generation EGFR TKI, lazertinib, which showed promising clinical efficacy in phase 1-2 study. The patients showed resistance to the treatment by acquiring the additional EGFR C797S mutation in cis which is also confirmed from the patient-derived cell lines.

Keywords: Non-small cell lung cancer; Lazertinib; Third-generation EGFR tyrosine kinase inhibitor; ErbB receptors

Introduction

Non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation treated with either a first- or second-generation tyrosine kinase inhibitor (TKI) can experience treatment failure, most commonly by acquiring an additional genomic alteration in EGFR T790M [1]. Lazertinib (YH25448) is a potent irreversible third-generation EGFR TKI that targets both T790M and activating EGFR mutation with high penetration to the blood-brain barrier. Lazertinib showed promising anti-tumor efficacy with a 57% overall response rate and 9.7-month median progression-free survival in EGFR T790M-positive patients [2]. However, there is no previous report showing the mechanism of tumor resistance acquisition to lazertinib. In this case report, we conducted deep-targeted sequencing of resistant tumor samples and established patient-derived cell lines (PDC) from a patient treated with lazertinib to elucidate the underlying genomic alteration associated with resistance.

Case Report

A 38-year-old current male smoker presented with stage 4, cT1bN3M1b, NSCLC adenocarcinoma. Informed consent was received under supervision of institutional review board (SMC 2011-10-054-034). The patient was shown to harbor an EGFR exon 19 deletion using real-time polymerase chain reaction from the initial biopsy sample obtained from the mediastinal lymph node. Afatinib was administered as a first-line treatment and showed very good partial response with 7.1 months of progression-free survival. After first-line EGFR TKI failure, a second biopsy from the newly progressed metastatic lymph node showed acquired EGFR T790M mutation. As a subsequent treatment, the patient received lazertinib as a part of a clinical trial (NCT03046992, YH25448-201). However, after 6.2 months of partial response to lazertinib, the patient developed malignant ascites, suggesting peritoneal seeding due to resistance.

Deep-targeted sequencing (CancerSCAN [3]) of ascites samples demonstrated acquired EGFR C797S mutation in cis, variant allele frequency (VAF) of 9.4%, EGFR T790M (VAF of 3.5%), and EGFR exon 19 deletion (VAF 9.2%) (Fig. 1A). PDCs established from the same ascites sample showed EGFR exon 19 deletion (Fig. 1B). Cell viability of PDCs showed resistance to first- and third-generation EGFR TKIs including erlotinib, gefitinib, lazertinib, and osimertinib or the c-Met inhibitor savolitinib (Fig. 1C).

Fig. 1.

(A) Target sequencing in samples from lazertinib-resistant malignant ascites. Integrative genomic viewer of sample showing additional epidermal growth factor receptor (EGFR) C797S cis mutation. (B) Western blot of patient-derived cell line (PDC) samples. (C) Cell viability analyses conducted in samples after exposure to tyrosine kinase inhibitor for 72 hours. SNV, single nucleotide variant; INDEL, insertion/deletion; EpCAM, epithelial cell adhesion molecule.

Discussion

Diverse resistance mechanisms to third-generation EGFR TKI have been reported including loss of T790M, acquisition of EGFR C797S mutation, c-Met amplification, activation of other bypass tract, or small cell lung cancer transformation. Among them, EGFR C797S/T790M mutation is the most frequently observed, accounting for 20%-30% of cases. It is of note that tumors acquiring an additional mutation of EGFR C797X maintain the original EGFR T790M mutation [4]. In this report, we present the first clinical case of new EGFR C797S/T790M mutation in a patient who failed lazertinib. Further validation with a large number of patients and new treatment strategies to overcome this resistance mutation are warranted.

Notes

Conflict of interest relevant to this article was not reported.

References

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2. Ahn MJ, Han JY, Lee KH, Kim SW, Kim DW, Lee YG, et al. Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1-2 study. Lancet Oncol 2019;20:1681–90.

3. Shin HT, Choi YL, Yun JW, Kim NK, Kim SY, Jeon HJ, et al. Prevalence and detection of low-allele-fraction variants in clinical cancer samples. Nat Commun 2017;8:1377.

4. Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol 2018;4:1527–34.

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