Durable Clinical Response of Lung Adenocarcinoma Harboring EGFR 19Del/T790M/in trans-C797S to Combination Therapy of First- and Third-Generation EGFR Tyrosine Kinase Inhibitors

A 42-year-old woman was diagnosed with stage IV lung adenocarcinoma with metastases to brain and bone. Because of the detection of exon 19 deletion (19Del) of EGFR, she was started on erlotinib, chemotherapy, and osimertinib as the first-, second-, and third-line of treatment (Fig. 1). After progression on osimertinib, capture-based targeted sequencing on both formalin-fixed paraffin-embedded sample and plasma cell-free DNA revealed the harboring of EGFR 19Del and C797S, which was located in trans with T790M. The patient was firstly commenced on combination treatment of gefitinib (250 mg once a day) and osimertinib (80 mg once a day), and then switched to combination of erlotinib (150 mg once a day) and osimertinib (80 mg once a day) 2 months later due to the intolerance of gefitinib. In addition, bevacizumab (7.5 mg/kg every 3 weeks) was also administered to the patient during the combination treatment. Her clinical symptoms such as cough and dyspnea were remarkably relieved and radiograph revealed partial response in her lung lesion, accompanied with thinned alveoli septum and reduced pleural effusion (Fig. 2). Repeated liquid biopsy only detected 19Del 4 months after initiation of the combinatorial treatment. However, she returned to the clinic because of chest pain and dyspnea, and a computed tomography scan showed enlarged lung lesion and increased pulmonary nodules and pleural effusion, with progression-free survival (PFS) lasting 8 months (Fig. 2). Repeated liquid biopsies of both pleural fluid and plasma revealed the reappearance of EGFR C797S and T790M, along with pre-existed 19Del. C797S was located in cis with T790M this time (Fig. 3).Figure 2Computed tomography (CT) scans revealed the clinical response to combination therapy of first- and third-generation EGFR tyrosine kinase inhibitors (TKIs). The patient achieved partial response (PR) 2 months after the initiation of the combination treatment. Her PR was confirmed 2 months later. Finally, she progressed on combination therapy with progression-free survival of 8 months. PD, progressive disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Integrative genomics viewer (IGV) screenshots displaying the chimeric reads from targeted sequencing and revealing the allelic configurations of EGFR T790M/C797S before (A) and after (B) combination treatment of first-and third-generation EGFR tyrosine kinase inhibitors. (A) IGV showing the 2369C>T at codon 790 (EGFR T790M) mutation (red) located in trans with 2389T>A at codon 797 (EGFR C797S) mutation (green). (B) IGV highlighting the presence of a 2369C>T at codon 790 (EGFR T790M) mutation (red) oriented in cis with a 2389T>A at codon 797 (EGFR C797S) mutation (green) and 2390G>C at codon 797 (EGFR C797S) mutation (blue).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Recently, two groups presented the first two clinical evidences that lung adenocarcinomas harboring EGFR 19Del/T790M/in trans-C797S were sensitive to combination therapy of first- and third-generation EGFR tyrosine kinase inhibitors (TKIs). However, the two cases progressed rapidly 1 and 3 months after the combination therapy, respectively.1Wang Z. Yang J.J. Huang J. et al.Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR TKIs and shifts allelic configuration at resistance.J Thorac Oncol. 2017; 12: 1723-1727Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 2Arulananda S. Do H. Musafer A. et al.Combination osimertinib and gefitinib in C797S and T790M EGFR-mutated non–small cell lung cancer.J Thorac Oncol. 2017; 12: 1728-1732Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Here, we report a patient with lung adenocarcinoma with 19Del/T790M/in trans-C797S whose disease was durably well controlled under combination of first- and third-generation EGFR TKIs, with PFS lasting 8 months before the appearance of in cis C797S/T790M. This case foreshadows the future of durable and effective clinical management for this subset of patients through combination therapy of first- and third-generation EGFR TKIs. EGFR C797S was thought to mediate resistance by abolishing the covalent binding of osimertinib to EGFR, and the allelic relationship of C797S with respect to T790M was considered to have therapeutic implications both in in vitro and clinical practices. C797S most commonly located in cis with T790M (98%), which resistant to combination of first- and third-generation EGFR TKIs, whereas the in trans configuration of C797S and T790M occurred rarely (2%) but may respond to the combination therapy. Thus, understanding the resistance mechanisms is essential for designing treatment strategies and achieving more effective outcomes. Bevacizumab changes tumor vessel physiology and results in increased intratumoral uptake of drugs, indicating that the combination of EGFR-TKIs and bevacizumab has the potential to prolong PFS in this case. In addition, pre-clinical data showed the combination of brigatinib with anti-EGFR antibody could overcome in cis C797S/T790M.3Uchibori K. Inase N. Araki M. et al.Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non–small-cell lung cancer.Nat Commun. 2017; 8: 14768Crossref PubMed Scopus (250) Google Scholar Two clinical evidences from Zhao et al.4Zhao J. Zou M. Lv J. et al.Effective treatment of pulmonary adenocarcinoma harboring triple EGFR mutations of L858R, T790M, and cis-C797S by osimertinib, bevacizumab, and brigatinib combination therapy: a case report.Onco Targets Ther. 2018; 11: 5545-5550Crossref PubMed Scopus (28) Google Scholar and Wang et al.5Wang X. Zhou L. Yin J.C. et al.Lung adenocarcinoma harboring EGFR-19del/C797S/T790M triple mutations responds to brigatinib and anti-EGFR antibody combination therapy.J Thorac Oncol. 2019; 14: e85-e88Abstract Full Text Full Text PDF Scopus (26) Google Scholar further support the value of brigatinib in conquering in cis C797S/T790M. Therefore, combination therapies containing brigatinib sheds some light on potential treatment options for this subset of patients in future. The authors thank the patient and her family. This work was supported by the National Key R&D Program of China (2016YFC1303800). Letter to the Editor About the Adverse Effect of Combined Tyrosine Kinase InhibitorsJournal of Thoracic OncologyVol. 15Issue 11PreviewWe have read with great interest the recently published article by Zhou et al.,1 in which the authors illustrated the durable clinical response of lung adenocarcinoma harboring EGFR 19Del/T790M/in trans-C797S mutation to a combination therapy of first- and third-generation EGFR tyrosine kinase inhibitors (TKIs). It had been previously suggested that combined targeted therapy, on the basis of genetic testing, was effective in some specific cases, of which EGFR 19Del/T790M/in trans-C797S was frequently reported. Full-Text PDF Open Archive