Real‐world efficacy and potential mechanism of resistance of icotinib in Asian advanced non‐small cell lung cancer with EGFR uncommon mutations: A multi‐center study

Abstract

The response to icotinib in advanced non‐small cell lung cancers (NSCLC) with EGFR uncommon mutation (EGFRum) is unclear. Here we reported the efficacy and potential resistance mechanism of icotinib in Chinese EGFRum NSCLC patients. Between July 2013 and November 2016, 3117 NSCLC patients were screened for EGFRum in a multi‐center study in China. Circulating tumor DNA (ctDNA) was detected and analyzed using next‐generation sequencing (NGS) after progression from icotinib. The efficacy, safety and the potential resistance mechanism of icotinib were explored. After a median follow‐up of 6.2 months, 69 patients (70.41%) developed disease progression, the objective rate (ORR) and disease control rate (DCR) were 13.27% and 29.59% respectively, and the median progression‐free survival (PFS) was 5.5 months (95% CI: 1.2‐13.0 months). Both complex‐pattern with EGFR classical mutations (EGFRcm) and single‐pattern have better PFS than complex‐pattern without EGFRcm (median PFS was 7.2 (95% CI: 4.65‐9.75), 5.2 (95% CI: 3.24‐7.16) and 3.2 (95% CI: 2.97‐3.44) months, respectively, P < .05); patients harboring S768I mutation had the worst PFS than others (2.0 months, P < .05). Diarrhea was the most frequent side effect (42.9%). Forty‐eight (69.6%) patients developed drug resistance after 3.0 months and 81.2% of them acquired T790M mutation. Better response was observed in complex‐pattern with the EGFRcm group. S768I mutation carriers may not benefit from icotinib. Acquired T790M mutation was common in icotinib‐resistant EGFRum NSCLC patients.

Afatinib treatment response in advanced lung adenocarcinomas harboring uncommon mutations

“…Other several resistance mechanisms to icotinib in NSCLC harboring uncommon mutations include EGFR extracellular domain mutation, BCL2L11 loss, MET amplification, ERBB2 amplification, MYC amplification, PTEN mutation, and PIK3CA mutation. 18,37 In this study, apart from one patient with L858R mutation, one patient with L833V/H835L was detected with a secondary T790M mutation. This secondary drug resistance mechanism is consistent with a previous case report.…”

“…~93% are present in the first four exons (18)(19)(20)(21) of the gene encoding tyrosine kinase domain, including exon 18 Gly719Xaa (G719X) (~3%), exon 21 Leu861Gln (L861Q) (~1%), and exon 20 Ser768Ile (S768I) mutations (~1%), as well as other insertions in exon 19 or 20 (ins19; 0.6%, and ins20; ~6%). 10 Although at low frequency, approximately tens of thousands of new cases worldwide are reported each year because of the large population base of NSCLC.…”

“…16,17 Furthermore, the outcomes and resistance mechanisms of specific rare uncommon mutations have not yet been reported. 18 Therefore, there is a large unmet need for further detailed empirical evidence to focus on afatinib activity in uncommon mutations, especially for the "rare" group. 19 Therefore, this study was designed to evaluate the responses to afatinib treatment of patients with G719X, L861Q, S768I, and other rare uncommon mutations, as well as and determine the clinical demographics and underlying mechanisms of resistance.…”

The Predictive Values of Advanced Non-Small Cell Lung Cancer Patients Harboring Uncommon EGFR Mutations—The Mutation Patterns, Use of Different Generations of EGFR-TKIs, and Concurrent Genetic Alterations

“…Researchers analyzed the clinical data from the NEJ002 study involving 10 participants harboring uncommon mutations, and the results showed that gefitinib was ineffective against G719X or L861Q mutation (13). In contrast, several retrospective studies observed moderate efficacy of firstgeneration EGFR-TKIs against uncommon mutations, with ORR ranging from 13.27% to 48.40%, and mPFS ranging from 5.0 to 7.7 months (8,14,15). Meanwhile, increasing evidence has suggested improved efficacy of second-generation EGFR-TKIs on patients with uncommon mutations.…”

Research and application of single-cell sequencing in tumor heterogeneity and drug resistance of circulating tumor cells

“…Therefore, increasing studies are conducted on tumor resistance through CTC. Scholars study choriocarcinoma [ 22 ], colorectal cancer [ 23 – 26 ], liver cancer [ 27 ], lung cancer [ 28 , 29 ], breast cancer [ 30 , 31 ], lymphoma [ 32 ], gastric cancer [ 33 ] and other malignant tumors through CTC to explore the drug resistance of tumor cells. However, most current CTC analyses are based on CTC epithelial biomarkers, and epithelial biomarkers may not be expressed in several tumor types [ 34 ].…”