Elsevier

Lung Cancer

Volume 117, March 2018, Pages 27-31
Lung Cancer

Coexistence of sensitive and resistant epidermal growth factor receptor (EGFR) mutations in pretreatment non-small cell lung cancer (NSCLC) patients: First or third generation tyrosine kinase inhibitors (TKIs)?

https://doi.org/10.1016/j.lungcan.2018.01.006Get rights and content

Highlights

  • Knowledge about patients harboring primary sensitive and resistant mutations is poor.

  • The compound mutations account for 1% of the entire EGFR mutation spectrum.

  • First generation TKIs are ineffective even with the presence of sensitive mutations.

  • Osimertinib should be preferentially considered due to the great survival benefit.

Abstract

Objectives

Occasionally, primary 20 T790M/insertion plus sensitive mutations can be detected within a single tumor sample by routine molecular testing, but the optimal clinical management for these patients is unclear. Herein, we determined the optimal treatment strategy for these patients.

Materials and methods

From January 2011 to January 2017, patients diagnosed with epidermal growth factor receptor (EGFR) mutation were screened. For these harboring primary 20 T790M/insertion plus sensitive mutations, the effectiveness of the first or third generation tyrosine kinase inhibitors (TKIs) were retrospectively analyzed.

Results

16,842 individuals were screened during the study period with 5900 positive patients identified. Sixty-one patients were confirmed to have primary 20 T790M/insertion plus sensitive mutations (1% of all EGFR-mutant patients, 95% CI, 0.8%–1.3%). Among them, 31 eligible patients were included for survival analyses. The median progression–free survival (PFS) of the 15 osimertinib–treated patients was 18.0 months (95% CI, 15.1–20.9 months), which was greatly longer than the 16 patients who were treated with first generation TKIs (1.2 months, 95% CI, 0.9–1.6, P < 0.001). Similar results were also observed in overall survival (OS) with 25.1 months (95% CI, not calculable) in the osimertinib group and 17.3 months (95% CI, 9.3–25.4 months) in the first generation TKI group (P = 0.02).

Conclusions

For patients harboring primary resistant and sensitive mutations detected by routine clinical methods, first generation TKIs are ineffective even with the presence of sensitive mutations. However, osimertinib shows great survival benefit, and thus, should be considered during the whole clinical management.

Introduction

Lung cancer is increasing in frequency among malignant diseases both in China and worldwide [[1], [2]]. Molecular biological studies of non-small cell lung cancer (NSCLC) have contributed to the development of targeted anticancer agents, representing a major breakthrough in NSCLC management. Activating mutations in the epidermal growth factor receptor (EGFR) involve one of the most common genetic alterations in NSCLC. These mutations can be detected in 15% of Caucasians and 40%–50% of East Asians with advanced NSCLC [3]. It has been well established that active EGFR mutations confer sensitivity to first generation tyrosine kinase inhibitors (TKIs), which provide survival benefits compared with conventional chemotherapy [[4], [5], [6]]. Among the mutations, single classical mutations, including a deletion in exon 19 (Del-19) and a point mutation in exon 21 (21 L858R), are the most robust positive predictors of clinical response.

In addition to Del-19 and 21L858R, substitution of threonine with methionine in exon 20 (T790M mutation) and insertion in exon 20 have been identified and associated with drug resistance [7]. Previously, the presence of the T790M mutation was regarded as a second hit mutation due to TKIs exposure [8]. However, several studies suggested that the T790M mutation can be detected in TKI-naïve patients, and a de novo T790M mutation predicts a poorer objective response rate (ORR) and progression–free survival (PFS) when treated with gefitinib [[9], [10], [11]].

Sensitive and resistant mutations can also be concomitantly detected within a single tumor sample by routine clinical molecular testing in TKIs-naïve patients. These clinical findings may cause a dilemma for the treating physicians concerning whether and which TKIs should be recommended. In this study, we summarized the clinical data of TKI–naïve advanced NSCLC patients harboring compound mutations with drug–resistant patterns detected by routine molecular methods (e.g., 20T790M+19del/21L858R mutations) and analyzed the therapeutic efficacy of first and third generation TKIs.

Section snippets

Patients

Between January 2011 and January 2017, consecutive advanced stage NSCLC patients with concurrent sensitive (Del-19, 21L858R and other atypical mutations) and drug–resistant mutations (20T790M or 20 insertion) were identified from molecular pathology reports based on our registration system. The inclusion criteria were as follows: a) NSCLC confirmed pathologically or cytologically, b) positron emission tomography/computed tomography (PET/CT) or other radiological evaluation was performed to

Frequency and characteristics of patients harboring complex mutations with de novo drug-resistant patterns

During the study period, a total of 16,842 patients were screened with 5900 positive individuals. Mutation types were as follows: 2633 in the exon 19 deletion, 2637 in the 21 L858R point mutation, 311 with single atypical mutations in exons 18–21, and 147 with complex mutations but without drug–resistant patterns (e.g., 18G719X+20S768I or 20S768I+21L861Q). Among the remaining 172 cases, 111 individuals were excluded because T790M mutation was a result of TKI exposures. Finally, the coexistence

Discussion

Our study showed that baseline coexistence of resistant and sensitive mutations were rare, accounting for 1.0% of the entire EGFR mutation spectrum when analyzed by routine clinical detection methods. First generation TKIs, including gefitinib, erlotinib, and icotinib, are ineffective even with the presence of sensitive mutations, while osimertinib carries survival benefits for those patients, and thus should be considered during the whole clinical management period.

The T790M mutation was

Conflict of interest statement

None.

Disclosure of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

We would like to acknowledge all the patients and their families for their contributions to this study. No writing assistance was received.

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    Bo Zhang and Jianlin Xu contributed equally to this work.

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