Icotinib, an Effective Treatment Option for Patients With Lung Adenocarcinoma Harboring Compound EGFR L858R and A871G Mutation

doi:10.21203/rs.3.rs-331165/v1

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Icotinib, an Effective Treatment Option for Patients With Lung Adenocarcinoma Harboring Compound EGFR L858R and A871G Mutation

https://doi.org/10.21203/rs.3.rs-331165/v1

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Journal Publication

published 09 Apr, 2021

Read the published version in Investigational New Drugs →

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Compound epidermal growth factor receptor (EGFR) mutations are defined as double or multiple independent mutations of the EGFR tyrosine kinase domain (TKD), in which an EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutation is identified together with a mutation of unclarified clinical significance. Lung adenocarcinoma with compound EGFR mutation shows poor clinical response to EGFR-TKIs. Kobayashi et al. reported a non-small-cell lung cancer (NSCLC) patient whose tumor had EGFR exon21 L858R/A871G mutation presented rapid disease progression to erlotinib. However, in this case, we present an EGFR exon21 L858R/A871G mutation patient exerted significant benefit to icotinib, another first-generation EGFR-TKI, indicating that different EGFR-TKIs have diversiform sensitive sites and therapeutic effects, consistent mutation sites might achieve heterogeneous benefits from different EGFR-TKIs. Our case report provides promising EGFR-TKI for clinical treatment with EGFR exon21 L858R/A871G mutation in NSCLC. More dedicated efforts are needed to clarify their biologic effects on disease course and drug responsiveness.

Drug Discovery, Design, & Development

Icotinib

Lung adenocarcinoma

Compound EGFR L858R and A871G mutation

Partial response

A 59-year-old female was admitted to hospital for intermittent cough in March 2020. Chest computed tomography revealed space-occupying lesion in the right lung. CT-guided percutaneous lung biopsy was conducted. The hematoxylin and eosin staining and immunohistochemical staining results (TTF-1(+), Napsin-A (+), CK7 (+), CK5/6 (-), P40 (-) and Ki67 (15%)) revealed a typical morphology for adenocarcinoma cells. Afterwards, the biopsy specimen was subjected to next-generation sequencing analysis (CAP certificated laboratory), EGFR exon21 L858R/ A871G mutation was detected (Fig 1), and no other key driver gene mutation was identified. Subsequently, icotinib (125mg, tid) was immediately administered from Apirl 9^th 2020. Clinical and radiological follow-up after 3 months showed no evidence of progression and recurrent and the disease showed partial response (Fig 2 A-B’). On July 6^th 2020, radical resection of the right lower lung was performed, postoperative pathologic results revealed invasive lung adenocarcinoma.

Recent advances in tumor genotyping techniques provide not only accurate data, but also a higher probability of identifying atypical and multiple mutations in the EGFR-TKD in a single sample. Two major activating mutations in EGFR are an in-frame deletion in exon 19 and the L858R substitution in exon 21.[3] The vast majority of EGFR mutations are incisively sensitive to EGFR-TKIs, but other rare mutations including L747S, D761Y, T790M, and T854A confer resistance to EGFR-TKIs.[4]

Previous studies have shown that there are differences in the responses to the EGFR-TKIs among compound EGFR mutations. Compound mutations that contain sensitizing mutations such as G719X or L858R seem to have good responses to EGFR-TKIs.[5] However, those comprised of rare atypical mutations have poor response to EGFR-TKIs. In previous reports, a patient whose tumor had EGFR exon21 L858R/A871G mutation presented rapid disease progression to erlotinib, indicating that this compound mutation may confer primary resistance to first-generation EGFR-TKIs. However, in this case, we present an EGFR exon21 L858R/A871G mutation patient exerted significant benefit to icotinib, another first-generation EGFR-TKI, indicating that different EGFR-TKIs have diversiform sensitive sites and therapeutic effects, consistent mutation sites might achieve heterogeneous benefits from different EGFR-TKIs.

With the clinical application of more sensitive and precise tumor genotyping systems, rare EGFR mutations of unknown biological and clinical significance are frequently encountered in routine clinical practice. Our case report provides promising EGFR-TKI for clinical treatment with EGFR exon21 L858R/A871G mutation in NSCLC. More dedicated efforts are needed to clarify their biologic effects on disease course and drug responsiveness.

Author declarations section:

Ethics approval and consent to participate: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the patient for participating this case.

Consent to publication: Informed consent was obtained from the patient for publication of this case.

Availability of data and material: Not applicable.

Competing interests: The authors declare that they have no conflict of interest.

Funding: This work was supported by National Natural Science Foundation of China under Grant No.81800090.

Authors' contributions:

Conception/Design: Lin-ling Jin, Zhen-zhen Wu

Provision of study material or patients: Yan-li Wang, Dong-sheng Chen

Collection of data: Si Li, Mingzhe Xiao

Data analysis and interpretation: Lin-ling Jin, Zhen-zhen Wu

Manuscript writing: Lin-ling Jin, Dong-sheng Chen

Final approval of manuscript: All authors

Acknowledgment: We thank Chuang Qi from Jiangsu Simcere Diagnostics for his kindly assistance.

Compliance with Ethical Standards section:

Disclosure of potential conflicts of interest: The authors declare that they have no conflict of interest.

Research involving Human Participants and/or Animals: YES, Research involving Human Participants. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent: Informed consent was obtained from the patient for participating and publication of this case.

Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA, Huberman MS, Costa DB (2013) Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol 8:45–51. https://doi.org/10.1097/JTO.0b013e3182781e35
Kim EY, Cho EN, Park HS, Hong JY, Lim S, Youn JP, Hwang SY, Chang YS (2016) Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma. Cancer Biol Ther 17:237–245. https://doi.org/10.1080/15384047.2016.1139235
Castellanos E, Feld E, Horn L (2017) Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer. J Thorac Oncol 12:612–623. https://doi.org/10.1016/j.jtho.2016.12.014
Mitsudomi T, Yatabe Y (2007) Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 98:1817–1824. https://doi.org/10.1111/j.1349-7006.2007.00607.x
Wu J-Y, Yu C-J, Chang Y-C, Yang C-H, Shih J-Y, Yang P-C (2011) Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 17:3812–3821. https://doi.org/10.1158/1078-0432.CCR-10-3408

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Journal Publication

published 09 Apr, 2021

Read the published version in Investigational New Drugs →

Editorial decision: Accept as is.
18 Mar, 2021
Reviewers invited by journal
16 Mar, 2021
Reviews received at journal
16 Mar, 2021
Editor assigned by journal
15 Mar, 2021
First submitted to journal
14 Mar, 2021

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Icotinib, an Effective Treatment Option for Patients With Lung Adenocarcinoma Harboring Compound EGFR L858R and A871G Mutation

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