Afatinib and Cetuximab in Four Patients With EGFR Exon 20 Insertion–Positive Advanced NSCLC

Veggel, Bianca van; Langen, Adrianus J. de; Hashemi, S.; Monkhorst, Kim; Heideman, Daniëlle A.M.; Thunnissen, Erik; Smit, Egbert F.

doi:10.1016/j.jtho.2018.04.012

Cited by 59 publications

(40 citation statements)

References 15 publications

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“…79,81 More recently, a clinical study found that three out of four EGFR exon 20 insertion-positive NSCLC patients had partial responses to a combination of afatinib and cetuximab, with a median PFS of 5.4 months. 82 These results suggest that the cetuximab and EGFR inhibitor combination may have some efficacy in patients with exon 20 insertions; however, with limited clinical data, further work is necessary to determine the impact of the insertion size and location on the response to cetuximab combinations.…”

Section: Treatment Options For Egfr Exon 20 Insertion Nsclcmentioning

confidence: 96%

Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer

Vyse

Huang

2019

Sig Transduct Target Ther

269

233

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Inframe insertions of three or more base pairs in exon 20 of the epidermal growth factor receptor ( EGFR) gene were among the first EGFR mutations to be identified as oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike the classical EGFR L858R point mutation or exon 19 deletions, which represent the majority of EGFR mutations in NSCLC, low frequency EGFR exon 20 insertion mutations are associated with de novo resistance to targeted EGFR inhibitors and correlate with a poor patient prognosis. Here, we review the developments over the last 5 years in which pre-clinical studies, including elucidation of the crystal structure of an EGFR exon 20 insertion mutant kinase, have revealed a unique mechanism of kinase activation and steric conformation that define the lack of response of these EGFR mutations to clinically approved EGFR inhibitors. The recent development of several novel small molecule compounds that selectively inhibit EGFR exon 20 insertions holds promise for future therapeutic options that will be effective for patients with this molecular subtype of NSCLC.

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Section: Treatment Options For Egfr Exon 20 Insertion Nsclcmentioning

confidence: 96%

Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer

Vyse

Huang

2019

Sig Transduct Target Ther

269

233

View full text Add to dashboard Cite

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“…Increased exposure of the malignant cells to different anticancer agents amplifies the heterogeneity of the tumor and several overcoming therapies against drug resistance are proposed [139]. These include (i) combination therapy against single target (i.e., TKI afatinib against EGFR and monoclonal antibody cetuximab against EGFR) [150] or against multiple targets (i.e., a third generation TKI of EGFR(T790M) and navitoclax an inhibitor of ABC transporters) [151]; (ii) sequential therapy to reduce the toxicity induced by combination of chemotherapeutic agents [152] or (iii) targeted therapy after identification of genetic markers (i.e., patients with EGFR(T790M) mutation which can benefit from osimertinib treatment compared to patients with activating mutations in EGFR who can benefit by gefinitib/erolotinib/afatinib administration) [153]. New experimental studies and different therapeutic approaches are required to find the optimal way to interfere with development of tumor malignancy.…”

Section: Tumor Heterogeneitymentioning

confidence: 99%

Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer

Costea

Vlad

Miclea

et al. 2020

IJMS

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The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.

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“…Two patients carrying EGFR D770_P772delinsKG and EGFR D770>GY, respectively, were treated with one such antibody-cetuximab--as part of their regimen, and achieved ongoing partial response at 6+ and 42+ months [9]. In another study, 3 of 4 patients receiving cetuximab combined with afatinib also achieved responses [10]. This strategy has been explored in ErbB2/HER2 exon 20 mutation-positive patients: a trastuzumab-based regimen combined with lapatinib showed remarkable tumor regression in a case of metastatic lung adenocarcinoma [11].…”

Section: Therapeutic Approaches Aimed At Egfr Exon 20 Insertions In Lmentioning

confidence: 99%

New therapeutic approaches to overcoming resistant EGFR exon 20 alterations

Boichard

Felip

et al. 2020

Critical Reviews in Oncology/Hematology

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EGFR exon 20 alterations are rare events seen mainly in non-small cell lung cancer (NSCLC). They include EGFR T790 and C797S mutations (associated with secondary resistance to classic EGFR tyrosine kinase inhibitors (TKIs)), and EGFR exon 20 in-frame insertions (associated with resistance to first-and second-generation EGFR TKIs). In silico modeling of structural changes in aberrant proteins has informed selection of compounds with potential clinical activity: poziotinib (whose smaller size permits access to the restricted kinase pocket created by EGFR and ERBB2 exon 20 insertions); cetuximab (an antibody that attenuates dimerization caused by EGFR exon 20 insertions), and TAK-788 (another EGFR/ERBB2 TKI). Other alterations, such as EGFR T790M, are responsive to osimertinib, while the EGFR C797S alteration seen in osimertinib resistance demonstrates preclinical sensitivity to combined brigatinib and cetuximab. These observations indicate that clinical resistance can be overcome by utilizing advanced genomic interrogation coupled with computer modeling.

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Afatinib and Cetuximab in Four Patients With EGFR Exon 20 Insertion–Positive Advanced NSCLC

Abstract: Dual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion-positive NSCLC.

Cited by 59 publications

References 15 publications

Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer

Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer

Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer

New therapeutic approaches to overcoming resistant EGFR exon 20 alterations

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