MA13.07 Structural Classification of Atypical EGFR Mutations Identifies 4 Major Subgroups with Distinct Patterns of Drug Sensitivity

Robichaux, Jacqulyne P.; Le, Xiuning; Vijayan, Ramachandran; Hicks, Kristin C.; Elamin, Yasir Y.; Tran, Hai T.; Varghese, Susan; He, Jie; Zhang, F.; Hu, Lemei; Poteete, Alissa; Rinsurongkawong, Waree; Zhang, X.; Nilsson, Monique B.; Liu, X.; Diao, Lixia; Zhang, J.; Madison, Russell; Schrock, Alexa B.; Saam, Jennifer; Fang, Bingliang; Wang, J.; Cross, Jason B.; Gray, Jhanelle E.; Heymach, John V.

doi:10.1016/j.jtho.2021.01.268

Cited by 3 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, both E709X and L747X have been identified as pocket volume reducing (PVR) mutations that are predicted to be more sensitive to second-generation EGFR TKIs than firstor third-generation agents (10). We also assessed the activity of afatinib against mutations that have been implicated in the acquired resistance to osimertinib, including G724S (n = 13), L718X (n = 5) and C797S (n = 1), all of which have been identified as PVR mutations (10). G724S mutations showed some sensitivity towards afatinib with an ORR of 17% and DCR of 100%.…”

Section: Discussionmentioning

confidence: 99%

Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report

et al. 2022

View full text Add to dashboard Cite

IntroductionPreviously, we developed a database of 693 patients with NSCLC and uncommon EGFR mutations treated with afatinib. Here, we provide an update of >1000 patients, with more data on specific mutations.MethodsPatients were identified from a prospective database developed by Boehringer Ingelheim and via literature review. Mutations were categorized as T790M-positive, exon 20 insertions, major uncommon (G719X, L861Q, S768I) and ‘others’. Patients with compound mutations (≥2 EGFR mutations) were analyzed separately. Key endpoints were time to treatment failure (TTF) and objective response rate (ORR).ResultsOf 1023 patients included, 587 patients were EGFR TKI-naïve and 425 were EGFR TKI-pretreated. The distribution of mutation categories was: major uncommon (41.4%); exon 20 insertions (22.3%); T790M (20.3%); and ‘others’ (15.9%); 38.6% had compound mutations. Overall, median TTF (TKI naïve/pretreated) was 10.7 and 4.5 months. ORR was 49.8% and 26.8%, respectively. In TKI-naïve patients, afatinib demonstrated activity against major uncommon mutations (median TTF: 12.6 months; ORR: 59.0%), ‘other’ mutations (median TTF: 10.7 months; ORR: 63.9%) including strong activity against E709X (11.4 months; 84.6%) and L747X (14.7 months; 80.0%), and compound mutations (11.5 months; 63.9%). Although sample sizes were small, notable activity was observed against specific exon 20 insertions at residues A763, M766, N771, and V769, and against osimertinib resistance mutations (G724S, L718X, C797S).ConclusionAfatinib should be considered as a first-line treatment option for NSCLC patients with major uncommon, compound, ‘other’ (including E709X and L747X) and some specific exon 20 insertion mutations. Moderate activity was seen against osimertinib resistance EGFR mutations.

show abstract

Section: Discussionmentioning

confidence: 99%

Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Using the data from patients with NSCLC, cell lines, and computer models, Jacquulyne Robichaux et al. found that EGFR mutations can be divided into four functional subgroups including classcical-like mutation, T790M-like mutations, exon 20 insertions and pocket volume reducing (PVR) mutation (interior of the ATP binding pocket or in α-helix/P-loop) ( 8 ). The mechanisms of resistance to third-generation EGFR TKIs have been demonstrated in recent years.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Dacomitinib Overcomes Osimertinib Resistance in NSCLC Patient Harboring L718Q Mutation: A Case Report

Shen

Chen

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

BackgroundAdvanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations has been successfully treated with tyrosine kinase inhibitors (TKIs). However, resistance to osimertinib, a third-generation TKI, can be difficult to overcome in this small subset of patients and is attributed to secondary resistant mutations. Here, we report a case of acquired EGFR L858R/L718Q mutation with advanced NSCLC that resistant to osimertinib, which was successfully overcome using dacomitinib.Case PresentationA 64-year-old non-smoker woman was diagnosed with stage IV non-small cell lung adenocarcinoma with EGFR L858R mutation and brain metastasis in November 2018. Treatment with gefitinib and gamma knife radiosurgery was started as the first-line treatment. After 7 months, she experienced disease progression with increased primary lung lesions and switched to osimertinib based on an acquired EGFR T790M mutation. After another 4 months, the disease progressed, and she was switched to chemotherapy. During chemotherapy, brain MRI showed an increasing number of parietal lobe metastases. Hence, gamma knife radiosurgery was performed again. After 12 months, the disease progression resumed, and an EGFR L718Q mutation was found on biopsy. The patient was then challenged with dacomitinib, and the disease was partially responsive and under control for 6 months.ConclusionCurrently, there are no established guidelines for overcoming osimertinib resistance caused by the L718Q mutation. The acquired EGFR L718Q mutation in subsequent resistance to osimertinib could be overcome using dacomitinib, indicating a promising treatment option in the clinic.

show abstract

Allelic Context of EGFR C797X–Mutant Lung Cancer Defines Four Subtypes With Heterogeneous Genomic Landscape and Distinct Clinical Outcomes

Lu,

Wei,

Wang

et al. 2024

Journal of Thoracic Oncology

View full text Add to dashboard Cite

MA13.07 Structural Classification of Atypical EGFR Mutations Identifies 4 Major Subgroups with Distinct Patterns of Drug Sensitivity

Abstract: March 2021Abstracts S183osimertinib. These findings define subgroups of EGFR mutations that may better guide future treatment approaches for atypical EGFR mutations.

Cited by 3 publications

References 0 publications

Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report

Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report

Case Report: Dacomitinib Overcomes Osimertinib Resistance in NSCLC Patient Harboring L718Q Mutation: A Case Report

Allelic Context of EGFR C797X–Mutant Lung Cancer Defines Four Subtypes With Heterogeneous Genomic Landscape and Distinct Clinical Outcomes

Contact Info

Product

Resources

About