Uncommon EGFR mutations in lung adenocarcinoma: features and response to tyrosine kinase inhibitors

Brindel, Aurélien; Althakfi, Wajd Ahmed; Barritault, Marc; Watkin, Emmanuel; Maury, Jean‐Michel; Bringuier, Pierre‐Paul; Girard, Nicolas; Brevet, Marie

doi:10.21037/jtd-19-3790

Cited by 22 publications

(23 citation statements)

References 26 publications

(26 reference statements)

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“…For specific mutation subtypes, G719X (40.6%) and L861Q (21.9%) were the two most frequent single uncommon mutations. Overall, 34.4% of patients (11/32) had compound mutations, and G719X + S768I was the most common compound mutation (81.8%, 9/11), consistent with the mutation profiles reported by Yamada et al ( Yamada et al, 2020 ) and by Brindel et al ( Brindel et al, 2020 ).…”

Section: Discussionsupporting

confidence: 88%

“…Patients with compound uncommon mutations have better tumor response and prognosis than patients with single uncommon mutations ( Brindel et al, 2020 ; Yamada et al, 2020 ; Yang et al, 2020 ; Passaro et al, 2021 ; Tan et al, 2021 ). In the study by Yang et al, afatinib yielded better anti-tumor activity against compound uncommon mutations than against major uncommon mutations in both TKI-naïve patients and TKI-pretreated patients ( Yang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China

Gao

Cai³

et al. 2022

Front. Pharmacol.

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Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited.Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1–2 months. Adverse events were assessed by CTCAE 5.0.Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1–14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4–5 adverse events (AEs) occurred, but all patients had grade 1–2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs.Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China

Gao

Cai³

et al. 2022

Front. Pharmacol.

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“…Common EGFR mutations are exon 19 deletions and exon 21 L858R point mutation, constituting approximately 85% of EGFR mutations. The remaining 10-15% are made up of uncommon EGFR mutations, including exon 18 mutations and exon 20 insertion mutations, along with rarer exon 19 and 21 mutations, such as L861Q on exon 21 [12][13][14].…”

Section: Key Pointsmentioning

confidence: 99%

Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis

et al. 2022

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Background Information on the epidemiology of uncommon EGFR mutations including exon 20 insertions amongst nonsmall-cell lung cancer (NSCLC) is lacking. Objective The objective of this pragmatic literature review (PLR) and meta-analysis was to generate robust prevalence and incidence estimates based on ranges of exon 20 insertion mutations reported in the literature. Materials and methods Searches of MEDLINE, Embase, congresses and reference lists for articles published from 2013 in key European countries of interest (

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“…Emerging evidence from a few recent studies suggest that the efficacy of PD-1 blockade therapy is relatively more favorable in NSCLC patients bearing uncommon EGFR mutations compared to those with the classical mutations ( 46 , 69 , 90 ). Approximately 10% of EGFR mutant NSCLC is classified as the uncommon subtypes ( 91 ), including G719X, L861Q, S768I, and exon 20 insertion, which have different clinicopathological characteristics and response to EGFR TKIs ( 92 – 96 ). Most recently, Chen et al.…”

Section: Nsclc Patients Harboring Egfr Mutations Show Poor Response To Anti-pd-1/pd-l1 Immunotherapymentioning

confidence: 99%

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Fong

Cho

2021

Front. Oncol.

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Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

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Uncommon EGFR mutations in lung adenocarcinoma: features and response to tyrosine kinase inhibitors

Cited by 22 publications

References 26 publications

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China

Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

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