Clinical and molecular characteristics of epidermal growth factor receptor exon 20 insertion mutations in non-small-cell lung cancer

Geng, Di; Guo, Qiaoru; Huang, Siyuan; Zhang, H; Guo, Sen; Li, X

doi:10.1007/s12094-021-02701-x

Cited by 10 publications

(20 citation statements)

References 38 publications

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“…Our study identified and reported 35 different kinds of heterogeneous ex20ins subtypes, in which V769_D770insASV and D770_N771insSVD were the most common insertion variants, overall representing 40% of all ex20ins subtypes. This finding was in accordance with two previous large sample Chinese studies, 8 , 25 and also was similar to that discovered in the American databases. 33 , 34 Similarly, we also found TP53 occurred as the most frequent concomitant alteration together with EGFR ex20ins, with a prevalence of 52.1% in this study, which was much alike with those of 35%–56% reported by other studies.…”

Section: Discussionsupporting

confidence: 93%

“… 33 , 34 Similarly, we also found TP53 occurred as the most frequent concomitant alteration together with EGFR ex20ins, with a prevalence of 52.1% in this study, which was much alike with those of 35%–56% reported by other studies. 10 , 11 , 23 , 24 , 25 , 33 , 35 As clarified by current reports, EGFR ex20ins was associated with much lower levels of TMB (2.8–3.6/Muts/Mb) than WT EGFR , as well as with a low TPS of PD‐L1 expression, which suggested lack of comparable benefit of ICI in EGFR ex20ins as observed in NSCLC harboring common EGFR mutations. 10 , 21 , 22 , 33 In our study, only 2 patients carrying 1 ≤ TPS˂50% showed response to C + I (ORR, 2/6), with a median PFS of 6.57 months.…”

Section: Discussionmentioning

confidence: 70%

“…Outcomes of C + I observed in our study were well correlated with previous observations reported worldwide, indicating a limited activity of ICI for NSCLC patients with EGFR ex20ins. 8 , 10 , 12 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 …”

Section: Discussionmentioning

confidence: 99%

“…20 Although some uncommon EGFR mutations were reported to derive clinical benefit from immunotherapy, 21,22 the correlation between NSCLC with EGFR ex20ins and its response to ICI was controversial by several studies, covering a possible trend that ICI might not be a favorable option for ex20ins patients. 8,10,12,[22][23][24][25][26] Yet, there lacks comprehensive study evaluating the exact efficacy of combination therapy with chemotherapy plus Ai or ICI for advanced NSCLC with EGFR ex20ins in China. Besides, we acquired little about the heterogeneously molecular landscape of EGFR ex20ins in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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First‐line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non‐small cell lung cancer with EGFR exon 20 insertions: Real‐world evidence from China

et al. 2022

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Background Currently, survival benefit of immunotherapy in advanced non‐small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins) is controversial, though it generally indicates poor response and activity. Compared with standard chemotherapy in combination with bevacizumab, first‐line chemotherapy plus immune checkpoint inhibitor (ICI) in advanced NSCLC with EGFR ex20ins remains elusive and lacks real‐world evidence. Patients and Methods A retrospective real‐world study was conducted to evaluate clinical outcomes of chemotherapy alone (C), chemotherapy plus ICI (C + I), or chemotherapy plus angiogenesis inhibitors (C + A) as first‐line strategies for advanced NSCLC patients with EGFR ex20ins. Investigator‐assessed response and survival outcomes were compared between subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to reveal concomitant alterations and explore the molecular landscape of ex20ins. Results A total of 164 patients were screened, identifying 35 kinds of ex20ins, and 122 cases treated with C, C + I, and C + A were finally included in the first‐line analysis. C + A achieved much better objective response rate (ORR, 38.1% vs. 18.2%) and significant progression‐free survival (PFS) benefit compared with C (median, 7.73 vs.5.93 months, HR = 0.60, 95% CI: 0.40–0.90, p = 0.014), and it showed similar ORR (38.1% vs. 40.0%), but higher disease control rate (DCR, 96.8% vs. 80.0%) and numerically longer median PFS (7.73 vs. 6.53 months, HR = 0.83, 95% CI: 0.44–1.56, p = 0.30) than C + I. There was no PFS difference between C + I and C, despite of PD‐L1 expression or tumor mutational burden. KEGG analysis revealed concomitant upregulation of PI3K/AKT signaling might mediate intrinsic resistance to ICI in ex20ins. Conclusion First‐line chemotherapy plus angiogenesis inhibitors might yield more survival benefits than chemotherapy alone for NSCLC with EGFR ex20ins, whereas, it suggests that chemotherapy in combination with ICI might not obtain a better survival benefit for this subset of patients. Activation of PI3K/AKT signaling might mediate intrinsic immunosuppression in NSCLC with EGFR ex20ins.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

First‐line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non‐small cell lung cancer with EGFR exon 20 insertions: Real‐world evidence from China

et al. 2022

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“…Codon Asp770 (D770) is located in the pivot point of the EGFR C-helix, and the replacement of D770 with the inserted glycine potentially restores the wild-type C-helix conformational changes and the affinity for TKIs ( Kosaka et al, 2017 ). Given the low frequency of A763_Y764insFQEA (3%–8%) ( Riess et al, 2018 ; Yang et al, 2020 ; Yang G et al, 2021 ; Geng et al, 2022 ) and D770delinsGY (2.0%–4.8%) ( Yang et al, 2020 ; Yang J et al, 2021 ) variants, their response to diverse EGFR TKIs in the real world NSCLC cohorts is ambiguous. In addition, their structures and binding affinity to EGFR TKIs have also not been ascertained.…”

Section: Introductionmentioning

confidence: 99%

EGFR exon 20 insertion variants A763_Y764insFQEA and D770delinsGY confer favorable sensitivity to currently approved EGFR-specific tyrosine kinase inhibitors

Gao

Yang²,

Hu³

et al. 2022

Front. Pharmacol.

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Background: The EGFR exon 20 insertions (ex20ins) D770_N771insSVD and V769_D770insASV are most frequent in non-small-cell lung cancer (NSCLC) and are associated with intrinsic resistance to currently approved EGFR tyrosine kinase inhibitors (TKIs). A763_Y764insFQEA and D770delinsGY, respectively, account for 3%–8% and 2.0%–4.8% of EGFR ex20ins in NSCLC and are associated with a more favorable response to EGFR-specific TKIs as per case reports. The aim of this study was to elucidate the molecular structures of these mutants and their binding affinities to diverse EGFR TKIs and compare the clinical outcomes in NSCLC patients harboring these mutations.Methods: A real-world cohort study was conducted to evaluate and compare the clinical outcomes of EGFR TKIs among NSCLC patients with different EGFR ex20ins mutants in response to EGFR TKIs. The structures of A763_Y764insFQEA and D770delinsGY were also analyzed and drug binding simulations were performed.Results: With a median follow-up of 24.0 months, the first-line objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) were, respectively, 0 (0/16), 50.0% (8/16), and 2.07 months (95%CI, 0–6.25) in patients harboring D770_N771insSVD and V769_D770insASV variants and 33.3% (4/12), 83.3% (10/12), and 9.97 months (95%CI, 4.75–15.19) in patients with A763_Y764insFQEA and D770delinsGY variants. There was a significant difference between the PFS of these two subgroups (median, 9.97 vs.2.07 months, HR = 0.33, 95%CI, 0.13–0.85, p = 0.02). Similarly, the PFS was significantly longer after second-line treatment with EGFR TKIs in patients harboring A763_Y764insFQEA and D770delinsGY compared to those with other insertions (median, 6.77 vs.2.23 months, HR = 0.14, p < 0.001). Computational simulations indicated that A763_Y764insFQEA and D770delinsGY mutants were structurally similar to wild-type EGFR. In contrast, the C-helix and phosphate-binding loop of D770_N771insSVD and V769_D770insASV had shifted into the drug-binding pocket, resulting in significant steric hindrance and a lack of affinity for the currently approved EGFR inhibitors.Conclusion: NSCLC patients harboring A763_Y764insFQEA and D770delinsGY insertions of EGFR are responsive to the currently approved EGFR TKIs as opposed to patients with the D770_N771insSVD and V769_D770insASV variants. Therefore, A763_Y764insFQEA and D770delinsGY should be classified as active mutations among heterogeneous EGFR ex20ins subtypes and the carriers can be treated with the suitable EGFR TKIs.

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Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

Viteri¹,

Minchom

Bazhenova

et al. 2022

Molecular Oncology

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Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) account for ≤ 12% of all EGFR-mutant nonsmall cell lung cancers. We analysed real-world datasets to determine the frequency of ex20ins variants, and the ability of polymerase chain reaction (PCR) and nextgeneration sequencing (NGS) to identify them. Three real-world United States NGS databases were used: GENIE, FoundationInsights, and GuardantINFORM. Mutation profiles consistent with in-frame EGFR ex20ins were summarized. GENIE, FoundationInsights, and Guardant-INFORM datasets identified 180, 627, and 627 patients with EGFR ex20ins respectively. The most frequent insertion region of exon 20 was the near loop (~70%), followed by the far loop (~30%) and the helical (~3-6%) regions. GENIE, FoundationInsights, and GuardantINFORM datasets identified 41, 102, and 96 unique variants respectively. An analysis of variants projected that ~50% of EGFR ex20ins identified by NGS would have been missed by PCR-based assays. Given the breadth of EGFR ex20ins identified in the real-world US datasets, the ability of PCR to identify these mutations is limited. NGS platforms are more appropriate to identify patients likely to benefit from EGFR ex20ins-targeted therapies.

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Clinical and molecular characteristics of epidermal growth factor receptor exon 20 insertion mutations in non-small-cell lung cancer

Cited by 10 publications

References 38 publications

First‐line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non‐small cell lung cancer with EGFR exon 20 insertions: Real‐world evidence from China

First‐line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non‐small cell lung cancer with EGFR exon 20 insertions: Real‐world evidence from China

EGFR exon 20 insertion variants A763_Y764insFQEA and D770delinsGY confer favorable sensitivity to currently approved EGFR-specific tyrosine kinase inhibitors

Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

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