Dataset Information

EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy.

ABSTRACT: EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14-not reach(NR) 95% confidence interval(CI) vs. 29 months (17-NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment.

SUBMITTER: Chelabi S

PROVIDER: S-EPMC8534282 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy.

Chelabi Samy S Mignard Xavier X Leroy Karen K Monnet Isabelle I Brosseau Solenn S Theou-Anton Nathalie N Massiani Marie-Ange MA Friard Sylvie S Duchemann Boris B Fabre Elizabeth E Giroux-Leprieur Etienne E Cadranel Jacques J Wislez Marie M

Cancers 20211013 20

EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patient ...[more]

PMID: 34680280

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Project description:No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Project description: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.

Project description:IntroductionMechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors have not been extensively studied in either robust preclinical models or patient-derived rebiopsy specimens. We sought to characterize on-target resistance mutations identified in EGFR exon 20 insertion-mutated lung cancers treated with mobocertinib or poziotinib and evaluate whether these mutations would or would not have cross-resistance to next-generation inhibitors zipalertinib, furmonertinib, and sunvozertinib.MethodsWe identified mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors and then used preclinical models of EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, V773_C774insH) plus common EGFR mutants to probe inhibitors in the absence/presence of EGFR-T790M or EGFR-C797S.ResultsMobocertinib had a favorable therapeutic window in relation to EGFR wild type for EGFR exon 20 insertion mutants, but the addition of EGFR-T790M or EGFR-C797S negated the observed window. Zipalertinib had a favorable therapeutic window for cells driven by EGFR-A767_V769dupASV or EGFR-D770_N771insSVD in the presence or absence of EGFR-T790M. Furmonertinib and sunvozertinib had the most favorable therapeutic windows in the presence or absence of EGFR-T790M in all cells tested. EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib.ConclusionsThis report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance-robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.

Dataset Information

EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy.

Publications

EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy.

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