Spotlight on Amivantamab (JNJ-61186372) for EGFR Exon 20 Insertions Positive Non-Small Cell Lung Cancer.
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ABSTRACT:
SUBMITTER: Brazel D
PROVIDER: S-EPMC8648093 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveAmivantamab plus chemotherapy has been proved to be an efficient treatment strategy for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions. The aim of this study was to conduct the cost-effectiveness analysis of amivantamab-chemotherapy compared with chemotherapy alone in NSCLC harboring EGFR exon 20 insertion mutations.MethodsWe constructed a Markov model based on the data derived from the PAPILLON trial. We evaluated the cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were used to evaluate the influence of different parameters on this model.ResultsCompared with chemotherapy alone, amivantamab combined with chemotherapy treatment gained an incremental effectiveness of 0.473 QALYs and an incremental cost of $361,950.952, which resulted in an ICER of $765,224/QALY. The ICER was much higher than the willingness-to-pay threshold of 15,0000/QALY. One-way sensitivity analysis revealed that amivantamab cost was the leading influential factor in the model.ConclusionsCompared with chemotherapy alone, amivantamab plus chemotherapy is not a cost-effective first-line treatment choice for NSCLC patients with EGFR exon 20 insertions. The costly price of amivantamab is one of the major reasons for the high cost of this combined treatment strategy. Therefore, it is imperative to take into account the high cost of amivantamab in the subsequent clinical application and strive to attain a relative equilibrium between its significant clinical benefit and economic encumbrance.
| S-EPMC10995216 | biostudies-literature
Project description:Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (Exon20ins) account for 4-12% of all EGFR mutations in non-small cell lung cancer (NSCLC) patients. Data on the differences in clinical characteristics between patients with Exon20ins and major mutations (M-mut) such as exon 19 deletion and L858R are limited. We retrospectively reviewed advanced NSCLC patients with EGFR mutations, who were treated with systemic therapy between January 2011 and December 2019. We identified 23 patients with Exon20ins and 534 patients with M-mut. In Exon20ins patients, the median age was 60 (range 27-88) years, and females and never-smokers were predominant. Clinical characteristics were similar in the two groups. In Exon20ins patients, 17 patients received platinum doublet as first-line therapy, and the overall response rate (ORR) and median progression-free survival (mPFS) were 11.8% and 8.9 months. Additionally, seven patients received conventional EGFR-tyrosine kinase inhibitors (TKIs), and eight patients anti-PD-1 antibodies in any-line therapy. ORR and mPFS of EGFR-TKIs and anti-PD-1 antibodies were 0%, 2.2 months and 25%, 3.1 months, respectively. Overall survival was significantly shorter in Exon20ins patients than in M-mut patients (29.3 vs. 43.4 months, p = 0.04). The clinical outcomes in Exon20ins patients were not satisfactory compared to M-mut patients.
| S-EPMC8455549 | biostudies-literature
Project description: Not available
| S-EPMC8474363 | biostudies-literature
Project description:A 20-year-old woman was diagnosed with stage 4 lung adenocarcinoma with an epidermal growth factor receptor (EGFR) exon 20 insertion gene mutation. Although the patient underwent chemotherapy, her lesions progressed. Liquid biopsy for EGFR T790M mutation showed negative results. After administering osimertinib, reduction of the lesions at the primary site was observed, and the patient's respiratory condition improved. Previous reports showing successful treatment of EGFR exon 20 insertion-positive lung adenocarcinoma with the standard osimertinib dose of 80 mg are limited. The present case demonstrated that osimertinib could be a possible treatment option for EGFR exon 20 insertion-positive lung adenocarcinoma.
| S-EPMC6806250 | biostudies-literature
Project description:A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non-small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain-Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.
| S-EPMC8113745 | biostudies-literature
Project description:EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next-generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co-occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins-positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression-free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insFQEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first-generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insFQEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first-line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co-occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs, suggesting the clinical importance of selecting proper EGFR TKI treatment based on the specific EGFR e20ins type.
| S-EPMC7400778 | biostudies-literature
Project description:Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. Cancer Res; 77(10); 2712-21. ©2017 AACR.
| S-EPMC5596996 | biostudies-literature
Project description:Osimertinib, a third-generation (3G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is now considered the standard of care for the first-line (1L) treatment of advanced EGFR+ NSCLC due to statistically significant improved progression-free survival (PFS) and overall survival (OS) compared with first-generation (1G) treatment from the FLAURA trial. Recently two other 3G EGFR TKIs (aumolertinib and furmonertinib) have been approved in China for treatment of EGFR T790M+ NSCLC. Randomized Phase 3 trials of these two 3G EGFR TKIs have also demonstrated PFS over gefitinib respectively. Among these two Chinese home-grown, 3G EGFR TKIs, furmonertinib seems to most closely resemble osimertinib in terms of dosing regimen, efficacy and adverse events profile. In this article, we reviewed the clinical activity and adverse events of furmonertinib at 80 mg daily (approved dose), potential usage of 160 mg daily for CNS metastasis in EGFR+ NSCLC, and usage of 160 mg or 240 mg daily in EGFR exon20 insertion positive (EGFRex20ins+) NSCLC patients.
| S-EPMC9617553 | biostudies-literature
Project description: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.
| S-EPMC6405763 | biostudies-literature
Project description:IntroductionThe clinical efficacy of osimertinib for patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations is unclear. Few case reports exist on the successful treatment of such tumors with osimertinib. We report a case wherein osimertinib administration had no effect in a patient with EGFR exon 20 insertion-positive lung adenocarcinoma.Patient concernsA 48-year-old never-smoking woman was referred to our hospital for chronic cough. Computed tomography (CT) and positron emission tomography-CT revealed a nodule in the right middle lobe, consolidation in the right upper lobe, multiple lymph node metastases, liver metastasis, and multiple bone metastases.DiagnosisOn the basis of further examination using transbronchial lung biopsy, the patient was diagnosed with cT1N3M1 stage IVB lung adenocarcinoma. An EGFR exon 20 insertion, without any additional mutations, was identified.InterventionsDaily oral administration of 80 mg osimertinib was initiated to treat the EGFR exon 20 insertion-positive lung adenocarcinoma.OutcomesAlthough the disease appeared to be stable 2.5 months after the administration of osimertinib, the tumor started to grow 3 months after administration, and carcinoembryonic antigen levels became higher than those before treatment. Thus, osimertinib was discontinued, and treatment with carboplatin as well as pemetrexed and bevacizumab was started, which the patient responded to.ConclusionEGFR exon 20 insertion mutations must be classified in more detail to assess the efficacy of EGFR tyrosine kinase inhibitors. Osimertinib doses that provide favorable therapeutic windows should be considered. Further clinical research is required to clarify the efficacy of osimertinib and other drugs for exon 20 insertion mutations.
| S-EPMC7572000 | biostudies-literature