EGFR A767_V769dup

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. This 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.

A new modality of treatment for NSCLC patients with EGFRx20ins has been established with the approval of mobocertinib and amivantamab. There are also numerous novel targeted treatments for NSCLC with EGFRex20ins in development, which are anticipated to improve this patient population's survival even further. This review provides a reference for the clinical management of these patients by summarizing the most recent epidemiological, and clinicopathological characteristics, diagnostic techniques, and therapeutic advances of EGFRex20ins in NSCLC.

This study investigated the distribution of EGFR E20ins in the Asian population, with p.A767_V769dup and p.S768_D770dup being the most frequently observed mutations. Since some studies have reported single EGFR E20ins sequences using different names, it is important to be cautious when describing EGFR E20ins. To ensure comprehensive coverage in real-world settings, each method used for the detection of EGFR E20ins must be annotated according to the HGVS nomenclature.

Furmonertinib has shown encouraging antitumor activity and CNS activity in patients with advanced NSCLC with EGFR ex20ins. Moreover, furmonertinib had a good safety profile and no dose-dependent toxicity.

Here we also explore amivantamab versus docetaxel (DOC), EGFR tyrosine kinase inhibitors (TKIs) or immuno-oncology (IO) in RW practice in Japan using a lung cancer genomic screening platform (LC-SCRUM-Asia) with more than 16,000 NSCLC pts from 2013. Conclusions Amivantamab-treated pts had better clinical benefits compared to DOC, TKIs and IO. Amivantamab should be considered a standard therapy after platinum-based chemotherapy for EGFR E20i aNSCLC pts.

The POSITION20 study showed modest antitumor activity in patients with EGFRex20 + NSCLC treated with 160 mg osimertinib, with a confirmed ORR of 28% and acceptable toxicity.

"Five of the 7 ex20ins were found in advanced stage patients, two of them received first line chemotherapy and two an EGFR TKI (afatinib or osimertinib), with short responses. Conclusion Implementation of NGS in routine clinical practice allows identifying rare ex20ins in EGFR, including new variants, which would be missed by other methodologies. New therapeutic approaches are needed for ex20ins p, which respond poorly to current treatments."

The ORR and median PFS of 2nd-4th line docetaxel with or without ramcirumab/bevacizumab were 29% and 6.1 months (95%CI, 5.1-8.5), respectively. The NSCLC patients with EGFR Ex20ins responded poorly to TKIs and had a worse prognosis compared to the NSCLC patients with EGFR common mutations. Development of a novel treatment strategy for EGFR Ex20ins is needed. The NSCLC patients with EGFR Ex20ins showed poor responses to PD-1/PD-L1 monotherapy and TKIs.

Further, 2nd generation TKI, afatinib significantly improved the TTF compared with 1st generation TKI. In this study, for the first time, we applied the structure-based classification approach to characterize the mutational landscape of EGFR-mutant patients in Chinese patients with NSCLC. Adopting this structure-function-based EGFR classification into clinical practice may improve the precision medicine for EGFR mutant NSCLC patients as well as benefit future drug development and clinical trial design.

The recently approved targeted drugs Amivantamab and Mobocertinib shift the treatment paradigm for NSCLC patients harboring EGFR exon 20 insertion mutations. There are also several new compounds targeting NSCLC EGFR exon 20 insertion mutations are in development. In this article, we provide a through overview on the treatment development in EGFR exon 20 insertion mutant NSCLC..

Although patients with EGFR exon 20 mutations accounted for only about 5% LUAD patients, and had worse response rates in general, certain subtypes had significantly different prognoses compared with other subtypes.

The results of this study in ≥2 lines patients treated with twice the conventional dose had a good curative effect (compared with 3 times of conventional dosage in FAVOUR study), which provided more treatment options for NSCLC patients in multiple lines of treatment and could alleviate part of their economic pressure, but the PFS and OS data still need further follow-up and verification of a larger sample size. The overall findings suggested that furmonertinib is a third generation EGFR-TKI with good efficacy and acceptable safety. Given the heterogeneity of EGFR Ex20ins mutation, the efficacy of targeted therapy may vary in different mutation types and requires further investigation.

In general, patients with EGFR ex20ins shared a similar age and gender to patients with other EGFR mutations or without EGFR ex20ins. Overall, our results revealed the molecular and clinicopathologic features of EGFR ex20ins in Chinese LUAD patients, which will be helpful for drug development and in clinical trials targeting EGFR ex20ins.

We described the landscape of EGFR Ex20ins in Chinese NSCLC patients cohort. Based on the large sample size, the frequency of the Ex20ins mutation in Chinese NSCLC patients was 2.2%, and the types of EGFR Ex20ins mutation were highly heterogeneous.

Detection of EGFRex20ins is necessary to identify patients suitable for amivantamab and mobocertinib. Commonly used PCR assays may fail to detect EGFRex20ins in 50% of patients potentially suitable for approved targeted therapies. Identification of EGFRex20ins can be improved with NGS-based testing. Our data confirm that NGS is superior to PCR-based assays and is the preferred NSCLC genotyping technology.

Our findings suggested that afatinib is effective in patients with uncommon mutations. Mechanisms of afatinib resistance vary and need further investigation.

Low PD-L1 expression and TMB were observed in NSCLC patients harboring EGFR ex20ins mutations. Further investigations are needed to confirm the therapeutic sensitivity of ICIs in this subgroup of EGFR mutations.

Specific targeted therapies are not available for patients with EGFR ex20ins+ NSCLC, regardless of insertion variant status; however, mobocertinib and amivantamab are currently in development. It is projected that commercially available PCR kits could have missed >40% of patients with NSCLC harboring ex20ins. Given the diverse profile of EGFR ex20ins variants, NGS-based genetic testing can substantially improve their identification in NSCLC.