EGFR A763_Y764insFQEA

In conclusion, MD simulations can effectively predict patient outcomes by connecting computational results with clinical data and advancing our understanding of EGFR mutations and their therapeutic responses.

P1, N=53, Active, not recruiting, Takeda | Trial completion date: Mar 2024 --> Mar 2025

P1, N=53, Active, not recruiting, Takeda | Phase classification: P1/2 --> P1

A further classification can be achieved using a structure-function modeling approach and experimental data using patient-derived cell lines. The detailed overview of TKI responses for each EGFRex20+ mutation can assist treating physicians to select the most optimal drug for individual NSCLC patients.

P1/2, N=53, Active, not recruiting, Takeda | N=33 --> 53

Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations. Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon EGFR mutations and specific EGFR or HER2 mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.

However, a novel EGFR-TKI, mobocertinib, was approved by the US FDA for NSCLC patients with EGFR exon20 insertion. We examined efficacy of mobocertinib and other EGFR-TKIs (erlotinib, afatinib, poziotinib, CLN-081, sunvozertinib , osimertinib, and brigatinib) using murine pro-B-cell line (Ba/F3) models harboring one of five most common EGFR exon 20 insertions (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH). These findings indicate that T790M or C797S, depending on the original activating mutations, will cause acquired resistance to mobocertinib in NSCLCs with EGFR exon 20 mutations. Further analyses suggest that sunvozertinib will be effective against acquired resistant cells with T790M mutation. However, except for A763_Y764insFQEA plus C797S mutation that is sensitive to erlotinib, other treatment strategy, such as cytotoxic chemotherapy, should be considered for patients who develop C797S secondary mutation.

This is the largest preclinical/clinical report to highlight that EGFR-K745_E746insIPVAIK and other mutations with exon 19 XPVAIK amino-acid insertions are rare but sensitive to clinically available 1st, 2nd, and 3rd generation as well as EGFR exon 20 active TKIs; in a pattern that mostly resembles the outcomes of models with EGFR-L861Q and EGFR-A763_Y764insFQEA mutations. These data may help with the off-label selection of EGFR TKIs and clinical expectations of outcomes when targeted therapy is deployed for these EGFR mutated lung cancers.

With the successive approval of new specific targeted drugs for EGFR ex20ins in Food and Drug Administration (FDA) and other national regulatory agencies, the development and clinical research of targeted drugs for EGFR ex20ins in China have also developed rapidly and Mobocertinib has been approved recently in China...How to detect it comprehensively and accurately in clinical practice, so as to enable more patients to benefit from targeted therapy, is a very important and urgent problem to be solved. This review introduces the molecular typing of EGFR ex20ins, then discusses the importance of EGFR ex20ins detection and the differences of various detection methods, and summarizes the research and development of new drugs progress of EGFR ex20ins, in order to optimize the diagnosis and treatment path of EGFR ex20ins patients by selecting accurate, rapid and appropriate detection methods, so as to improve the clinical benefits of the patients..

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.

P1/2, N=33, Active, not recruiting, Takeda | Trial primary completion date: Mar 2024 --> Nov 2021

Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. Although they are rare, at GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.

P1/2; N=33; Active, not recruiting; Sponsor: Takeda; Trial primary completion date: Sep 2021 --> Mar 2024

Two patients (EGFR A763_Y764insFQEA and EGFR T751_I759>S) had received erlotinib during their treatment course and both of them showed stable disease with a progression-free survival of 5.9 and 10.1 months, respectively...The most overlooked mutations were exon 20 insertions. A comprehensive EGFR mutation assay can provide significant benefit to NSCLC patients, especially in an area with a high prevalence of EGFR mutations.

We used models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations to probe representative first- (gefitinib, erlotinib), second- (afatinib), third-generation (osimertinib), and in-development EGFR exon 20-specific (poziotinib, mobocertinib [TAK-788]) TKIs. Mechanisms of acquired TKI resistance of this mutant remain underreported, but do seem to align with those of common mutations. To our knowledge, this is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is sensitive to clinically available first-, second-, third-generation, and in-development EGFR TKIs.

P1/2, N=33, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting | N=63 --> 33

This study demonstrates that ctDNA monitoring is a useful method for molecular genotyping of advanced lung cancer patients. Genomic profiling of liquid biopsy may help to identify gene signatures for biomarkers predictive of response to treatment. The gene mutations identified in the individual patient of this study may help access the clinical benefit of therapy with ICIs or other drugs.

P1/2, N=63, Recruiting, Takeda | Trial primary completion date: Nov 2020 --> Sep 2021

No abstract available

EGFR exon20-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 complicate the clinical studies. 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.

P1/2, N=63, Recruiting, Takeda | Phase classification: P1 --> P1/2 | N=33 --> 63 | Trial completion date: Jan 2022 --> Mar 2024