P2.01-100 Spectrum of EGFR Exon 20 Insertion Mutations and Co-Occurring Genetic Alterations in Patients with Non-Small-Cell Lung Cancer

Montenegro, G. Bravo; Nagasaka, Misako; Ma, Patrick; Naqash, Abdul Rafeh; Mamdani, Hirva; Spira, Alexander I.; Subramaniam, Deepa; Feldman, Rebecca; Kim, C.

doi:10.1016/j.jtho.2019.08.1443

Cited by 2 publications

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“…Studies Presented in the Table Utilized Different Sample Collection Methods, Elamin et al Evaluated Tumour Specimens Pre-Poziotinib and on Progression from 20 Patients Who Responded to Poziotinib. 39 Riess et al and Montenegro et al Were Observational Studies to Identify the Most Common Co-Occurring Genetic Alterations at Baseline from Formalin Fixed Embedded Ex20ins NSCLC Tumour Specimens from 263 (Riess et al) 40 and 104 (Montenegro et al) 41 Patients Genetic Alteration Genetic Alteration (Prevalence %) Baseline/Post-Treatment Confers Poziotinib Resistance (Confirmed/Putative/Unknown) Ref Mutation EGFR T790M (10%) Post-treatment Confirmed (T790M)/putative (V774A, D770, PIK3CA E545K and MAP2K2 S94L) Elamin et al 39 EGFR V774A (5%) EGFR D770A (5%) PIK3CA E545K (5%) MAP2K2 S94L (5%) Amplification MET amplification (5%) Post-treatment Putative EGFR amplification (10%) CDK6 amplification (10%) Mutation TP53 (56%) Baseline Unknown Riess et al 40 CDKN2A (22%) CDKN2B (16%) RB1 (11%) CTNNB1 (5–10%) PIK3CA (5–10%) Amplification NKX2-1 (14%) Baseline Unknown NFKBIA (5–10%) MDM2 (5–10%) MYK (5–10%) CDK4 (5–10%) Mutation TP53 (51%) Baseline <...>…”

Section: Known Mechanisms Of Ex20ins Tki Resistancementioning

confidence: 99%

Tackling Drug Resistance in EGFR Exon 20 Insertion Mutant Lung Cancer

Pacini

Jenks

Vyse

et al. 2021

PGPM

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Insertion mutations in exon 20 (Ex20ins) of the epidermal growth factor receptor ( EGFR ) gene are the largest class of EGFR mutations in non-small cell lung cancer (NSCLC) for which there are currently no approved targeted therapies. NSCLC patients with these mutations do not respond to clinically approved EGFR tyrosine kinase inhibitors (TKIs) and have poor outcomes. A number of early phase clinical trials are currently underway to evaluate the efficacy of a new generation of TKIs that are capable of binding to and blocking Ex20ins. Although these agents have shown some clinical activity, patient responses have been restricted by dose-limiting toxicity or rapid acquisition of resistance after a short response. Here we review the current understanding of the mechanisms of resistance to these compounds, which include on-target EGFR secondary mutations, compensatory bypass pathway activation and acquisition of an EMT phenotype. Taking lessons from conventional EGFR inhibitor therapy in NSCLC, we also consider other potential sources of resistance including the presence of drug-tolerant persister cells. We will discuss therapeutic strategies which have the potential to overcome different forms of drug resistance. We conclude by evaluating recent technological developments in drug discovery such as PROTACs as a means to better tackle TKI resistance in NSCLC harbouring Ex20ins mutations.

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