Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

Abstract

EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a thirdgeneration tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.

Overcoming acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589)

“…In this study, the combination of osimertinib with the pan‐HDAC inhibitor LBH589 effectively inhibited the growth of different osimertinib‐resistant cells and tumors, demonstrating the potential of LBH589 in overcoming acquired resistance to osimertinib. Notably, this combination also was effective in decreasing cell survival and inducing apoptosis in PC‐9/3M cells carrying the C797S resistance mutation, which is a newly defined mechanism for the emergence of acquired resistance to osimertinib and accounts for 20% to 30% of osimertinib‐resistant cases in the clinic, in addition to 19del and T790M mutations. Given the lack of effective options for the treatment of resistant tumors with triple mutations of EGFR at 19del, T790M, and C797S, our findings are of particular significance in terms of treating C797S‐induced osimertinib resistance.…”

Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation

“…7,8 This led to the development of third-generation EGFR-TKIs, including osimertinib (Tagrisso, AZD9291), nazartinib, naquotinib, mavelertinib, avitinib, and lazertinib. [9][10][11] Among them, osimertinib is the only approved therapy worldwide, which was first approved in 2015 on the basis of targeting EGFR T790M resistance and then received an additional approval in 2018 as first-line therapy with improvement in progression-free survival (PFS) over a standard EGFR-TKI (gefitinib or erlotinib). 9,[12][13][14] Other candidates are in various stages of clinical development.…”

“…[9][10][11] Among them, osimertinib is the only approved therapy worldwide, which was first approved in 2015 on the basis of targeting EGFR T790M resistance and then received an additional approval in 2018 as first-line therapy with improvement in progression-free survival (PFS) over a standard EGFR-TKI (gefitinib or erlotinib). 9,[12][13][14] Other candidates are in various stages of clinical development. Osimertinib remains the most robust option to overcome the T790M mutation with a manageable toxicity profile.…”

The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer

“…Point mutations of target genes also contribute to non-T790M mutations such as HER2 amplification, MET amplification, BRAF mutation and PIK3CA mutation (12). Osimertinib is a third-generation EGFR-TKI used for the treatment of patients with the T790M mutation; however no special treatment has been discovered for patients harboring non-T790M mutations (13,14). Therefore, further elucidation of other potential mechanisms that are critical for the development of effective therapeutic strategies targeting patients without the T790M mutation is urgent.…”