State of the Art: Concise Review
Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

https://doi.org/10.1016/j.jtho.2020.11.028Get rights and content
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Abstract

Single-agent osimertinib is the standard of care for the first-line treatment of advancedEGFR+ NSCLC and remained the only marketed third-generation EGFR tyrosine kinase inhibitor (TKI) until March 2020 when almonertinib (HS-10296) was approved in the People’s Republic of China for the treatment of advanced EGFR T790M+ NSCLC based on a phase 2 expansion study of a phase 1/2 trial. In this review, we profiled many of the third-generation EGFR TKIs in late-stage clinical development (e.g., almonertinib, lazertinib, alflutinib1, rezivertinib, ASK120069, SH-1028, D-0316, and abivertinib) based on their interim results from phase 1 and phase 2 trials, and included the designs of the phase 3 trials and their chemical structures when publicly available. We also listed other third-generation EGFR TKIs in pipeline development based on the search of clinical trial registration websites. In addition, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, mavelertinib), including phase 3 results of rociletinib and naquotinib. We further profiled combination clinical trial design of the third-generation EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704), and ACROSS2 (NCT04500717) that if positive can potentially usher in the next standard of care for advanced EGFR+ NSCLC.

Keywords

Osimertinib
Almonertinib
Lazertinib
Rezivertinib
Alflutinib
T790M
Furmonertinib

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Drs. Nagasaka and Zhu contributed equally to this work.

Disclosure: Dr. Nagasaka has received honorarium from AstraZeneca, Caris Life Sciences, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Blueprint Medicines and Tempus. Dr. Zhu has received honoraria from AstraZeneca, Blueprint, Roche-Foundation Medicine, Roche/Genentech, and Takeda; and had stock ownership of TP Therapuetics until May 2020. Dr. Lim has received honorarium from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Takeda and research funding from AstraZeneca and Yuhan Corporation. Dr. Greco is an employee of and has stock options in Beta Pharma. Dr. Wu has received honorarium from Roche and AstraZeneca. Dr. Ou has stock ownership and was on the scientific advisory board of Turning Point Therapeutics, Inc. (until February 28, 2019); is a member of the scientific advisory board of Elevation Oncology and has stock ownership in Elevation Oncology, and has received speaker honorarium from Merck, Roche/Genentech, AstraZeneca, Takeda/ARIAD, and Pfizer; and has received advisory fees from Roche/Genentech, AstraZeneca, Takeda/ARIAD, Pfizer, Foundation Medicine Inc., Spectrum, Daiichi Sankyo, and Janssen/Johnson & Johnson.

1

The name of ‘Alflutinib’ was changed as per the requirements of the National Pharmacopoeia Committee of China and the “China drug generic naming principle”, and the name of the drug has been changed from ‘Alflutinib’ to ‘Furmonertinib’.