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Review
. 2021 Dec;6(6):100280.
doi: 10.1016/j.esmoop.2021.100280. Epub 2021 Oct 9.

Treating disease progression with osimertinib in EGFR-mutated non-small-cell lung cancer: novel targeted agents and combination strategies

V Di Noia  1 , A D'Aveni  2 , E D'Argento  3 , S Rossi  4 , P Ghirardelli  2 , L Bortolotti  2 , V Vavassori  2 , E Bria  5 , G L Ceresoli  2
Affiliations
Review

Treating disease progression with osimertinib in EGFR-mutated non-small-cell lung cancer: novel targeted agents and combination strategies

V Di Noia et al. ESMO Open. 2021 Dec.

Abstract

A precision medicine approach has been successfully applied in medical oncology for the treatment of non-small-cell lung cancer (NSCLC) through the identification of targetable driver molecular aberrations; activating mutations of epidermal growth factor receptor (EGFR) are the most common. Osimertinib, a third-generation, wild-type sparing, irreversible EGFR tyrosine kinase inhibitor (TKI), originally showed a striking activity after progression to first- and second-generation EGFR-TKIs when T790M resistance mutation was identified. Thereafter, upfront use of osimertinib became the standard of care based on overall survival benefit over first-generation TKIs erlotinib and gefitinib as reported in the FLAURA trial. For patients progressing on osimertinib, identification of resistance mechanisms is crucial to develop novel targeted therapeutic approaches. Moreover, innovative drugs or combination therapies are being developed for cases in which a specific resistance mechanism is not identifiable. In this review, the post-osimertinib treatment options for EGFR-mutated NSCLC are analyzed, with an outlook to ongoing clinical trials. An algorithm to guide clinicians in managing progression on osimertinib is proposed.

Keywords: EGFR; non-small-cell lung cancer; osimertinib; progression; tyrosine kinase inhibitors.

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Conflict of interest statement

Disclosure VDN received speakers’ fees from AstraZeneca, MSD, BMS, Istituto Gentili, and Boehringer Ingelheim; grant consultancies from AstraZeneca, MSD, BMS, and Boehringer Ingelheim; travel fees from MSD and Boehringer Ingelheim; and institutional research grants from Roche. EB received speakers’ and travel fees from MSD, AstraZeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis, and Roche; consultant fees from Roche and Pfizer; and received institutional research grants from AstraZeneca and Roche. GLC received speakers’ fees from Novocure, Zai Lab, and MSD and consultant fees from Novocure and Zai Lab. The remaining authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanisms of resistance to osimetinib and potential strategies of treatments to overcome resistance. CT, chemotherapy; IO, immunotherapy. ∗Activity demonstrated across resistance mechanisms.
Figure 2
Figure 2
Proposed algorithm for managing epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer progressing on osimertinib. CNS, central nervous system; CT, computed tomography; LAT, locally ablative therapy; MRI, magnetic resonance imaging; SCC, squamous cell carcinoma; SCLC, small-cell lung cancer; TKI, tyrosine kinase inhibitor.
See this image and copyright information in PMC

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