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Updated: Feb 7, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Osimertinib
Umberto Malapelle1, Biagio Ricciuti2, Sara Baglivo2
1Department of Public Health, University of Naples Federico II, Naples, Italy.
Abstract:
Epidermal growth factor receptor (EGFR)-mutated (exons 18-21) advanced non-small cell lung cancers (NSCLCs) are generally characterized by exquisite sensitivity to treatment with an EGFR-tyrosine kinase inhibitor (-TKI). First-generation or reversible EGFR-TKIs include gefitinib and erlotinib, while, more recently, second-generation or irreversible EGFR-TKIs have been developed, namely afatinib and dacomitinib, with the aim of overcoming/delaying acquired resistance to treatment. Nevertheless, clinical trials have shown that resistance eventually emerges after a median time of slightly less than one year, regardless of whether first- or second-generation EGFR-TKIs are used. In this context, a secondary EGFR mutation in exon 20, namely T790M, has been found to be responsible for approximately 60% of cases of acquired resistance. Alternatively, T790M resistance mutation can be found de novo, in which case it limits the antitumor activity of both first- or second-generation EGFR-TKIs. Osimertinb is an orally bioavailable, third-generation EGFR-TKI that acts by irreversibly binding both EGFR activating mutations and T790M, while sparing wild-type EGFR. On this basis, osimertinib has proven more efficacious than platinum-based chemotherapy in the setting of EGFR T790M-positive NSCLCs pretreated with a first- or second-generation EGFR-TKI. More recently, in another phase 3 trial, osimertinib outperformed gefitinib or erlotinib as first-line treatment of EGFR-mutated (ex19del or L858R) advanced NSCLCs, thus emerging as a new standard of care in this setting. In the present review, we will discuss the preclinical and clinical development of osimertinib, briefly touching upon its activity in special populations and biomarkers of sensitivity to treatment.
Insights
Osimertinib, a third-generation EGFR-TKI, effectively treats non-small cell lung cancer (NSCLC) with EGFR mutations, including T790M resistance. It shows superior efficacy as both first-line and subsequent therapy for advanced NSCLC.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Advanced non-small cell lung cancer (NSCLC) with EGFR mutations (exons 18-21) initially responds to EGFR-TKIs.
- Acquired resistance to first- and second-generation EGFR-TKIs emerges within a year, often due to the T790M mutation.
- T790M mutations, found de novo or acquired, limit the efficacy of earlier EGFR-TKIs.
Purpose of the Study:
- To review the preclinical and clinical development of osimertinib, a third-generation EGFR-TKI.
- To discuss osimertinib's efficacy in EGFR-mutated NSCLC, including T790M-positive cases.
- To explore osimertinib's activity in special populations and identify biomarkers for treatment sensitivity.
Main Methods:
- Review of preclinical data and clinical trial results for osimertinib.
- Comparison of osimertinib's efficacy against platinum-based chemotherapy and earlier EGFR-TKIs.
- Analysis of osimertinib's performance in first-line and subsequent treatment settings for advanced NSCLC.
Main Results:
- Osimertinib demonstrates superior efficacy compared to platinum-based chemotherapy in T790M-positive NSCLC after prior EGFR-TKI treatment.
- In first-line treatment of EGFR-mutated advanced NSCLC, osimertinib outperformed gefitinib or erlotinib.
- Osimertinib acts as a new standard of care for EGFR-mutated advanced NSCLC.
Conclusions:
- Osimertinib is a highly effective third-generation EGFR-TKI for advanced NSCLC with specific EGFR mutations.
- Its ability to target both activating and T790M resistance mutations offers a significant therapeutic advantage.
- Osimertinib represents a major advancement in the treatment of EGFR-mutated NSCLC, establishing a new standard of care.