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Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations:
E G Pizzutilo1, A G Agostara1, S Oresti1
1Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.
Background:
Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted.
Patients And Methods:
The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method.
Results:
Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy.
Conclusion:
The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.
Insights
Osimertinib shows activity in advanced non-small-cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) alterations, particularly compound mutations. The study highlights potential resistance mechanisms to EGFR inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osimertinib is standard for advanced non-small-cell lung cancer (NSCLC) with common EGFR mutations.
- Uncommon EGFR alterations (uEGFR) have limited treatment options and lower sensitivity to EGFR inhibitors.
- Data on osimertinib efficacy in NSCLC with uEGFR are scarce.
Purpose of the Study:
- To evaluate the activity of osimertinib in advanced NSCLC patients with uncommon EGFR alterations.
- To analyze treatment outcomes based on specific uEGFR subtypes and presence of brain metastases.
- To identify potential resistance mechanisms to osimertinib in this patient population.
Main Methods:
- Retrospective analysis of the ARTICUNO study data from 21 centers (August 2017-March 2023).
- Inclusion of advanced NSCLC patients with uEGFR treated with osimertinib.
- Response evaluation using RECIST v1.1 criteria; survival outcomes estimated by Kaplan-Meier method.
Main Results:
- Eighty-six patients with uEGFR were identified.
- Major uEGFR mutations (G719X, L861X, S768I) showed 50% ORR and 9-month mPFS.
- Minor mutations had 31% ORR and 4-month mPFS; exon 20 insertions had 14% ORR.
- Compound mutations showed best outcomes; 58% intracranial ORR in 30 patients with brain metastases.
- Resistance mechanisms included EGFR/MET amplification, TP53 mutations, and E709K.
Conclusions:
- Osimertinib demonstrates activity in NSCLC patients with uEGFR, especially those with compound or major uEGFR mutations.
- Efficacy is observed even in the presence of brain metastases.
- EGFR alterations at the E709 residue are associated with osimertinib resistance.
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