EGFR-V834L combined with L858R mutation reduced afatinib sensitivity and associated to early recurrence in lung
Nanao Terada1, Hayato Koba1, Shigeki Nanjo1
1Department of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan.
Background:
The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is widely used as a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC). However, there is no established treatment for osimertinib resistance, so second-generation afatinib is an alternative treatment option. The purpose of this study was to elucidate gene alterations associated with afatinib efficacy and resistance by analyzing cell-free DNA (cfDNA) obtained from patients with EGFR-mutated NSCLC.
Methods:
This study was conducted as a prospective clinical trial in patients with EGFR-mutated NSCLC at multiple institutions. We analyzed plasma cfDNA from the patients treated with afatinib as the first-line therapy.
Results:
Paired specimens were obtained before and at the time of resistance to afatinib treatment, and specimens only at afatinib resistance were obtained from 22 and 18 patients, respectively. In plasma cfDNA from the 22 cases, driver EGFR mutations were detected in 13 cases (59.1%), and the compound V834L mutation was detected in two cases in cis with EGFR-L858R mutation. The median progression-free survival (mPFS) was remarkably shorter in patients with V834L than in all 22 cases (4.2 vs. 9.2 months). Moreover, we detected V834L and T790M combined with EGFR-L858R in the cfDNA from one patient resistant to afatinib. Preclinical experiments using EGFR-L858R, with or without V834L, in Ba/F3 cells revealed that V834L with L858R conferred resistance to low concentrations of EGFR-TKIs, including afatinib and osimertinib. In three cases of EGFR-L858R+V834L, other co-mutations, including TP53, CTNNB1, and RB1, were detected either before or after afatinib resistance.
Conclusions:
These results suggested that V834L cooperates with other coexisting mutations to influence the therapeutic efficacy of EGFR-TKIs.
Insights
The V834L mutation in epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) is linked to resistance against afatinib treatment. This mutation, often co-occurring with others, impacts EGFR-tyrosine kinase inhibitor efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is a standard first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC).
- Established treatments for osimertinib resistance are lacking, making second-generation afatinib a potential alternative therapy.
- Understanding gene alterations associated with afatinib efficacy and resistance is crucial for optimizing NSCLC treatment strategies.
Purpose of the Study:
- To identify gene alterations influencing afatinib efficacy in patients with EGFR-mutated NSCLC.
- To elucidate the mechanisms of resistance to afatinib treatment.
- To analyze cell-free DNA (cfDNA) for genetic markers associated with treatment response and resistance.
Main Methods:
- A prospective clinical trial involving patients with EGFR-mutated NSCLC treated with afatinib as first-line therapy.
- Analysis of plasma cfDNA collected before and at the time of afatinib resistance.
- Preclinical experiments using engineered cell lines to validate the functional impact of identified mutations.
Main Results:
- Driver EGFR mutations were detected in 59.1% of cfDNA samples from patients treated with afatinib.
- The compound V834L mutation, in cis with EGFR-L858R, was identified in two patients and was associated with significantly shorter progression-free survival (4.2 vs. 9.2 months).
- V834L, alone or in combination with T790M or other co-mutations (TP53, CTNNB1, RB1), conferred resistance to afatinib and osimertinib in preclinical models.
Conclusions:
- The V834L mutation is a key genetic alteration associated with afatinib resistance in EGFR-mutated NSCLC.
- V834L cooperates with other coexisting mutations to influence the therapeutic efficacy of EGFR-TKIs.
- Identification of V834L and associated co-mutations may guide future treatment decisions for NSCLC patients.
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