Novel Resistance Mechanisms to Second-Generation EGFR Tyrosine Kinase Inhibitor Afatinib and Associations With
Fengwu Lin1, Miaoqing Zhao2, Qiang Wu3
1Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
Background:
Afatinib, an irreversible pan-ERBB family inhibitor, has demonstrated promising efficacy in non-small cell lung cancer (NSCLC) patients with uncommon EGFR activating mutations. However, besides the acquisition of the secondary T790M mutation, other resistance mechanisms to afatinib remain to be explored.
Materials And Methods:
This study retrospectively included 37 NSCLC patients harboring either EGFR or ERBB2 activating mutations, who had received afatinib as first-line treatment. Targeted next-generation sequencing data on the baseline and post-progression samples were subjected to analysis. Comparative analyses of clinical parameters and genomic features were performed.
Results:
Overall, the progression-free survival of the EGFR-mutated patients on first-line afatinib was longer than that of the ERBB2-positive patients (hazard ratio = 0.35 [95% confidence interval = 0.15-0.79], p = 0.008). Primary resistance was associated with the presence of exon 20 insertion mutation (p = 0.011), higher tumor mutational burden (p = 0.009), and higher proportion of APOBEC signature (p = 0.012), which were all enriched in the ERBB2-mutated cohort. We further characterized acquired resistance to afatinib and discovered that baseline EGFR exon 19 deletions and higher levels of chromosomal instability and age-related mutational signatures would contribute to the development of known resistance mechanisms such as EGFR T790M or MET amplification. We also report gaining EGFR activating mutations and losing CDKN2A, NF1, or the original ERBB2 mutations as novel resistance mechanisms to afatinib for ERBB2-mutated patients.
Conclusion:
The study identified multiple genomic characteristics associated with primary and secondary resistance to first-line afatinib treatment in EGFR- and ERBB2-positive subpopulations.
Insights
Afatinib shows efficacy in non-small cell lung cancer (NSCLC) with EGFR mutations. This study reveals genomic markers for primary and acquired resistance to afatinib in NSCLC patients, including ERBB2 mutations.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Afatinib is an irreversible pan-ERBB inhibitor effective in non-small cell lung cancer (NSCLC) with EGFR mutations.
- Mechanisms of afatinib resistance beyond T790M mutation require further investigation.
Purpose of the Study:
- To identify genomic characteristics associated with primary and acquired resistance to first-line afatinib in NSCLC patients with EGFR or ERBB2 mutations.
Main Methods:
- Retrospective analysis of 37 NSCLC patients treated with first-line afatinib.
- Targeted next-generation sequencing of baseline and post-progression samples.
- Comparative analysis of clinical and genomic features.
Main Results:
- EGFR-mutated patients had longer progression-free survival than ERBB2-positive patients.
- Primary resistance linked to ERBB2 mutations, exon 20 insertions, high tumor mutational burden, and APOBEC signature.
- Acquired resistance involves EGFR T790M, MET amplification, new EGFR mutations, and loss of tumor suppressors like CDKN2A and NF1.
Conclusions:
- Multiple genomic features predict primary and secondary resistance to afatinib in EGFR- and ERBB2-mutated NSCLC.
- Novel resistance mechanisms were identified in ERBB2-mutated NSCLC.
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