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Rare mutations at EGFR L747 position: molecular characteristics and superior response to afatinib in NSCLC patients
1Phase I Clinical Trial Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
Background:
Little is known about the molecular characteristics and responses to different therapies in missense mutations at epidermal growth factor receptor (EGFR) L747 position (EGFR L747X) due to their low prevalence and frequent misidentification by routine PCR kit. We aimed to investigate the molecular features through next-generation sequencing (NGS) and responses in lung cancer patients with EGFR L747X.
Patients And Methods:
The distribution and molecular characteristics of EGFR L747X mutations were analyzed through NGS tests carried out in 41 369 lung cancer patients. Ba/F3 cells expressing EGFR L747P, L747S and L747V were established to evaluate the sensitivity to different EGFR tyrosine kinase inhibitors (TKIs). Binding affinity was predicted through structural modeling. Data from advanced non-small-cell lung cancer (NSCLC) patients with EGFR L747X were retrospectively collected to evaluate the clinical responses to different therapies in the real world.
Results:
EGFR mutations were detected in 17 084 patients (41.3%, 17 084/41 369), including 68 EGFR L747X (0.4%, 68/17 084). Compared with EGFR L747S and L747V, EGFR L747P tended to exist as a single EGFR mutation. In vitro models and structural analysis demonstrated enhanced sensitivity and binding affinity for afatinib compared with other TKIs. Afatinib showed stronger inhibition in EGFR phosphorylation and downstream signaling pathway in three EGFR L747X-mutant models. Clinically, afatinib-treated patients achieved significantly longer median progression-free survival (PFS) (7.0 months) versus first-generation (1G) TKIs (1.4 months, P = 0.0026) and third-generation (3G) TKIs (3.1 months, P = 0.016), with comparable efficacy to chemotherapy (9.3 months). Objective response rates (ORRs) favored afatinib (44.4%) over 1G (20%) and 3G TKIs (16.7%), while chemotherapy showed the highest ORR (63.6%).
Conclusions:
This study showed the first NGS-based research on EGFR L747X mutations, which accounted for 0.4% in EGFR-mutated NSCLC patients. EGFR L747P was found to have a different genomic profile than other EGFR L747 variants. Through this largest known treatment cohort analysis, we found that EGFR L747X mutations might exert superior sensitivity to afatinib and chemotherapies.
Insights
This study reveals that epidermal growth factor receptor (EGFR) L747X mutations, though rare in lung cancer, show increased sensitivity to afatinib. Afatinib demonstrated superior progression-free survival compared to other tyrosine kinase inhibitors for these specific EGFR mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Epidermal growth factor receptor (EGFR) L747X mutations are rare and often misidentified, limiting understanding of their molecular characteristics and treatment responses.
- Previous research has not fully elucidated the specific genomic profiles and therapeutic sensitivities of EGFR L747X mutations.
Purpose of the Study:
- To investigate the molecular features of EGFR L747X mutations using next-generation sequencing (NGS).
- To evaluate the sensitivity of EGFR L747X mutations to various EGFR tyrosine kinase inhibitors (TKIs) and chemotherapies in lung cancer patients.
Main Methods:
- Analyzed EGFR L747X mutation distribution and characteristics in 41,369 lung cancer patients via NGS.
- Established Ba/F3 cell models for EGFR L747P, L747S, and L747V to assess TKI sensitivity and binding affinity through structural modeling.
- Retrospectively collected clinical data from advanced non-small-cell lung cancer (NSCLC) patients with EGFR L747X to evaluate real-world treatment responses.
Main Results:
- EGFR L747X mutations were found in 0.4% of EGFR-mutated NSCLC patients.
- EGFR L747P mutations showed a distinct genomic profile compared to L747S and L747V.
- Afatinib demonstrated enhanced sensitivity and binding affinity in vitro and in vivo, leading to significantly longer progression-free survival (7.0 months) compared to first-generation (1.4 months) and third-generation (3.1 months) TKIs.
- Afatinib achieved an objective response rate (ORR) of 44.4%, while chemotherapy showed the highest ORR (63.6%).
Conclusions:
- This NGS-based study provides the first comprehensive analysis of EGFR L747X mutations in NSCLC.
- EGFR L747X mutations exhibit unique genomic characteristics, particularly EGFR L747P.
- EGFR L747X mutations may confer superior sensitivity to afatinib and chemotherapy, offering new therapeutic insights for this patient subgroup.
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