Clinicopathologic Characteristics, Treatment Outcomes, and Acquired Resistance Patterns of Atypical EGFR Mutations
Tejas Patil1, Rao Mushtaq1, Sydney Marsh2
1Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.
Background:
The clinicopathologic characteristics, acquired resistance patterns, and outcomes among patients with atypical EGFR mutations and HER2 alterations remain underexplored.
Patients And Methods:
A single-center retrospective review was conducted. Oncogenes assessed include typical EGFR (t-EGFR; exon 19 del and L858R), atypical EGFR (a-EGFR; G719X, exon 20, L861Q), HER2 (exon 19, exon 20, amplifications), gene fusions (ALK, ROS1, RET), RAS (KRAS, NRAS), and RAF (BRAF V600E). Progression-free survival (PFS), overall survival (OS), disease control rate, and objective response rate (Response Evaluation Criteria in Solid Tumors 1.1) were collected.
Results:
Among 570 patients, we found 55 a-EGFR mutations (13 G719X, 38 exon 20, 4 L861Q) and 31 HER2 alterations (2 exon 19 mutations, 27 exon 20 insertions, 2 amplifications). Patients with EGFR and HER2 alterations had increased lung and bone metastases relative to patients with gene fusions, RAS/RAF mutations, and no identified driver oncogenes (P < .001). Patients with EGFR exon 20 insertions had a median PFS to EGFR tyrosine kinase inhibitors (TKIs) of 5 months and an OS of 16 months-significantly worse than exon 19 del and L858R (Bonferroni correction; P < .001), but not G719X or L861Q. Relative to t-EGFR mutations, T790M and MET amplification occurred less frequently as acquired resistance mechanisms among a-EGFR samples (P < .001). Ten patients with a-EGFR mutations and HER2 alterations received single-agent immune checkpoint inhibitors (ICIs) with no radiographic responses and a median PFS of 2 months.
Conclusion:
EGFR and HER2-mutated NSCLC have a high rate of synchronous lung and bone metastases. Patients with a-EGFR mutations have inferior responses to EGFR-directed therapies with lower rates of acquired T790M and MET amplification. Responses to ICIs are uniformly poor. Novel therapeutic approaches are needed.
Insights
Patients with atypical EGFR mutations and HER2 alterations in NSCLC experience more metastases and worse outcomes with standard therapies. Novel treatments are crucial as immune checkpoint inhibitors show limited efficacy.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Atypical EGFR mutations and HER2 alterations in non-small cell lung cancer (NSCLC) are not well understood.
- Clinicopathologic features, resistance patterns, and treatment outcomes require further investigation.
Purpose of the Study:
- To investigate the characteristics, resistance mechanisms, and clinical outcomes of patients with atypical EGFR mutations and HER2 alterations.
- To compare outcomes between patients with atypical EGFR/HER2 alterations and those with typical EGFR mutations, gene fusions, or RAS/RAF mutations.
Main Methods:
- Retrospective review of 570 NSCLC patients.
- Analysis of various oncogenic drivers including typical EGFR (t-EGFR), atypical EGFR (a-EGFR), HER2, ALK, ROS1, RET, KRAS, NRAS, and BRAF V600E.
- Collection of progression-free survival (PFS), overall survival (OS), and response rates.
Main Results:
- 55 a-EGFR mutations and 31 HER2 alterations were identified.
- EGFR/HER2 alterations correlated with increased lung and bone metastases compared to other driver mutations.
- EGFR exon 20 insertions showed significantly worse PFS and OS with EGFR tyrosine kinase inhibitors (TKIs) compared to t-EGFR.
- Acquired resistance via T790M and MET amplification was less frequent in a-EGFR compared to t-EGFR.
- Immune checkpoint inhibitors (ICIs) demonstrated poor efficacy in this patient group.
Conclusions:
- EGFR and HER2-mutated NSCLC frequently present with lung and bone metastases.
- Atypical EGFR mutations are associated with poorer responses to EGFR-directed therapies and different resistance profiles.
- Current immune checkpoint inhibitor therapies show limited benefit for these patients, necessitating novel therapeutic strategies.
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