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Updated: Sep 9, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
De Novo EGFR -ALK and EGFR -ROS1 Co-Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment
Lili Shen1,2, Hongyu Deng3, Wei Liao1,2
1Department of Pathology, Chongqing University Cancer Hospital, China.
Background:
De novo epidermal growth factor receptor-anaplastic lymphoma kinase (EGFR-ALK) and EGFR-ROS proto-oncogene 1 (EGFR-ROS1) co-mutations in non-small-cell lung cancer (NSCLC), conditions traditionally considered mutually exclusive. We present the first large‑scale analysis of their clinical and genomic profiles.
Methods:
We identified 26 patients with EGFR-ALK (n = 20) or EGFR-ROS1 (n = 6) co-mutations from two institutions and compared them with cohorts of EGFR-only, ALK-only, ROS1-only, and non-co-mutated (NC) controls. Additionally, we validated findings in 66 published co-mutation cases through a literature review (2010-2023).
Results:
The co-mutation frequencies were 0.36% for EGFR-ALK and 0.11% for EGFR-ROS1. EGFR-ALKco-mutations were more commonly diagnosed at earlier stages (50.0% stage 0-II vs. 22.6% in ALK-only, p = 0.03). Patients with EGFR-ALK co-mutations were older than those with ALK-only mutations (≥ 60 years: 60.0% vs. 24.5% in ALK-only, p = 0.01), a trend validated in external pooled cases (51.9% vs. 24.5%, p = 0.01). All EGFR-ROS1cases were never-smokers and predominantly female (66.7%), a trend consistent with external pooled cases. Co-mutated tumors were enriched for EGFR exon 19 deletion (19del, 60.0% vs. 42.2% EGFR-only) and depleted for L858R. Additionally, 80.0% of EGFR-ALK cases harbored the EML4-ALKV3. Non-smokers exhibited superior overall survival (OS) in both cases (internal p = 0.002, external pooled cases p = 0.03). Among 10 advanced-stage patients with sufficient clinical follow-up, two had received dual-targeted TKI therapies. Both patients tolerated dual-targeted TKI therapies well, with one requiring dose adjustment due to initial toxicity and subsequently achieving an overall survival exceeding 51 months; however, limited sample size precludes definitive conclusions regarding efficacy.
Conclusion:
De novo co-mutations represent a distinct NSCLC subset with unique clinical and genomic features, and dual-targeted therapy shows promise as a strategy that warrants evaluation in prospective studies.
Insights
This study reveals that co-mutations in epidermal growth factor receptor-anaplastic lymphoma kinase (EGFR-ALK) and EGFR-ROS proto-oncogene 1 (EGFR-ROS1) are distinct non-small-cell lung cancer (NSCLC) subsets. Dual-targeted therapy shows promise for these rare NSCLC cases.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Epidermal growth factor receptor-anaplastic lymphoma kinase (EGFR-ALK) and EGFR-ROS proto-oncogene 1 (EGFR-ROS1) co-mutations in non-small-cell lung cancer (NSCLC) were previously considered mutually exclusive.
- This study presents the first large-scale analysis of the clinical and genomic profiles of these co-mutations.
Purpose of the Study:
- To characterize the clinical and genomic features of de novo EGFR-ALK and EGFR-ROS1 co-mutations in NSCLC.
- To compare these co-mutation profiles with EGFR-only, ALK-only, ROS1-only, and non-co-mutated NSCLC cohorts.
Main Methods:
- Identified 26 patients with EGFR-ALK (n=20) or EGFR-ROS1 (n=6) co-mutations from two institutions.
- Compared these patients with control cohorts and validated findings in 66 published co-mutation cases (2010-2023).
Main Results:
- EGFR-ALK co-mutations were diagnosed at earlier stages and in older patients compared to ALK-only mutations.
- EGFR-ROS1 co-mutations were predominantly found in never-smokers and females.
- Non-smokers with co-mutations showed superior overall survival; dual-targeted therapy was tolerated in advanced-stage patients.
Conclusions:
- De novo EGFR-ALK and EGFR-ROS1 co-mutations represent a distinct NSCLC subset with unique clinical and genomic characteristics.
- Dual-targeted therapy demonstrates potential efficacy and warrants further investigation in prospective studies for NSCLC patients with these co-mutations.
