De Novo EGFR -ALK and EGFR -ROS1 Co-Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective Analysis.

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.