Impacts of co-mutations in oligometastatic and oligoprogressive non-small cell lung cancer with EGFR/ALK mutations—a narrative review of the current literature

Background and Objective: Non-small cell lung cancer (NSCLC) remains one of the primary causes of cancer mortality globally, with an increasing focus on advanced targeted therapies. Despite these advancements, oligometastatic NSCLC, particularly cases with actionable mutations such as those in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), presents unique therapeutic challenges and opportunities for improved outcomes. Recent studies indicate that consolidative local ablative therapies (LAT) such as stereotactic body radiation therapy (SBRT) combined with tyrosine kinase inhibitors (TKIs) may enhance progression-free and overall survival for patients with oligometastatic NSCLC harboring these mutations. This narrative review aims to summarize current evidence on the clinical impact of co-mutations in EGFR/ALK-positive oligometastatic NSCLC. Methods: The relevant literature was identified by using PubMed and ClinicalTrials.gov (last search phase November 2024) and was restricted to English language. Peer-reviewed manuscripts but also conference abstracts that did not undergo peer-review were included. Key Content and Findings: Co-mutations complicate treatment by potentially influencing radiosensitivity and resistance to systemic therapies. This review discusses current findings on co-mutations in EGFR/ALK-positive oligometastatic NSCLC, examining their impact on LAT and systemic treatment outcomes, with a particular focus on synchronous and oligoprogressive disease states. Moreover, emerging biomarkers such as circulating tumor DNA may guide therapeutic strategies and optimize personalized treatment plans. Conclusions: As clinical trials continue to investigate combinative and sequential LAT-TKI strategies, understanding the genomic landscape of co-mutations in oligometastatic NSCLC is important for refining treatment approaches and enhancing long-term survival.