Targeted therapies in thoracic neuroendocrine tumors: challenges and failures of tyrosine kinase inhibition in lung and thymic carcinoids.

Abstract

Lung (LCs) and thymic carcinoids (ThCs) belong to thoracic well-differentiated neuroendocrine tumors (NETs), whose therapeutic options for advanced stages are limited. In the era of precision medicine, tyrosine kinase inhibitors (TKIs) remain a key focus of clinical investigation. This review evaluates the evolving role of TKIs in this setting. This critical review analyzes the clinical evidence from pivotal trials regarding FDA/EMA-approved TKIs and those in advanced phases of clinical investigation for thoracic NETs, including combination strategies and tumor microenvironment modulators. Despite regulatory approvals (<i>e.g</i>. cabozantinib in 2025), TKI development faces ongoing challenges in balancing incremental efficacy with significant toxicity concerns. While some agents significantly improve progression-free survival, these gains are often overshadowed by high rates of grade 3-4 adverse events and treatment-related mortality. Consequently, alternative strategies with more manageable safety profiles are emerging. While an unfavorable benefit-to-toxicity ratio has hindered late-phase clinical trials, the persistent discrepancy in TKI performance across different malignancies suggests a developmental plateau in the NEN setting. Future research must shift toward multiomic profiling and the identification of novel actionable targets to prioritize personalized, better-tolerated therapies that balance clinical outcomes with quality of life.