Actionable Genomic Alterations in Large Cell Neuroendocrine Carcinoma: A European Case Series of Patients Treated With a Small Molecule Inhibitor

PURPOSE: Actionable genomic alterations (AGA) are rare in large cell neuroendocrine carcinoma (LCNEC), and outcomes with small molecule inhibitors (SMI) are not well studied. We evaluated SMI response in LCNEC with AGAs, and also assessed molecular testing rates using the nationwide Netherlands Cancer Registry (NCR).

MATERIALS AND METHODS: In this European multicenter cohort, clinical data were collected from patients with LCNEC harboring AGAs (age 18 years and older) who were treated with an SMI. Overall survival (OS) was calculated from first-line systemic treatment to death or last follow-up. Radiologic response was evaluated for each treatment line. Molecular (AGA and retinoblastoma 1 gene [RB1]) and immunohistochemical (protein RB1 [pRb] and Ki-67) data were collected. NCR data were analyzed to determine molecular testing frequency and AGA types in stage IV LCNEC (2016-2022).

RESULTS: In total, 28 patients with LCNEC were identified. The most common AGAs were epidermal growth factor receptor mutations (35.7%) and anaplastic lymphoma kinase fusions (32.1%). Median OS was 14.6 months (95% CI, 11 to 32). Across 38 SMI treatment lines, partial response was observed in 19 (50%). A trend toward longer survival was seen in patients with functional RB1 versus inactivated RB1 (hazard ratio, 0.32 [95% CI, 0.12 to 1.03]; P = .057). Within the NCR, molecular testing was conducted in 498/927 (53.7%) patients with stage IV LCNEC in the Netherlands, with AGAs detected in 111/498 (22.3%).

CONCLUSION: In our series, patients with LCNEC harboring AGAs who are treated with SMIs achieved a response in 50% of cases, including durable responses. However, only half of the patients with LCNEC are screened for AGAs. These findings highlight the need for standardized testing for AGAs in LCNEC.