Chylopericardium and chylous effusions during treatment with selective RET inhibitors, selpercatinib and pralsetinib, in non-small cell lung cancer (NSCLC).

Abstract

e20694 Background: Selective RET tyrosine kinase inhibitors (RETi) revolutionized the treatment of patients (pts) with advanced NSCLC harboring RET fusions and is broadly considered first-line standard of care treatment. Chylous effusions have emerged as a RETi-associated adverse event (AE) and are challenging to distinguish from disease progression. Given the rarity of this AE, a greater appreciation of incidence is needed. Methods: The Genomic Marker-guided Therapy Initiative (GEMINI) database at MD Anderson Cancer Center was used to identify patients with RET fusion-positive NSCLC between 2011 and 2024. Pts were included in chylous effusion incidence analyses if they received at least one month of treatment and had a confirmed diagnosis of chylous effusion, based on both radiographic imaging and body fluids sampling, requiring medical intervention. We defined the time to chylous effusion diagnosis as the interval between the treatment start date and the chylous effusion collection date. This study protocol was approved by the MD Anderson Institutional Review Board. Results: We identified 103 pts with RET fusion-positive NSCLC, of whom 73 received a RETi. Among these, we identified 12% of pts (n=9) who developed a chylous effusion: 14% (n= 7 of 51) and 13% (n= 2 of 15) were treated with selpercatinib or pralsetinib, respectively. Additionally, 7 pts received both RETi, and none of them developed a chylous effusion. Among pts who developed a chylous effusion, the mean age was 64 years old, 88% were White, and all pts had either never-smoking or light-smoking (≤ 10 pack-years) tobacco histories. Eight of nine pts had adenocarcinoma histology, and of the 9 pts fully characterized fusions, KIF5B was the predominant RET fusion partner (n= 5). Of the nine pts with chylous effusions, two had chylopericardium, two had chylous ascites, one had chylothorax and four had both chylous ascites and chylothorax. Triglyceride levels across pts ranged from 478mg/dl to >5200mg/dl. The mean time from RETi initiation to chylous effusion diagnosis was 17 months (range: 1 to 60 months). All pts underwent fluid drainage for symptom relief, 2 of 10 successfully underwent lymphangiography and embolization of the chylous leak, and one patient was successfully treated with pleurodesis. Additionally, 3 of 9 pts required a RETi dose reduction, which one had improvement and two had no effect on the effusion. One patient switched from selpercatinib to pralsertinib which did not affect the effusion. No cases of drug discontinuation due to these AEs were reported. Conclusions: We identified chylous effusion as an AE following RETi exposure in 12% of pts in our cohort, including 2 cases of chylopericardium. These adverse events can occur with either selpercatinib or pralsetinib, and making a differential diagnosis, including ruling out disease progression, is crucial for effective management.