Selpercatinib and Pralsetinib Induced Chylous Ascites in RET-Rearranged Lung Adenocarcinoma: A Case Series

Lung cancer is the leading cause of cancer-related death in both men and women with over 130,000 deaths and more than 220,000 new cases expected each year in the United States 1 Siegel RL Miller KD Wagle NS Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023; 73: 17-48 Crossref PubMed Scopus (695) Google Scholar . Eighty to ninety percent of newly diagnosed cases are Non-Small Cell Lung Cancer (NSCLC) with 50% of those being histologically adenocarcinoma 2 Servetto A Esposito D Ferrara R et al. RET rearrangements in non-small cell lung cancer: Evolving treatment landscape and future challenges. Biochim Biophys Acta Rev Cancer. 2022; 1877188810 Crossref PubMed Scopus (1) Google Scholar . Rearranged during Transfection (RET), a proto-oncogene coding for a tyrosine kinase receptor, was discovered in NSCLC in 2012 as on oncogenic driver 3 Gainor JF Shaw AT. The new kid on the block: RET in lung cancer. Cancer Discov. 2013; 3: 604-606 Crossref PubMed Scopus (0) Google Scholar , 4 Roosan MR Mambetsariev I Pharaon R et al. Evaluation of Somatic Mutations in Solid Metastatic Pan-Cancer Patients. Cancers (Basel). 2021; : 13 PubMed Google Scholar . RET fusion /rearrangement occurs 2 % of lung adenocarcinomas with most patients being never smokers and a median age of 61 years 5 Kohno T Tsuta K Tsuchihara K Nakaoku T Yoh K Goto K. RET fusion gene: translation to personalized lung cancer therapy. Cancer Sci. 2013; 104: 1396-1400 Crossref PubMed Scopus (100) Google Scholar , 6 Gautschi O Milia J Filleron T et al. Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global. Multicenter RET Registry. 2017; 35: 1403-1410 Google Scholar . Tyrosine kinase inhibitors (TKI) with anti-RET activity have been effective for RET fusion-positive NSCLC treatment, and in 2020, the FDA approved two potent RET inhibitors, i.e., selpercatinib and pralsetinib 7 Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer. 2020;383:813-824. Google Scholar , 8 Gainor JF Curigliano G Kim DW et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021; 22: 959-969 Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar . Since RET-rearranged NSCLC therapy became a standard approach, there have been recent reports indicating that chylous ascites (CA) can be a rare adverse effect of RET tyrosine kinase inhibitor (TKI) treatment. Specifically, in patients receiving selpercatinib, CA was observed in approximately 7% of cases, while no occurrences were reported with pralsetinib 9 Kalchiem-Dekel O Falcon CJ Bestvina CM et al. Brief Report: Chylothorax and Chylous Ascites During RET Tyrosine Kinase Inhibitor Therapy. J Thorac Oncol. 2022; 17: 1130-1136 Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar , 10 Prete A Gambale C Cappagli V et al. Chylous effusions in advanced medullary thyroid cancer patients treated with selpercatinib. Eur J Endocrinol. 2022; 187: 905-915 Crossref PubMed Scopus (0) Google Scholar . Interestingly, it has been reported in medullary thyroid cancer patients on selpercatinib as well and no cases have been reported with pralsetinib 10 Prete A Gambale C Cappagli V et al. Chylous effusions in advanced medullary thyroid cancer patients treated with selpercatinib. Eur J Endocrinol. 2022; 187: 905-915 Crossref PubMed Scopus (0) Google Scholar . In this report, we present the cases of two patients who experienced chylous ascites (CA) while undergoing treatment with RET tyrosine kinase inhibitors (TKIs). One patient was receiving selpercatinib, and the other represents the first reported case of CA associated with pralsetinib. Additionally, we delve into the discussion regarding the management of chylous ascites in the context of RET TKI therapy.