Selpercatinib treatment of RET mutated thyroid cancers is associated with gastrointestinal adverse effects

<strong>Background:</strong> Metastatic medullary thyroid carcinoma (MTC) and radioactive iodine refractory differentiated thyroid carcinoma (RAI-R DTC) have poor prognosis and limited treatment options. Selpercatinib (LOXO-292), a selective kinase inhibitor targeting the <em>RET</em> gene, has shown a 69-79% objective responses have been observed in this cohort (1) with benefits in other tumours harbouring the same oncogenic driver (2). Published reports describe only 17% of patients experiencing gastrointestinal Adverse effects (AE) which is in contrast to our local experience. Here we characterise the AE and correlate with radiological and histopathological findings. <strong>Methods:</strong> Sequential patients enrolled in LIBRETTO-001 at Royal North Shore Hospital, Sydney with available imaging (n=22) were recruited. Patients had regular visits with AE documented and CT scans 3 monthly. CT at screening, at time of gastrointestinal AE and at most recent follow up were reviewed and scored. Endoscopic examination was performed in five patients. <strong>Results:</strong> Of 22 patients in this cohort, the majority had somatic <em>RET </em>alterations (n=18), most commonly <em>p.Met918Thr</em> (n=14). Ten patients (50%) developed gastrointestinal adverse effects. Dose reduction was required in 8 of the 10 patients, but none discontinued therapy. The majority had stable disease (n=17). Gastric and small bowel oedema was evident in symptomatic patients after a median time of 67 weeks’ treatment. Histological correlation in five patients revealed mucosal oedema correlating with radiological evidence of congestion and oedema. <strong>Discussion: </strong> Gastrointestinal AEs with selpercatinib may be more common than previously described. Most are self-limiting but often require dose adjustments. Histological evidence of mucosal oedema observed in conjunction with the radiological findings of congestion and wall thickening suggest that bowel wall oedema is a predominant mechanism of abdominal pain in these patients.