Background: Identifying molecular alterations in thyroid cancer has led to successful targeted therapies particularly in RET (REarranged during Transfection) altered cancers. Medullary and differentiated thyroid cancer can harbor RET alterations upregulating intracellular oncogenic pathways, including RAS/RAF/ERK and P13-kinase/AKT pathways. In Phase II studies, selpercatinib, a novel selective RET inhibitor has shown objective responses of >70% and its appeal lies in its efficacy, but also its tolerable adverse effect profile compared with other MKIs. Gastrointestinal SE have not yet been reported in these patients.
Methods: Clinical data from 20 patients enrolled in a selpercatinib clinical trial at Royal North Shore Hospital were retrospectively reviewed. CT scans as per protocol were analysed by radiologists for signs of oedema and scored for inflammation.
Results: 10/20 (50%) of patients reported gastrointestinal adverse effects. The most common symptoms were changes in bowel habits (n=8), abdominal swelling (n-7), abdominal discomfort (n=7), anorexia and nausea. Weight changes were also observed and dose reductions occured in 40% of patients. Endoscopy and biospies were performed in 4 patients. Histopathology demonstrated mild non-specific mucosal oedema characterised by myxoid change in the lamina propria of the stomach and subtle accumulation of oedema fluid in the tips of the duodenal villi and submucosa. There was no histological evidence of inflammation and no increase in intra-epithelial lymphocytes.
Conclusion: We describe the clinical and histopathological presentation of a novel adverse effect of selepercatinib seen in a significant proportion of patients. This previously unreported adverse effect necessitated dose reductions. CT changes can be correlated with onset of symptoms. The presence of mucosal oedema observed histologically in conjunction with the radiological findings of congestion suggest that bowel wall oedema may be a mechanism of abdominal pain in these patients.