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

Background:

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 RET 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. 

Methods:

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.

Results:

Of 22 patients in this cohort, the majority had somatic RET alterations (n=18), most commonly p.Met918Thr (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.

Discussion:

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.