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Selpercatinib Treatment of RET-Mutated Thyroid Cancers Is Associated With Gastrointestinal Adverse Effects
Venessa Tsang1,2, Anthony Gill2,3, Matti Gild1,2
1Department of Endocrinology, Royal North Shore Hospital, NSW 2065, Sydney, Australia.
Context:
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% to 79% objective response rate in this cohort with benefits in other tumors including lung cancer harboring the same oncogenic driver. Published reports describe only 17% of patients experiencing gastrointestinal (GI) adverse effects (AEs), which is in contrast to our local experience.
Objective:
Here we characterize the AEs and correlate them with radiological and histopathological findings.
Methods:
Sequential patients enrolled in LIBRETTO-001 at Royal North Shore Hospital, Sydney, Australia, with available imaging (n = 22) were recruited. Patients had regular visits with AEs documented and computed tomography (CT) scans every 3 months. CT at screening, at time of GI AE, and at most recent follow-up were reviewed and scored. Endoscopic examination was performed in 5 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 GI AEs. 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 edema was evident in symptomatic patients after a median time of 67 weeks' treatment. Histological correlation in 5 patients revealed mucosal edema correlating with radiological evidence of congestion and edema.
Conclusion:
GI AEs with selpercatinib may be more common than previously described. Most are self-limiting but often require dose adjustments. Histological evidence of mucosal edema observed in conjunction with the radiological findings of congestion and wall thickening suggest bowel-wall edema is a predominant mechanism of abdominal pain in these patients.
Insights
Gastrointestinal adverse effects from selpercatinib may be more common than reported, often requiring dose adjustments. Bowel-wall edema appears to be a primary cause of abdominal pain in these patients.
Area of Science:
- Oncology
- Pharmacology
- Gastroenterology
Background:
- Metastatic medullary thyroid carcinoma (MTC) and radioactive iodine-refractory differentiated thyroid carcinoma (RAI-R DTC) have limited treatment options and poor prognoses.
- Selpercatinib, a RET kinase inhibitor, shows high response rates in RET-altered tumors but published gastrointestinal adverse effect (GI AE) rates are low.
- Local clinical experience suggests a higher incidence of GI AEs with selpercatinib than previously reported.
Purpose of the Study:
- To characterize the incidence and nature of GI AEs associated with selpercatinib treatment.
- To correlate observed GI AEs with radiological and histopathological findings.
- To investigate the underlying mechanisms of selpercatinib-induced GI AEs.
Main Methods:
- A cohort of 22 sequential patients treated with selpercatinib at Royal North Shore Hospital was recruited.
- Patients underwent regular AE monitoring and computed tomography (CT) scans every 3 months.
- CT scans were reviewed, and endoscopic examinations were performed in 5 patients for histopathological correlation.
Main Results:
- Ten out of 22 patients (50%) experienced GI AEs, necessitating dose reduction in 8 patients; none discontinued therapy.
- The majority of patients (17/22) achieved stable disease.
- Radiological evidence of gastric and small-bowel edema was observed in symptomatic patients, correlating with histological findings of mucosal edema and congestion.
Conclusions:
- GI AEs associated with selpercatinib may occur more frequently than previously documented.
- While often self-limiting, these AEs commonly require dose adjustments.
- Bowel-wall edema, evidenced by radiological and histological findings, is suggested as a primary mechanism for abdominal pain in patients receiving selpercatinib.
