Hypercalcaemia associated with Tovorafenib discontinuation in three paediatric patients

<h2>Abstract</h2><h3>Background</h3> We present three patients who developed symptomatic hypercalcaemia following discontinuation of the Type II RAF inhibitor, Tovorafenib. <h3>Methods</h3> We report three paediatric cases who had been enrolled in the phase 2 FIREFLY-1 (PNOC026; NCT04775485)l[1], which was investigating the safety and efficacy of Tovorafenib monotherapy in patients with relapsed or refractory paediatric low-grade glioma (pLGG) harbouring a KIAA-BRAF-fusion or BRAF V600E mutation. Hypercalcaemia was detected within weeks after discontinuation of Tovorafenib. <h3>Results</h3> Adjusted serum calcium concentrations at first presentation were 2.91mmol/L at 21 days (Patient 1), 3.06mmol/L at 14 days (Patient 2), and 3.58mmol/L at 26 days (Patient 3) following cessation of Tovorafenib. Calcium concentrations normalised following treatment with additional fluid and, in two of the patients, a single dose of bisphosphonate. <h3>Conclusion</h3> We suspect that the hypercalcaemia reflects a rebound increase in bone turnover following Tovorafenib discontinuation and recommend that monitoring bone biochemistry after treatment cessation be considered as part of management protocols.