3 │ DISCUSSION
BRAF inhibitors were originally approved to treat melanomas with theBRAFV600E mutation after demonstrating improved survival in patients with unresectable or metastatic melanoma.5,13 In pediatric gliomas harboring aBRAFV600E alteration, BRAFV600E inhibitors not only produce dramatic imaging responses but also may halt or reverse tumor-induced functional impairments.4,14 Despite the promising efficacy of BRAF inhibitors in a variety of BRAF -mutant cancers, dabrafenib or vemurafenib frequently cause intolerable adverse effects, such as severe cutaneous reactions.13
A patient with vemurafenib-induced toxic epidermal necrolysis (TEN) experienced successful transition from vemurafenib to dabrafenib by slowly increasing dabrafenib over 1 week to the maximum adult dose without a return of toxicity.8 Another patient experienced a hypersensitivity reaction to vemurafenib and after 2 weeks was administered dabrafenib.9 However, the patient experienced a hypersensitivity reaction, including generalized urticaria with angioedema, within 1 hour after the second dose of dabrafenib.9 Because of PD, the patient received a desensitization protocol with escalating doses of dabrafenib, in addition to premedication prednisone and promethazine. The patient tolerated the desensitization and was able to receive full-dose dabrafenib without further adverse effects.9
Cross-reactivity between vemurafenib and dabrafenib and other sulfonamides may contribute to intolerance.5 A patient who experienced vemurafenib-induced TEN did not continue further dabrafenib treatment because a lymphocyte transformation test confirmed cross-reactivity to sulfamethoxazole, vemurafenib, and dabrafenib.5 However, in vitro and skin test studies suggest that cross-reactivity with sulfonamide-containing antibiotics and non-antibiotics is unlikely.15
Combination therapy with a MEK inhibitor, such as trametinib or cobimetinib, increase progression-free survival and overall survival by decreasing resistance and cutaneous reactions in patients with melanoma.7,16–18 Only one pediatric study has reported tolerance and response to a dabrafenib and trametinib combination therapy in a patient with previous vemurafenib intolerance.7 The patient experienced pyrexia and rigors upon treatment with dabrafenib, but these symptoms resolved by withholding therapy for 24 hours, and the patient experienced disease resolution without toxicity.7 In addition, an adult patient who experienced vemurafenib-induced TEN tolerated a gradual dose escalation of dabrafenib in combination with trametinib and corticosteroids.10 Over 17 weeks, the dose and frequency of dabrafenib were increased with daily trametinib and prednisone.10 This desensitization approach allowed successful dabrafenib transition without further cutaneous reactions.10
The patient we describe here experienced a cutaneous reaction during her first course of vemurafenib and within 3 hours of receiving a reduced dose. Radiation therapy was considered, but because of her young age and the potential for long-term neurocognitive and endocrine adverse effects, a desensitization approach with dabrafenib in addition to trametinib was pursued to prevent recurring cutaneous or more severe allergic reactions. She not only tolerated the dose escalation without antihistamines or corticosteroids but also has had no cutaneous reactions. She continues to experience a positive tumor response and improved vision.