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.