Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder primarily affecting children. BRAF mutations have been reported in >50% of patients with LCH. The selective BRAF inhibitor, dabrafenib, in combination with the MEK1/2 inhibitor, trametinib, has been approved in select BRAF V600-mutant solid tumors. Two open-label phase 1/2 studies were conducted in pediatric patients with BRAF V600-mutant, recurrent/refractory malignancies treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). The primary objectives of both studies were to determine safe and tolerable doses that achieve similar exposure to the approved doses for adults. Secondary objectives included safety, tolerability, and preliminary antitumor activity. Thirteen and 12 patients with BRAF V600-mutant LCH received dabrafenib monotherapy and in combination with trametinib, respectively. Investigator-assessed objective response rates per Histiocyte Society criteria were 76.9% (95% confidence interval [CI], 46.2-95.0) and 58.3% (95% CI, 27.7-84.8) in the monotherapy and combination studies, respectively. More than 90% of responses were ongoing at study completion. The most common treatment-related adverse events (AEs) were vomiting and increased blood creatinine with monotherapy and pyrexia, diarrhea, dry skin, decreased neutrophil count, and vomiting with combination therapy. Two patients each discontinued treatment with monotherapy and combination therapy because of AEs. Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600-mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib.

Graphical abstract

Figure 1.

Duration of exposure to study treatment and best overall response (investigator assessment) among patients with BRAF V600–mutant LCH. Duration of exposure to dabrafenib monotherapy (A) or dabrafenib plus trametinib (B) in pediatric patients with BRAF V600–mutant LCH; best overall response per investigator assessment using the Histiocyte Society response assessment guidelines. Categories of nonactive disease include CR, which indicates resolution of all disease signs or symptoms (no evidence of disease), and regressive disease, which indicates regressions of disease signs and symptoms with no new lesions. Categories of persistent active disease include SD, which indicates the persistence of signs and symptoms but no new lesions, and progressive disease, which indicates the progression of signs or symptoms and/or the appearance of new lesions. ^aindicates patients who have continued therapy on a rollover study, and ^bindicates that 2 patients did not have any postbaseline assessment because of early discontinuation and were considered to be nonresponders. REG, regressive disease.

Figure 2.

Kaplan-Meier plots for PFS, per investigator assessment, for patients with BRAF V600–mutant LCH receiving dabrafenib monotherapy or dabrafenib plus trametinib. Kaplan-Meier plots showing PFS based on investigator assessment among pediatric patients with BRAF V600–mutant LCH treated with dabrafenib monotherapy (A) or dabrafenib plus trametinib (B).