Vemurafenib in Patients with Erdheim-Chester Disease (ECD) and Langerhans Cell Histiocytosis (LCH) Harboring BRAF^V600 Mutations: A Cohort of the Histology-Independent VE-Basket Study

Background: ECD and LCH are rare disorders for which no approved therapies are available. BRAF^V600E mutations have been observed in 50% of patients with LCH and in 50-60% of patients with ECD. Here we present data from a planned Week 16 analysis of patients with ECD/LCH who were enrolled in the VE-BASKET study (ClinicalTrials.gov identifier NCT01524978).

Methods: This open-label, Simon 2-stage adaptive-design, phase 2 study included patients with BRAF^V600E-mutant ECD and LCH. Patients received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed response rate at Week 8; secondary endpoints included best overall response rate, clinical benefit rate, progression-free survival (PFS), and overall survival (OS). For a subset of patients (n=15), metabolic response by ¹⁸F-FDG-PET was assessed; five target lesions were selected and their maximal standardized uptake value (SUV_max), normalized for body weight (BW), was compared with background (liver) SUV. Data cut-off was 2 October 2015.

Results: 26 patients (22 with ECD and 4 with LCH; median age 61y) were enrolled. Seven patients (27%) had one prior therapy, six (23%) had two prior therapies, four (15%) had ≥3 prior therapies, and nine (35%) had no prior systemic therapy. Six patients were in follow-up at data cut-off; 16 were on treatment.

Best overall response (according to RECIST v1.1) in 25 patients with measurable disease at baseline was 60% (95% CI 38.7-78.9%) with complete response (CR) in two patients (8%) and partial response (PR) in 13 patients (52%) (Figure). Responses were seen in patients with ECD (1 CR, 10 PRs) and LCH (1 CR, 3 PRs). After a median treatment exposure of 14.2 months (range 4.2-22.5 months), median OS and PFS have not been reached.

All of the 15 patients assessed by ¹⁸F-FDG-PET showed a response: 12 patients had a complete metabolic response (normalization of all lesions' SUV_max-BW to background SUV) and three had a partial metabolic response (>50% decrease in sum of baseline SUV_max of all target lesions) (Figure).

Overall, safety data were consistent with prior studies of vemurafenib. Arthralgia (n=17; 65%), fatigue (n=15; 58%), rash macropapular (n=14; 54%), alopecia (n=14; 54%), skin papilloma (n=14; 54%), prolonged QT (n=12; 46%), and palmar-plantar erythrodysesthesia syndrome (n=12; 46%) were the most common all-grade adverse events (AEs). Seventeen patients had serious AEs, including 10 with squamous cell carcinoma of the skin. Seven patients discontinued vemurafenib due to AEs.

Conclusion: These data, which represent the only prospective clinical trial data of BRAF inhibition in histiocytosis to date, reveal that vemurafenib has potent single-agent activity in patients with ECD/LCH. Moreover, vemurafenib treatment had remarkable durability of response in histiocytosis, such that no evidence of resistance has been encountered following a median of 14.2 months of treatment. These results are distinct from vemurafenib use in other solid or hematologic malignancies.

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