Background: Use of BRAF inhibitors in BRAFV600 mutant Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) leads to near universal and prolonged response and has transformed the management of these disorders. However, nearly 50% of histiocytosis patients lack a BRAFV600-mutation and therefore cannot receive BRAF inhibitors creating an ongoing need for new therapies in histiocytosis. Comprehensive profiling of these BRAFV600 wildtype (BRAF-wt) ECD/LCH patients has demonstrated that nearly all harbor mutations activating the Mitogen Activated Protein Kinase (MAPK) pathway. This finding raised the possibility of treatment of BRAF-wt histiocytosis with MEK1/2 inhibition. Here we present data on 11 patients with histiocytosis treated with single-agent of the MEK1/2 inhibitor Cobimetinib (Clinicaltrials.gov, NCT02649972).

Methods: This is an open-label phase 2 trial of Cobimetinib 60mg daily for patients with (1) BRAF-wt histiocytosis or (2) BRAFV600-mutant histiocytosis intolerant or without access to BRAF inhibitor therapy. The primary outcome is metabolic response by 18F-FDG PET scan. Maximal FDG standardized uptake value (SUV) was observed in up to 5 target lesions, normalized for body weight; this was compared between baseline and subsequent scans. Secondary endpoints included progression-free survival (PFS) as determined by 18F-FDG PET scan, overall survival (OS), and patient-centered outcomes measuring disease-related symptoms (with a disease-specific symptom scale), symptoms of systemic inflammation (Sickness Behavior Inventory; SBI), and psychological states (Hospital Anxiety and Depression Scale). Based on prior data identifying systemic immune perturbation in the sera of histiocytosis patients, we quantitatively analyzed 40 cytokines, chemokines, and growth factors in serial sera of the patients in this trial. Data cut-off was June 22, 2017.

Results: 11 patients (8 ECD, 1 Rosai-Dorfman disease [RDD], 1 mixed ECD/RDD, 1 LCH) have enrolled with a median age of 53. Eight patients have BRAF-wt disease, the remainder are BRAFV600-mutant positive. Ten patients have had response assessments at the time of data cut-off. The response rate was 90% (9/10), with 40% (4 patients) having a complete metabolic response (resolution of FDG avidity to organ background), 50% (5 patients) a partial metabolic response (50% or greater reduction in FDG avidity), and 10% (one patient) stable metabolic disease (Figure A-B). No patient has developed progressive disease. Mean symptom severity (scored 0-50) decreased by 31% (mean score 38 to 27) after 4 cycles of treatment for 9 patients with longitudinal assessment. 8 of these 9 patients with either anxiety or depression at baseline, and 4 had neither after 4 cycles of treatment. Mean SBI (scored 0-36) decreased 39% (mean score 22 to 13) in 5 patients with longitudinal assessment (Figure C). Cytokine analysis identified dramatic effects of Cobimetinib upon reducing IL-8, TNF-alpha, and MIP1b levels (amongst other cytokines) as well as coordinate increase in eotaxin and Flt3-L levels (Figure D). One patient died on study from Grade 5 respiratory failure, unrelated to drug, and one patient was removed from study due to drug toxicity (Grade 3 retinal vein occlusion). Grade 3/4 toxicities have been decreased lymphocyte count (23%), hyponatremia (23%), increased lipase (15%), diarrhea (8%), and hypocalcemia (8%).

Conclusions: This trial demonstrates robust efficacy of single-agent MEK1/2 inhibition with Cobimetinib in histiocytic disorders, across both BRAF-wt and BRAFV600-mutant patients, measured by radiologic as well as patient-centered outcomes. Toxicities have been manageable and largely similar to those observed in previous trials of Cobimetinib. These data extend the spectrum of patients eligible to be treated with therapies targeting the activating somatic MAPK alterations driving histiocytoses.


Dogan: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Consultancy; Peer Review Institute: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.