Results from a proof-of-concept clinical trial of single-agent therapy with the MEK1/2 inhibitor, cobimetinib, in patients with histiocytic neoplasms showed a very high rate of durable responses to treatment. The findings from this study were published online in Nature.

Histiocytic neoplasms, such as Erdheim-Chester disease, Rosai-Dorfman disease, and Langerhans cell histiocytosis, represent a diverse group of cancers arising from aberrant hematopoietic progenitor cells. A common feature of histiocytic neoplasms is one or more mutations in the mitogen-activated protein kinase (MAPK) pathway.  

While BRAF inhibitors have been shown to be very effective in the approximately 50% of patients with disease characterized by a BRAFV600 mutation, no standard treatment currently exists for those with disease not characterized by this genetic aberration.

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This study enrolled 18 patients with a variety of histiocytic neoplasms characterized by refractory or multiorgan disease, the majority (67%) of whom had Erdheim-Chester disease. The median age of these patients was 51.9 years. While all patients had disease characterized by at least 1 mutation in the MAPK pathway, these mutations were heterogeneous and included alterations in BRAF, MEK1, MEK2, ARAF, RAF1, KRAS, or NRAS. The primary end point of the study was overall response rate (ORR) to cobimetinib as assessed by fluorodeoxyglucose positron emission tomography (PET) imaging.

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Despite the fact that 28%, 56%, and 50% of patients enrolled in the study had an Eastern Oncology Cooperative Group performance score of 2 or higher, had previously received at least 2 lines of systemic therapy, and had disease characterized by CNS involvement, respectively, the ORR was 89%, with 72% of patients experiencing a complete response (CR) following treatment with cobimetinib.

Remarkably, at 1 year, 100% of responses were ongoing, and 94% of patients did not experience disease progression.

The median time to best response was 3.2 months. After a median follow-up of 11.9 months, the median duration of response and median progression-free survival had not been reached.

Treatment-related adverse events included rash (83%) and diarrhea (61%), although grade 3 or higher treatment-related adverse events were uncommon. Fifty-six percent of patients underwent at least 1 dose reduction of cobimetinib, although best response was subsequently maintained.

“Importantly, responses to cobimetinib were not only nearly universal but also durable; in fact, no acquired resistance has been observed to date. This finding suggests that

histiocytic neoplasms may lack the ability to adapt to tonic MEK1 and MEK2 inhibition, and that cobimetinib may markedly alter the natural history of these disorders,” the study authors noted in conclusion.

Disclosure: The authors disclosed various financial ties to the pharmaceutical industry and health institutions. For a full list of disclosures, please refer to the original study.


  1. Diamond EL, Durham BH, Ulaner GA, et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms [published online March 13, 2019]. Nature. doi: 10.1038/s41586-019-1012-y