FDA Grants Breakthrough Therapy Designation to Cobimetinib for MEK Inhibition in Histiocytic Neoplasms, Research Led by MSK


Bottom Line:

Memorial Sloan Kettering Cancer Center (MSK) announced today that the US Food and Drug Administration (FDA) has granted a Breakthrough Therapy Designation to cobimetinib in treatment of patients with histiocytic neoplasms (HN) (Erdheim-Chester Disease, Rosai-Dorfman, Langerhans Histiocytosis), who do not harbor the BRAF V600 mutation. Cobimetinib is an oral inhibitor of MEK1 and MEK2 currently approved to treat melanoma. This designation was granted based on data submitted by MSK, in collaboration with Genentech, a member of the Roche Group, from a phase II trial of single-agent cobimetinib for adults with histiocytic disorders (published in Nature in March 2019 by Eli Diamond, MD; Omar Abdel-Wahab, MD; and David Hyman, MD).


Histiocytosis is a family of blood diseases that affect both adults and children. These rare diseases are diagnosed in a few hundred people in the United States every year. The available treatment options for most adults with HN are limited, inconsistent in their therapeutic response, based primarily on anecdotal case reports, and associated with poor long-term tolerance.

Approximately 50 percent of people with histiocytosis have BRAF V600 mutations. For these people, BRAF inhibition with vemurafenib is highly efficacious and is the only FDA-approved treatment for histiocytosis. However, once those patients progress during or after treatment with vemurafenib, or if vemurafenib cannot be adequately tolerated, there are no FDA-approved treatments. Moreover, no standard therapy exists for the remaining 50 percent of patients who lack BRAF V600 mutations or for patients with BRAF V600 mutations and histiocytic disorders other than Erdheim-Chester disease.

Research and Findings:

Following the success of targeting BRAF V600 in two HNs, researchers have attempted to identify potential genomic drivers of disease in patients who do not posses this mutation. Consistent with the underlying hypothesis that non-BRAF V600 mutations are likely to drive HN, drugs that inhibit both the MEK1 and MEK2 kinases have previously been shown in case reports to evoke responses in patients with non-BRAF V600 mutations.

MSK researchers enrolled and treated 18 people in a phase II study of cobimetinib in adults with histiocytosis of any mutational status. The overall response rate was 89 percent. At one year, 100 percent of responses were ongoing, and 94 percent of patients remained progression free. Responses to cobimetinib were observed across histiocytosis subtypes and tumor genotypes. In this study, the selective inhibitor of MEK1 and MEK2 cobimetinib had marked and durable activity in adults with HN. These findings suggest that HN may lack the ability to adapt to MEK1 and MEK2 inhibition.

Expert Comments:

“Through a phase II trial, we were previously able to show that treatment with cobimetinib results in consistent and durable responses across clinical and genetic subtypes of HNs, which represents an area of previously unmet need for these patients,” explained Dr. Diamond, neuro-oncologist and neurologist at MSK. “We’ve recently seen great advances in the treatment of histiocytosis, with the first approval just two years ago. This designation will ensure that we are continuing on a path that may ultimately offer a viable treatment option for all histiocytosis patients.”

“This critical designation will allow patients access to this targeted treatment while it continues through the review process with the FDA,” said Dr. Hyman, Chief of the Early Drug Development Service at MSK.