Cobimetinib Granted FDA Breakthrough Therapy Designation for Histiocytic Neoplasms


The FDA has granted cobimetinib, a MEK inhibitor, with a breakthrough therapy designation for the treatment of adult patients with histiocytic neoplasms who do not harbor a <em>BRAF</em> V600 mutation.

Eli L. Diamond, MD

Eli L. Diamond, MD

Eli L. Diamond, MD

The FDA has granted cobimetinib (Cotellic), a MEK inhibitor, with a breakthrough therapy designation for the treatment of adult patients with histiocytic neoplasms who do not harbor aBRAFV600 mutation.1

The breakthrough designation was granted as a result of positive findings from the phase II trial of single-agent cobimetinib&nbsp;for adults with histiocytic disorders (NCT02649972).

&ldquo;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 histiocytic neoplasms, which represents an area of previously unmet need for these patients,&rdquo; stated study author Eli L. Diamond, MD, neuro-oncologist/neurologist, Memorial Sloan Kettering Cancer Center, in a statement.

The study enrolled 18 patients who had a histiocytic neoplasm, regardless of tumor genotype. Those withBRAFV600 mutations were eligible only if they intolerance or resistance to prior BRAF-targeted therapy or could not access BRAF inhibitor therapy. Patients received cobimetinib starting at 60 mg daily for 21 days of each 28-day cycle.

The primary endpoint for the study was overall response rate (ORR) by fluorodeoxyglucose PET, as assessed by a radiologist. The secondary endpoints were duration of response and progression-free survival (PFS) by PET as well as safety and ORR by RECIST v1.1 criteria.2

Results showed an ORR of 89% (90% CI, 73%-100%) by PET, consisting of complete responses in 13 patients and partial responses in 3 patients. By RECIST criteria, the ORR was 64% (90% CI, 44%-100%) with 2 complete responses and 7 partial responses.

Patients did not develop resistance to treatment, and responses were durable with 100% of patients still showing responses at 1-year follow-up. Additionally, the PFS rate at 1 year was 94%.

Neither the median duration of response nor the median progression-free survival had been reached after a median of 11.9 months (range, 1.6-23.7) of follow-up.

Patients with a variety of MAPK pathway mutations were treated, includingARAF,BRAF,RAF1,NRAS,KRAS,MEK1, andMEK2. Treatment with cobimetinib was effective regardless of mutational status.

The most common adverse events (AEs) of any grade observed in the trial were rash (83%), diarrhea (72%), creatine phosphokinase elevation (61%), hypomagnesemia (56%), alkaline phosphatase increase (50%), AST/ALT increase (44%), nausea (39%), and anemia (33%).

The study investigators believe that these trial data show that histiocytic neoplasms are unable to adapt to MEK1 and MEK2 inhibition.

&ldquo;This critical designation will allow patients access to this targeted treatment while it continues through the review process with the FDA,&rdquo; said study author David Hyman, MD, chief, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, in a statement.

Cobimetinib previously received FDA approval in combination with the BRAF kinase inhibitor vemurafenib (Zelboraf) for the treatment of patients withBRAF-positive melanoma.3The approval was based on the results of the phase III coBRIM study.

The drug is also being evaluated in the randomized, placebo-controlled, double-blind phase III COBRAH study of patients withBRAFwild-type histiocytosis (NCT04007848).


  1. FDA Grants Breakthrough Therapy Designation to Cobimetinib for MEK Inhibition in Histiocytic Neoplasms, Research Led by MSK [press release]. New York, NY: Memorial Sloan Kettering Cancer Center; October 2, 2019. Accessed October 4, 2019.
  2. Diamond EL, Durham BH, Ulaner GA, et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms.Nature. 2019;567(7749):521-524. doi: 10.1038/s41586-019-1012-y.
  3. FDA Approves Genentech&rsquo;s Cotellic&trade; (Cobimetinib) in Combination With Zelboraf&reg; (Vemurafenib) in Advanced Melanoma [press release]. San Francisco, Calif: Genetech; November 10, 2015. Accessed October 4, 2019.
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