FDA Approves Cobimetinib for Histiocytic Neoplasms

Based on findings from a phase 2 trial conducted by Memorial Sloan Kettering Cancer Center, the FDA has approved the use of cobimetinib for patients with histiocytic neoplasms.

The FDA has granted approval to the oral MEK1/2 inhibitor cobimetinib (Cotellic) for the treatment of patients with histiocytic neoplasms, including Erdheim-Chester disease, Rosai-Dorfman disease, and Langerhans cell histiocytosis.1

The basis of the approval comes from findings of a single-institution phase 2 trial (NCT02649972) conducted by Memorial Sloan Kettering Cancer Center (MSKCC) and Genentech in adult patients with histiocytic disorders.

“The approval of cobimetinib represents the collective hard work of several years of investigation by many MSK researchers. There have been tremendous advances in the field of rare cancers as a result of research and trials conducted at MSK, and this approval is an excellent example of a practice-changing outcome,” said Eli L. Diamond, MD, neuro-oncologist and neurologist at MSKCC and principal investigator of the trial, in the press release. “There has always been an unmet need for patients with histiocytosis, and we are thrilled that with this approval, these patients will now have access to a viable treatment option.”

Previously, cobimetinib received FDA approval in combination with the BRAF kinase inhibitor vemurafenib (Zelboraf) for the treatment of patients with BRAF-positive melanoma, based on phase III coBRIM study.2

In this phase 2 trial, patients with a histiocytic neoplasm were enrolled to determine the effects of cobimetinib in this patient population, regardless of tumor genotype. Patients with BRAF V600 mutations were eligible if they had intolerance or resistance to prior BRAF-targeted therapy or were unable to access BRAF inhibitor therapy.

Those enrolled in the study were administered cobimetinib starting at 60 mg daily for 21 days of each 28-day cycle. Investigators evaluated the primary end point of overall response rate (ORR) by fluorodeoxyglucose PET, as assessed by a radiologist, and the secondary end points of duration of response and progression-free survival (PFS) by PET as well as safety and ORR by RECIST v1.1 criteria.3

Patients harbored a variety of MAPK pathway mutations, including ARAF, BRAF, RAF1, NRAS, KRAS, MEK1, and MEK2.

Previously reported data showed treatment with cobimetinib to elicit an ORR of 89% (90% CI, 73%-100%) by PET. Complete responses were observed in 13 patients and partial responses were seen in 3 patients. The ORR by RESIST criteria was 64% (90% CI, 44%-100%) and included 2 complete responses and 7 partial responses.

None of those enrolled on the trial developed resistance to treatment. Responses were durable with 100% of patients still eliciting a response at a follow-up of 1-year. Further, the PFS rate at 1-year was 94%, and the median duration of response nor the median progression-free survival were reached after a median follow-up of 11.9 months (range, 1.6-23.7). Regardless of mutational status, treatment with cobimetinib was effective.

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

“Until now, no standard therapy has existed for the 50% of histiocytosis patients without the BRAF V600E mutation,” said Omar Abdel-Wahab, MD, hematologist/ oncologist at MSKCC, in the press release. “The research pioneered at MSK has led to a viable treatment option for adult patients who harbor this mutation. Looking ahead, we are working on advancing treatment options for pediatric patients with histiocytosis as we have done in adults.”

  1. FDA approves oral MEK inhibitor cobimetinib for histiocytic neoplasms, research led by Memorial Sloan Kettering Cancer Center. News release. Memorial Sloan Kettering Cancer Center. November 1, 2022. Accessed November 2, 2022. https://bit.ly/3sQxkgL
  2. FDA approves Genentech’s Cotellic (Cobimetinib) in combination with Zelboraf (Vemurafenib) in advanced melanoma. News release. Genetech; November 10, 2015.Accessed November 2, 2022. https://bit.ly/2MagGTJ.
  3. 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.