Cobimetinib Elicits Deep Responses in Rosai-Dorfman Disease, a Rare Cancer Type
The use of cobimetinib was effective in patients with Rosai-Dorfman disease, and responses were especially deep in those with KRAS or MEK alterations, according to findings from a recent retrospective study.
Cobimetinib (Cotellic) treatment prolonged survival and produced deeper responses in patients with KRAS- and MEK-variant Rosai-Dorfman disease (RDD) vs patients without MAPK pathway alterations, according to findings from a recent study published in JAMA Oncology.
Treatment with cobimetinib, however, was also associated with substantial adverse effects (AEs) regardless of disease alterations.
The overall response rate (ORR) was 63% (n = 10), which comprised 5 complete responses and 5 partial responses, across a population of 16 patients. Moreover, the 6- and 12-month rates of progression-free survival (PFS) were 78% and 65%, respectively.
KRAS or MEK alterations presented in half (n = 8) of the study population and correlated with both a higher ORR (88% vs 38%; P = .03) and more frequent complete responses (71% vs 0%; P = .002). Additionally, in terms of PFS, 100% of patients with these alterations were free from progression or death at 1 year vs 29% of those without alterations (P < .001).
“This is, to our knowledge, the largest reported series of patients with RDD treated with cobimetinib,” the investigators wrote. “[The agent] had positive outcomes in the entire cohort, with the majority of the responses seen among cases with KRAS/MEK alterations. Objective responses were observed even with low doses of cobimetinib, which caused fewer adverse effects.”
The retrospective cohort study drew participants from a population of 89 patients with RDD treated at the Mayo Clinic in Rochester, Minnesota, and the University of Alabama at Birmingham from January 2013 to December 2021. Cobimetinib was administered in the frontline setting to 7 of 16 enrolled patients, and those who received it as a subsequent line had a median of 3 prior treatments (range, 2-10).
The median age at treatment initiation was 57 years (range, 31-74), and most (n = 11; 69%) of the study population were women. All enrolled patients had extranodal disease.
Patients received oral cobimetinib at 20 to 60 mg once daily for 21 days of each 28-day cycle. Reduced doses of less than 60 mg were administered to 12 (75%) patients at the discretion of their treating physicians. The investigators graded AEs using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.
There were 2 complete and 2 partial responses among the 7 patients who started treatment at 20 mg, along with 1 and 3, respectively, among the 5 patients who started at 40 mg. These patients also had a similar ORR to those who started at a full dose (67% vs 50%; P = .55).
Additionally, response rates after frontline treatment with cobimetinib did not differ greatly from those after treatment in subsequent lines (71% vs 56%; P = .51).
Most patients (n = 9; 56%) experienced treatment-related AEs leading to dose reductions, withholding, or permanent discontinuation. Toxicities of grade 2 or higher were equally prevalent among patients with and without MAPK pathway alterations (75% vs 75%; P > .99) but were less frequent among those who started at lower vs higher doses (67% vs 100%; P = .09).
More than half of the patients (n = 9; 56%) eventually discontinued treatment because of AEs (n = 5) or disease progression (n = 4). At last follow-up, there were 2 deaths in the study population, one from therapy-related myelodysplastic syndrome in a patient who’d received multiple prior cytotoxic treatments and another after progression of RDD in the central nervous system (CNS).
“Further studies are needed to confirm activity of cobimetinib in patients with other bona fide MAPK pathway alterations and to evaluate alternate targeted therapies with better toxicity profile,” the investigators concluded. “Given that CNS-involved RDD may have detrimental outcomes, future studies should also focus on MEK inhibitors with improved CNS penetrance. Additionally, long-term follow-up will be necessary to establish the optimal duration of therapy with MEK inhibitors like cobimetinib.”
Reference
Abeykoon JP, Rech KL, Young JR, et al; Mayo Clinic–University of Alabama at Birmingham Histiocytosis Working Group. Outcomes after treatment with cobimetinib in patients with Rosai-Dorfman disease based on KRAS and MEK alteration status. JAMA Oncol. Published online October 6, 2022. doi:10.1001/jamaoncol.2022.4432.
