Efficacy of MEK Inhibitors in Erdheim Chester Disease

Background Erdheim Chester disease (ECD) is a rare histiocytosis with variable clinical behavior known to be driven by recurrent activating mutations in the MAP kinase pathway. BRAF inhibitors were the first targeted therapy used in this neoplastic disorder given the presence of the BRAF^V600E mutation in 50-60% of patients. Increased understanding of additional driver mutations within this pathway resulted in a study of MEK inhibitors (MEKi) in cases not harboring this mutation, ultimately leading to the FDA breakthrough designation of cobimetinib for BRAF^V600E negative histiocytic neoplasms. Herein, we present data from our institution on MEKi treatment of ECD, the largest cohort to date.

Methods We included all patients with ECD consecutively seen at Mayo Clinic and treated with one of the 3 available MEKi (cobimetinib, trametinib, or binimetinib) between 2019-2021. Tumor MAPK pathway mutation status was determined with next-generation sequencing (NGS) via the Tempus-xT® assay (Chicago, IL). If NGS data was unavailable, immunohistochemistry (IHC) or allele-specific PCR was used to determine BRAF-specific mutation status. Time-to-event analyses were calculated from the time of MEKi initiation to progression, therapy discontinuation due to intolerant side effects, or initiation of systemic non-MEKi therapies. Response assessment was done based on the established positron emission radiography (PET)-response criteria used for clinical trials of targeted therapies in histiocytosis. Adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria v5.0

Results A total of 22 patients with ECD underwent treatment with a MEKi and were included. Median follow up was 19 months (95% CI 10 - 28 months) and 55% (n=12) were female. Median age at diagnosis of ECD was 54 years (IQR 36.8 - 70.8 years). Most common system involvement included osseous (68%), retroperitoneal soft tissue (46%), central nervous system (41%), and cardiovascular (41%). Mutational assessment studies included NGS in 82% (n=18). The four remaining patients had assessment of BRAF^V600E by IHC or PCR. Tumor genomic profile included non-BRAF^V600E mutations in 15 patients (68%). BRAF^V600E was identified by IHC in one patient. All other patients did not have successful NGS (n=2) or had no pathogenic variants identified (n=3). Additional details presented in Table 1.

Median time on a MEKi was 6.5 months (IQR 3 - 15 months). It was used as first-line therapy in 72.7% (n=16) of cases. Within the 22 patients, 28 instances of MEKi initiation were observed in our cohort, as 5 patients (23%) received 2 different MEKi throughout follow up and one patient had cobimetinib rechallenge after first progression. MEKi used included: cobimetinib (n=23, 82%), trametinib (n=3, 11%), and binimetinib (n=2, 7%).

Response assessment after initiation of first MEKi was not available in 1 patient. In the remaining 21 cases, overall response rate was 81% including complete or near-complete response (CR/nCR) in 5 (24%), partial response (PR) in 12 (57%), stable disease (SD) in 2 (10%), and progressive disease (PD) in 2 (10%). Median EFS was 36 months (95%CI 9 - not reached), respectively. Intolerable AEs with MEKi included G3/4 diarrhea (n=2), G3 lower extremity edema (n=2), G3 acneiform rash (n=1), G2 pericardial effusion (n=1), and "dropped-head syndrome” (n=1). Of the 6 patients who were treated with a second MEKi (Figure 1), five had data for response assessment and had CR/nCR (n=2) or a PR (n=3) as best responses.

At time of last follow-up, 21 patients (96%) were alive and one died due to progression of ECD. Of the 22 patients, 10 patients (46%) remained on MEKi at the time of last follow-up. Reasons for therapy discontinuation included intolerable side effects (n=4), drug holiday after response achievement (n=4), disease progression on therapy (n=3), and change to other kinase inhibitors (n=1). Additional details regarding patient follow-up are presented in Figure 1.

Conclusion Our study suggests that MEK inhibitors are a highly efficacious treatment in patients with ECD. Main limitation of our study includes its retrospective nature and sample size. While treatment discontinuation due to severe toxicities / intolerance was common, this did not preclude from maintenance of tumor response for extended periods of time. Not all patients will respond to MEKi and further research to guide individualized therapies is required.

Shah:Astellas: Research Funding; Celgene: Research Funding; Marker Therapeutics: Research Funding. Vassallo:Bristol Myers Squibb: Research Funding; Sun Pharma: Research Funding; Pfizer: Research Funding. Goyal:Viracta Therapeutics: Research Funding; SeaGen: Research Funding; Sutro Biopharma: Research Funding; UpToDate: Patents & Royalties; 2nd.MD: Consultancy.