Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis

Abstract

Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs) for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at four major US care centers. The most common treatment-related toxicity was rash (27% of patients). For most patients, disease was effectively managed at lower doses (0.5-1.0 mg trametinib daily). The response rate in the 17 evaluable patients was 71% (with 73% (8/11) without a detectable BRAF V600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, while median progression-free and overall survival had not been reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAFV600E or other BRAF alterations); or alterations in other genes involved in the MAPK pathway, e.g., MAP2K1, NF1, GNAS or RAS. Most patients required lower than standard doses of trametinib but were responsive to the lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.

A Novel Lysosome Targeting Chimera for Targeted Protein Degradation via Split-and-Mix Strategy

“…To further investigate the universality of the platform, we tested this platform toward other tumor-associated antigens including cytoplasmic proteins MEK1/2 and BCR-ABL. − Based on previous research, we constructed cobimetinib-δδRR and dasatinib-δδRR for targeting MEK1/2 and BCR-ABL, respectively, and assembled them with KFERQ-Ahx-δδRR separately (Figures A,C and S9,11). Immunoblots of extracts from different tumor cell lines including A375 and K562 clearly showed a concentration- and time-dependent target protein degradation after the SM-CMAD treatment (Figures B,D, S10,12).…”

Molecular Targeting of the BRAF Proto-Oncogene/Mitogen-Activated Protein Kinase (MAPK) Pathway across Cancers

“…BRAF mutations have been associated with a more severe disease, a poorer prognosis, and a higher prevalence in younger patients [ 52 ]. On the other hand, Erdheim–Chester Disease (ECD) and Rosai–Dorfman Disease (RDD) are non-LCH with multiorgan involvement, including diffuse osteosclerotic lesions, orbital infiltration, lung, kidney, cardiac, and neurological involvement, as well as other endocrinopathies [ 78 ]. BRAFV600E mutations are found in half of patients with ECD, while patients without BRAFV600E mutations tend to have other mutations in components of the MAPK pathway, including the RAS and MEK1 genes [ 78 ].…”

“…In a retrospective study evaluating the benefit of trametinib in patients with ECD, 35% of patients had BRAFV600E mutations, and ORR was seen in 71% of patients, while OS and PFS were not reached at a median follow-up of 23 months [ 78 ]. Out of the responders, 73% of patients did not have the BRAFV600E mutation but instead had other alterations in the MAPK pathway, including MEK1 or RAS [ 78 ].…”

“…In a retrospective study evaluating the benefit of trametinib in patients with ECD, 35% of patients had BRAFV600E mutations, and ORR was seen in 71% of patients, while OS and PFS were not reached at a median follow-up of 23 months [ 78 ]. Out of the responders, 73% of patients did not have the BRAFV600E mutation but instead had other alterations in the MAPK pathway, including MEK1 or RAS [ 78 ]. In addition, given that the time-to-treatment failure was 37 months, ECD patients treated with trametinib have more durable responses and do not seem to have developed the acquired resistance like in other solid tumors [ 78 ].…”

“…Out of the responders, 73% of patients did not have the BRAFV600E mutation but instead had other alterations in the MAPK pathway, including MEK1 or RAS [ 78 ]. In addition, given that the time-to-treatment failure was 37 months, ECD patients treated with trametinib have more durable responses and do not seem to have developed the acquired resistance like in other solid tumors [ 78 ]. However, both dabrafenib and trametinib did not have specific FDA approval for histiocytosis neoplasms.…”