MEK Inhibition with Trametinib in Patients with Non-Langerhans Cell Histiocytosis

Background: Activation of the MAPK pathway through BRAF mutations or other molecular alterations is a hallmark of the non-Lagerhans cell histiocytosis (non-LCH) such Erdheim-Chester disease (ECD) or Rosai-Dorfman disease (RDD). Conventional clinical molecular testing of tumor tissue fails to identify targetable molecular alteration in about one third of patients with non-LCH. Targeting the MAPK kinase pathway in non-LCH with small molecule inhibitors can be effective in patients with BRAF or other MAPK molecular alterations. Methods: Patients with non-LCH with any, unknown or pending molecular profile (tumor tissue targeted next generation sequencing [NGS], plasma cell-free [cf] DNA targeted NGS) were treated with trametinib, an oral inhibitor of MEK1/2 kinase. Treatment outcomes such as response per RECIST 1.1 or RANO in case of central nervous system involvement, time on therapy and adverse event (AE) were analyzed. Results: Total of 16 patients with ECD (n=12) or RDD (n=3) or ECD/LCH (n=1) were started on oral trametinib dose of 1 mg to 2 mg daily. Of these 16 patients, 3 patients were found to have BRAF V600E mutation in tumor and/or plasma cfDNA, 7 patients had other alteration(s) putatively activating the MAPK pathway (CAPZA2-BRAF fusion [n=1], RAF1 amplification [n=1], GNAS mutation [n=3], HMGA2 rearrangement [n=1], NF1 mutation [n=1], KRAS mutation [n=1] and MAP2K1 mutation [n=1]) and 2 patients had no results from molecular testing. Patients were treatment-naive (n=9) or received 1 (n=3) or 2 (n=4) prior systemic therapies. To date, 5 (31%) patients had either partial (n=4) or complete response (n=1); 8 (50%) patients had stable disease (n=4) or non-CR/non-PD (n=4) in the absence of measurable disease and 3 (19%) did not have response assessed. At the median follow up of 10.1 months the median progression-free survival has not been reached as only two patients progressed on therapy while 14 remain progression-free for 1.1+ to 36+ months. The therapy was overall well tolerated with grade 1 rash being the most frequent AE. AE > grade 2 included mucositis (n=2), rash (n=2), dizziness (n=1), uveitis (n=1) and decrease in ejection fraction (n=1) and two patients discontinued therapy because of AEs. Conclusions: MEK inhibitor trametinib demonstrated encouraging activity in patients with non-LCH irrespective of underlying molecular profile. Further studies of trametinib in patients with non-LCH are warranted. Disclosures Janku: Ideaya: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees; Primmune Therapeutics: Consultancy; PureTech Health: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Deciphera: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Piqur: Research Funding; Bristol-Myers Squibb: Research Funding; IFM Therapeutics: Membership on an entity's Board of Directors or advisory committees; Synlogic: Membership on an entity's Board of Directors or advisory committees; Sotio: Consultancy; Astex: Research Funding; FujiFilm Corporation and Upsher-Smith Laboratories: Research Funding; Astellas: Research Funding; BioMed Valley Discoveries: Research Funding; Plexxikon: Research Funding; Symphogen: Research Funding; Bayer: Research Funding; Agios: Research Funding; Proximagen: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tovagene: Consultancy, Other: Ownership interests; Immunomet: Consultancy. OffLabel Disclosure: We will discuss trametinib (FDA approved for melanoma) to be used in non-LCH