Efficacy and Tolerability of Trametinib in Adults with Histiocytic Neoplasms
Authors: Amerikanou Rodothea , Munir Tahla , Bowles Kristian , McNamara Christopher , Chavda Nikesh Dhiraj , Ahmed Azeem , Adiyodi Jagdish , Coles Alasdair , Kelsey Philippa , Smith Jeffery , Adams Richard , Hussein Hayder KA , Zhao Rui , Taylor Amelia , Nguyen Trung , Gohil Satyen , Collin Matthew 
Published: December 2024

Histiocytic neoplasms are a group of rare myeloid neoplasms with an annual incidence of 1-2 per million in adults. They are caused by activating somatic mutations of the MAPK signalling pathway and include the clinical entities Langerhans cell histiocytosis (LCH), Erdheim Chester Disease (ECD), Rosai Dorfman Disease (RDD), and Histiocytic Sarcoma (HS). BRAFV600E is the most common mutation but in approximately 50% of patients, a range of other mutations involving MAP2K (MEK), CSF1R, NRAS, KRAS and gene fusions are observed, which may be susceptible to treatment with MEK inhibitors such as Cobimetinib or Trametinib. While there is an FDA license for Cobimetinib, experience with Trametinib is more limited. This retrospective analysis evaluates the outcomes of patients with high-risk histiocytic neoplasms treated with the Trametinib in the United Kingdom.
Patients over 18 years who commenced Trametinib as monotherapy or in combination with Dabrafenib before 31st December 2023 were included in the study. The majority of patients met predefined criteria for referral including failure of all conventional treatment or high risk of irreversible organ dysfunction. Ethical review is not required in the UK for anonymous reporting of clinical outcome by members of a clinical care team.
Thirty-eight patients were identified: 18 ECD (47%); 13 LCH (34%); 2 ECD/LCH (5%); 2 RDD (5%); 2 Histiocytic Sarcoma (5%); and 1 Indeterminate cell histiocytosis (3%). The median age at diagnosis was 48 (1-73) and the median age at the start of inhibitor therapy was 52 (20-74). Twenty-five (66%) were male. Most patients had received prior therapy with a median of 2 lines of treatment (range 0-6). ECOG at diagnosis was 1 (range 0-3). Fourteen patients had BRAFV600E and commenced Dabrafenib and Trametinib dual therapy; 21 patients without V600E mutations and 3 who could not be genotyped, received Trametinib monotherapy. The starting dose for Trametinib ranged from 0.5mg-2mg daily and the most prevalent final dose was 1mg daily.
At a median follow up of 20 months, the cohort of 38 includes 27 patients alive on Trametinib, 8 who have discontinued therapy after a median of 11 months and 3 who have died. Deaths all occurred in the Trametinib monotherapy group: 1 with HS who progressed, 1 diagnosed with indeterminate cell histiocytosis who evolved to AML and 1 with end-stage pulmonary LCH. Of the 8 who discontinued therapy, 2 in the dual therapy group dropped Trametinib owing to toxicity and remained on Dabrafenib alone while 6 in the Trametinib monotherapy group stopped owing to toxicity (3), compliance (2), or attainment of CR (1). Grade 3-4 toxicity leading to treatment cessation across the cohort included: hypertension; cardiac dysfunction; colitis; corneal oedema; interstitial lung changes. The 3 patients who withdrew from Trametinib monotherapy with toxicity remain alive and include 1 who attained CR, 1 with PR, and 1 with SD.
Thirty-six patients received dual therapy (12) or Trametinib monotherapy (24) continuously until an evaluable endpoint. A clinical response rate of 78% (28/36) and 2-year overall survival of 97% were observed. No clinical response was reported in 1/12 on dual therapy and in 7/24 on Trametinib monotherapy. Non-responders included the 3 patients who died, 4 who had no improvement in neurodegeneration and 1 with LCH. Radiological responses were observed in 64% patients (23/36), including 10/12 on dual therapy and 13/24 on monotherapy. The overall CR rate was 33% (12/36) and PR rate was 31% (11/36). Ten patients had stable disease but none except the 3 who died, had progression.
Trametinib has demonstrable clinical efficacy in this group of patients with high-risk histiocytic neoplasms, including a high rate of reported clinical responses and documented radiological improvement. Toxicity was problematic but a balance of disease response and tolerability was achieved in most patients. A small number achieved satisfactory responses while remaining off therapy. Irreversible neurodegeneration was the most common reason for non-response (4/8 patients) although earlier introduction of Trametinib may have improved response rates across the cohort. Further studies are required to define optimal patient eligibility, Trametinib dosing and modes of response assessment.
Note: the use of Trametinib to treat histiocytic neoplasms is off-label.