Outcomes with MEK Inhibitor Therapy Among Adults with Langerhans Cell Histiocytosis (LCH): A Multi-Institutional Study from the Adult LCH Working Group for the Histiocyte Society
Year: 2023
Type: conference-abstract
Abstract: Purpose: The discovery of MAPK/ERK pathway mutations has led to the approval of MEK-inhibitor (MEKi) cobimetinib in histiocytic neoplasms. However, the pivotal clinical trial that led to the approval of cobimetinib included only 4 patients with Langerhans cell histiocytosis (LCH). Therefore, there is a need to define outcomes with MEKi therapy in patients with LCH. We undertook a multi-center collaboration through the Adult LCH Working Group for the Histiocyte Society to address this gap in knowledge. Methods: Adults with LCH who received MEKi therapy were included from five institutions. Objective response rate (ORR) was evaluated using PET/CT criteria, and CT/MRI if PET scan was not available; response categories were categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Progression-free (PFS) and overall survival (OS) were calculated from the time of targeted therapy initiation. Risk organ disease was defined as liver, spleen, or bone marrow involvement. Results: 25 adults with LCH were included in this study; median age at MEKi initiation 43y (range, 18-85). Most common systems involved at diagnosis were bone (52%), pituitary (44%), and lung (36%). Risk organ involvement was observed in 7 (28%, 6 liver, 1 liver and spleen) and 2 (8%) patients had intra-axial CNS involvement. Median lines of prior therapy received were 2 (range: 1-5), and 4 (16%) patients received MEKi in first-line. MAPK/ERK pathway status was assessed via target capture next generation sequencing (NGS) in 22 (96%) cases. Amongst those who underwent NGS, alterations identified included: BRAF V600E (2/22, 9%), BRAF deletions (11/22 50%), MAP2K1 or MEK mutations (4/22, 18%), and MAPK1 or ERK2 (n=1, 5%). Overall, 5 patients also received BRAF inhibitors (4 patients as first therapy prior to MEKi and 1 concomitantly due to BRAF V600E positive melanoma). Specific MEKi agents utilized included cobimetinib (n=13) and trametinib (n=12). Among the response evaluable patients (n=23), ORR to MEKi treatment was 78% (9 CR, 9 PR, 4 SD, 1 PD). Among the 7 patients with liver involvement, responses were seen in 2 (29%) cases. ORR did not significantly differ according to mutation status among those with NGS data (78% MAPK mutated vs. 100% unmutated; p=1.0). In this subcohort, all of the 4 cases that did not respond to MEKi had liver involvement; 3 had BRAF deletions (2 SD and 1 PD), and one had MAPK1 mutation (SD). Median follow-up duration after MEKi initiation in the entire cohort was 18 months (95% CI 6 - 30). The median PFS and OS were not reached; 2-year PFS and OS were 78.1% and 79.9%, respectively (Figure 1A). The median PFS was much shorter in those with liver involvement (7 months [95% CI 0 - 14]) compared with those without liver disease (not reached [95% CI 19-not reached] P=0.047; Figure 1B). PFS did not differ significantly between MAPK pathway mutated and unmutated patients (p=0.34) Adverse events (AEs) were reported in 36% (n=9) and most commonly included rash (n=5) and fatigue (n=3). Four patients experienced grade 3-4 AEs including rash, fatigue, and thrombocytopenia. Common causes of MEKi discontinuation included AEs (n=3), progression (n=2), and drug holiday (n=2). At last follow-up, 5 patients died and 18 remained on MEKi. Death was attributable to LCH (n=3), concomitant malignancy (n=1), or unknown causes (n=1). Conclusions: In our multi-institutional study of adults with LCH, we found MEKi therapy to be highly efficacious. However, liver involvement correlated with a lack of response and worse PFS, while mutational status did not. Future studies are needed to evaluate optimum treatment for high-risk subgroups of LCH like liver disease.
Source: Blood
Authors: Gaurav Goyal, Aldo Adrian Acosta Medina, Xinxin Cao, Dana Bossert, Matthew P. Collin, Polyzois Makras, Omar Abdel-Wahab, Jithma Prasad Abeykoon, Rodothea Amerikanou, Corrie Bach, N. Nora Bennani, Benjamin Heath Durham, Jasmine H Francis, C Christopher Hook, Min Lang, Mario Lacouture, Kseniya Petrova-drus, Karen L Rech, Veronica Rotemberg, Gordon J Ruan, Mithun V Shah, Mariko Yabe, Jason R Young, Saurabh Zanwar, Ronald S. Go, Eli L. Diamond
Institutions: University of Alabama at Birmingham, UAB Medicine, Mayo Clinic, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Memorial Sloan Kettering Cancer Center, Newcastle University, Hellenic Air Force, Hellenic Airforce General Hospital, University College London, Mayo Clinic in Florida
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4389229481