Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3,4,5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73–100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling—and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.
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All datasets generated and/or analysed during the current study, including patient-level clinical data as well as all sequencing data have been deposited and are publicly available in the cBioPortal for Cancer Genomics under the accession code ‘Histiocytosis Cobimetinib (MSK, Nature 2019)’ (https://www.cbioportal.org/study?id=histiocytosis_cobi_msk_2019).
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We thank the patients and their families for participating in this study. We thank Z. J. Tang for assisting with whole-exome genomic analysis and R. Kundra for assisting with the cBioPortal. This work was supported by Genentech and grants from the Histiocyte Society, the Erdheim–Chester Disease Global Alliance, the Functional Genomics Initiative of Memorial Sloan Kettering Cancer Center, the Society of Memorial Sloan Kettering Cancer Center, the Histiocytosis Association, the Translational and Integrative Medicine Award of Memorial Sloan Kettering Cancer Center, the Geoffrey Beene Center of Memorial Sloan Kettering Cancer Center, the American Society of Hematology, the Leukemia & Lymphoma Society, Frame Fund, Nonna’s Garden Foundation and National Institutions of Health (P30 CA008748, 1 R01 CA201247 and K08 CA218901).
Nature thanks Barrett Jon Rollins and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare the following competing interests: E.L.D., grants from Erdheim–Chester Disease Global Alliance, The Histiocytosis Association, the Society of Memorial Sloan Kettering, the Translational and Integrative Medicine Award of Memorial Sloan Kettering, the American Society for Clinic Oncology, and the Frame Fund; B.H.D., grants from National Cancer Institute, American Society of Hematology and Erdheim–Chester Disease Global Alliance Foundation; G.U. personal fees from Sanofi and grants from Sanofi, Novartis and Genentech; R.J.Y., personal fees from Agios, PUMA, NordicNeuroLabs and Icon, and grants from Agios; R.R., personal fees from Incyte, Celgene, Agios, Jazz, BeyondSpring, Apexx and Partner Therapeutics, and research funding from Stemline and Constellation; M.L., personal fees and royalties from Roche/Genentech, and research funding from Veloce, Berg and US Biotest; A.D., personal fees from Roche, Corvus Pharmaceuticals, Physicians’ Education Resource, Seattle Genetics, Peerview Institute, Oncology Specialty Group, Pharmacyclics, Celgene and Novartis, and grants from National Cancer Institute and Roche; N.R., personal fees from Array BioPharma, Millennium Pharmaceuticals, AstraZeneca/MedImmune, Novartis, Eli Lilly, Boehringer Ingelheim, Merrimack Pharmaeutics, Chugai, Beigene, Daiichi Sankyo, Kura Oncology, ZAI Lab, F-Prime and Kadmon, and grants from Chugai, Bayer and Tarveda; A.I., personal fees from Mylan; O.A.-W., grants from National Cancer Institute, National Heart Lung and Blood Institute and H3B Biomedicine, and personal fees from H3B Biomedicine, Foundation Medicine, Merck and Jansen; D.M.H., personal fees from Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Debiopharm Group and Genetech, and grants from National Cancer Institute, AstraZeneca, Puma Biotechnology, Loxo Oncology, Bayer Pharmaceuticals, and The Nonna's Garden Foundation Initiative in Precision Oncology. The remaining authors have nothing to disclose.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Fig. 1 Waterfall plot of maximum change in tumour size by RECIST after treatment with cobimetinib in patients with histiocytosis.
The upper and lower dotted lines represent cut-offs for progressive disease and partial response, respectively. Colours of bars indicate the genomic alteration present. Notations above bars indicate the specific mutation. One patient (marked by an asterisk) had undergone previous BRAF inhibitor therapy that was discontinued owning to intolerance. One patient (marked by a dagger) died owing to underlying disease. n = 14 patients in total. Source data
This graph depicts the duration of response according to PET criteria in the 16 patients that responded to treatment, beginning with date of initial response. Source data
Extended Data Fig. 3 Histopathology of histiocytoses with activating mutations in MEK2, RAF1 and BRAF treated in this study.
a, Protein diagram (top) and histological images (bottom) from a patient with Erdheim–Chester disease with a MAP2K2Y134H mutation. b, Protein diagram (top) and histological images (bottom) from a patient with non-Langerhans cell histiocytosis with a RAF1K106N mutation. c, Protein diagram (top) and histological images (bottom) from a patient with Langerhans cell histiocytosis with a BRAFN486_T491delinsK mutation.
This diagram shows the flow of patients through all phases of study participation from enrolment and follow-up through to data analysis.
This file contains source data for the gel images and the complete and unredacted clinical protocol (ClinicalTrials.gov, NCT02649972). Both the initial and final versions of the protocol are included. A summary of changes itemizes modifications that occurred between these two versions.
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Diamond, E.L., Durham, B.H., Ulaner, G.A. et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature 567, 521–524 (2019). https://doi.org/10.1038/s41586-019-1012-y
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