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Efficacy of MEK inhibition in patients with histiocytic neoplasms


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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Fig. 1: Efficacy of MEK1 and MEK2 inhibition with cobimetinib, across molecular subtypes of histiocytoses.
Fig. 2: Characterization of activating mutations in MEK2, RAF1 and BRAF and their dependence on ERK signalling in histiocytoses.

Data availability

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)’ (


  1. Haroche, J. et al. Histiocytoses: emerging neoplasia behind inflammation. Lancet Oncol. 18, e113–e125 (2017).

    Article  Google Scholar 

  2. Allen, C. E., Merad, M. & McClain, K. L. Langerhans-cell histiocytosis. N. Engl. J. Med. 379, 856–868 (2018).

    CAS  Article  Google Scholar 

  3. Badalian-Very, G. et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116, 1919–1923 (2010).

    CAS  Article  Google Scholar 

  4. Haroche, J. et al. High prevalence of BRAF V600E mutations in Erdheim–Chester disease but not in other non-Langerhans cell histiocytoses. Blood 120, 2700–2703 (2012).

    CAS  Article  Google Scholar 

  5. Emile, J. F., Charlotte, F., Amoura, Z. & Haroche, J. BRAF mutations in Erdheim–Chester disease. J. Clin. Oncol. 31, 398 (2013).

    Article  Google Scholar 

  6. Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 Mutations. N. Engl. J. Med. 373, 726–736 (2015).

    CAS  Article  Google Scholar 

  7. Diamond, E. L. et al. Vemurafenib for BRAF V600-mutant Erdheim–Chester disease and Langerhans cell histiocytosis: analysis of data from the histology-independent, phase 2, open-label VE-BASKET Study. JAMA Oncol. 4, 384–388 (2018).

    Article  Google Scholar 

  8. Diamond, E. L. et al. Diverse and targetable kinase alterations drive histiocytic neoplasms. Cancer Discov. 6, 154–165 (2016).

    CAS  Article  Google Scholar 

  9. Brown, N. A. et al. High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood 124, 1655–1658 (2014).

    CAS  Article  Google Scholar 

  10. Chakraborty, R. et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 124, 3007–3015 (2014).

    CAS  Article  Google Scholar 

  11. Emile, J. F. et al. Recurrent RAS and PIK3CA mutations in Erdheim–Chester disease. Blood 124, 3016–3019 (2014).

    CAS  Article  Google Scholar 

  12. Nelson, D. S. et al. Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood 123, 3152–3155 (2014).

    CAS  Article  Google Scholar 

  13. Chakraborty, R. et al. Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis. Blood 128, 2533–2537 (2016).

    CAS  Article  Google Scholar 

  14. Cohen Aubart, F. et al. Targeted therapies in 54 patients with Erdheim–Chester disease, including follow-up after interruption (the LOVE study). Blood 130, 1377–1380 (2017).

    Article  Google Scholar 

  15. Jacobsen, E., Shanmugam, V. & Jagannathan, J. Rosai–Dorfman disease with activating KRAS mutation—response to cobimetinib. N. Engl. J. Med. 377, 2398–2399 (2017).

    Article  Google Scholar 

  16. Gounder, M. M., Solit, D. B. & Tap, W. D. Trametinib in histiocytic sarcoma with an activating MAP2K1 (MEK1) mutation. N. Engl. J. Med. 378, 1945–1947 (2018).

    Article  Google Scholar 

  17. Diamond, E. L. et al. Consensus guidelines for the diagnosis and clinical management of Erdheim–Chester disease. Blood 124, 483–492 (2014).

    CAS  Article  Google Scholar 

  18. Abla, O. et al. Consensus recommendations for the diagnosis and clinical management of Rosai–Dorfman–Destombes disease. Blood 131, 2877–2890 (2018).

    CAS  Article  Google Scholar 

  19. Allen, C. E., Ladisch, S. & McClain, K. L. How I treat Langerhans cell histiocytosis. Blood 126, 26–35 (2015).

    CAS  Article  Google Scholar 

  20. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    CAS  Article  Google Scholar 

  21. Arnaud, L. et al. CNS involvement and treatment with interferon-α are independent prognostic factors in Erdheim–Chester disease: a multicenter survival analysis of 53 patients. Blood 117, 2778–2782 (2011).

    CAS  Article  Google Scholar 

  22. Rosen, L. S. et al. A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Invest. New Drugs 34, 604–613 (2016).

    CAS  Article  Google Scholar 

  23. Larkin, J. et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 371, 1867–1876 (2014).

    Article  Google Scholar 

  24. Falchook, G. S. et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 13, 782–789 (2012).

    CAS  Article  Google Scholar 

  25. Pratilas, C. A. et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 68, 9375–9383 (2008).

    CAS  Article  Google Scholar 

  26. Solit, D. B. et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358–362 (2006).

    ADS  CAS  Article  Google Scholar 

  27. Gao, Y. et al. Allele-specific mechanisms of activation of MEK1 mutants determine their properties. Cancer Discov. 8, 648–661 (2018).

    CAS  Article  Google Scholar 

  28. Emery, C. M. et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc. Natl Acad. Sci. USA 106, 20411–20416 (2009).

    ADS  CAS  Article  Google Scholar 

  29. Cheng, D. T. et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J. Mol. Diagn. 17, 251–264 (2015).

    CAS  Article  Google Scholar 

  30. Durham, B. H. et al. Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations. Blood 130, 1644–1648 (2017).

    CAS  Article  Google Scholar 

  31. Zheng, Z. et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat. Med. 20, 1479–1484 (2014).

    CAS  Article  Google Scholar 

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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).

Reviewer information

Nature thanks Barrett Jon Rollins and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations



E.L.D., O.A.-W. and D.M.H. designed the study. M.K., L.B. and H.C. processed all patient material for isolation of DNA and RNA for genomic analyses. B.H.D. cloned all cDNA and performed in vitro studies of their effects on cell growth and signalling under the supervision of N.R. and O.A.-W. B.H.D. also analysed genomic data under the supervision of O.A.-W. J.B. collected data and samples for processing by M.K., L.B. and H.C. E.L.D., J.H.F., R.R., M.L. and L.A.B. enrolled and treated the patients. E.D. and A.I. performed statistical analyses. G.A.U. and R.J.Y. evaluated all radiographic studies. E.L.D., B.H.D., N.O., A.D., O.A.-W. and D.M.H. analysed the clinical and laboratory data. E.L.D., B.H.D., O.A.-W. and D.M.H. prepared the manuscript with help from all co-authors. The study was designed jointly by E.L.D., B.H.D., O.A.-W. and D.M.H. The investigators collected and analysed the data. All authors had access to the data, and E.L.D., B.H.D., O.A.-W. and D.M.H. wrote the first draft of the manuscript. All the authors were involved in the data analysis and manuscript preparation. All the authors vouch for the completeness and accuracy of the data and analyses, and for the adherence to the study protocols. All the authors made the decision to submit the manuscript for publication.

Corresponding authors

Correspondence to Omar Abdel-Wahab or David M. Hyman.

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Competing interests

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.

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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

Extended Data Fig. 2 PET-defined duration of response.

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.

Extended Data Fig. 4 Study CONSORT diagram.

This diagram shows the flow of patients through all phases of study participation from enrolment and follow-up through to data analysis.

Extended Data Table 1 Demographic and clinical characteristics for the 18 patients
Extended Data Table 2 Overall response rate
Extended Data Table 3 Safety of cobimetinib in phase 2 study in patients with histiocytosis
Extended Data Table 4 Safety regardless of attribution
Extended Data Table 5 Genomic testing methodology

Supplementary information

Supplementary Information

This file contains source data for the gel images and the complete and unredacted clinical protocol (, 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).

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