Efficacy of MEK inhibition in patients with histiocytic neoplasms

Eli L. Diamond, Benjamin H. Durham, Gary A. Ulaner, Esther Drill, Justin Buthorn, Michelle Ki, Lillian Bitner, Hana Cho, Robert J. Young, Jasmine H. Francis, Raajit Rampal, Mario Lacouture, Lynn A. Brody, Neval Ozkaya, Ahmet Dogan, Neal Rosen, Alexia Iasonos, Omar Abdel-Wahab () and David M. Hyman ()
Additional contact information
Eli L. Diamond: Memorial Sloan Kettering Cancer Center
Benjamin H. Durham: Memorial Sloan Kettering Cancer Center
Gary A. Ulaner: Weill Cornell Medical College
Esther Drill: Memorial Sloan Kettering Cancer Center
Justin Buthorn: Memorial Sloan Kettering Cancer Center
Michelle Ki: Memorial Sloan Kettering Cancer Center
Lillian Bitner: Memorial Sloan Kettering Cancer Center
Hana Cho: Memorial Sloan Kettering Cancer Center
Robert J. Young: Weill Cornell Medical College
Jasmine H. Francis: Memorial Sloan Kettering Cancer Center
Raajit Rampal: Weill Cornell Medical College
Mario Lacouture: Weill Cornell Medical College
Lynn A. Brody: Memorial Sloan Kettering Cancer Center
Neval Ozkaya: Memorial Sloan Kettering Cancer Center
Ahmet Dogan: Memorial Sloan Kettering Cancer Center
Neal Rosen: Weill Cornell Medical College
Alexia Iasonos: Weill Cornell Medical College
Omar Abdel-Wahab: Weill Cornell Medical College
David M. Hyman: Weill Cornell Medical College

Nature, 2019, vol. 567, issue 7749, 521-524

Abstract: Abstract 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 mutations3–5, 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1012-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:567:y:2019:i:7749:d:10.1038_s41586-019-1012-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1012-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().