BRAF inhibitors in HCL Thorsten Zenz, MD Dept. of Translational Oncology, National Center for Tumor Diseases (NCT) / German Cancer Research Center (DKFZ), Heidelberg Dept. of Haematology / Oncology / Rheumatic Disease, University Hospital Heidelberg thorsten.zenz@nct-heidelberg.de

Hairy Cell Leukemia BRAFV600E disease defining lesion Vemurafenib (B-raf inhibitor) transforming treatment landscape in melanoma High incidence thyroid cancer, colon cancer,… D c.T1799A, p.V600E Tiacci et al, NEJM 2011

BRAF V600E Incidence and clonal composition suggests that BRAF V600E could be an ideal therapeutic target

Blood Counts Dietrich et al, NEJM in pressDietrich, Glimm et al, NEJM 2012

Bone marrow infiltration (CD20) BRAF inhibition in HCL d 0 d 17 d 36 d 70 Bone marrow infiltration (CD20) 20x d 0 d 17 d 36 d 70 32% 1.04% <0.02% <0.02% Immunophenotyping peripheral blood CD103+ CD20+ Melanoma dose d 17 d 36 d 70 1920 Vemurafenib (mg) 1440 960 480 20 40 60 80 Days Dietrich, Glimm et al, NEJM 2012

Response to BRAF inhibition in HCL (blood counts) Dietrich et al, JCO

Treatment of hairy cell leukemia by BRAF-inhibition Dietrich Sascha, Andreas Pircher, Mindaugas Andrulis, Elena Ellert, Weichert, Frédéric Peyrade, Clemens-Martin Wendtner, Anita Gaehler, George A Follows, Martin JS Dyer, Thomas Elter, Robert Zeiser, Michael Herrmann, Michael Herold, Claire Dearden, Thorsten Haferlach, Martina Seiffert, Michael Hallek, Anthony D Ho, Michael Steurer and Thorsten Zenz, University of Heidelberg, Department of Medicine V, Heidelberg, Germany; Medical University Innsbruck, Innsbruck, Austria; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Centre Antoine Lacassagne, Nice, France; Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Hospital Munich-Schwabing, Munich, Germany; Kantonsspital Luzern, Luzern, Switzerland; Department of Haematology, Addenbrookes Hospital, Cambridge, United Kingdom; Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom; Department of Internal Medicine I, Center of Integrated Oncology (CIO), CECAD, University of Cologne, Cologne, Germany; Department of Haematology/Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany; Department of Hematology and Oncology, Helios Kliniken Erfurt, Erfurt, Germany; The Royal Marsden Hospital, London, United Kingdom; MLL Münchner Leukämielabor, München, Germany DKFZ, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (dkfz), Heidelberg, Germany;

Response Eight patients achieved a CR (38%) 12 PR (57%) 1 patient a minor response (5%)

Clincal studies exploring BRAFi A Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia (NCT01711632) A Phase II, Open-label, Study in Subjects With BRAF V600E-Mutated Rare Cancers With Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib (NCT02034110) A phase II, multi-center, open label study of the clinical activity and safety of the BRAF-V600 inhibitor vemurafenib (PLX-4032) in previously treated patients with hairy cell leukemia (HCL) carrying the BRAF-V600E mutation (2011-005487-13)

Phase II clinical trial of vemurafenib in Hairy Cell Leukemia (HCL) For patients with relapsed or refractory HCL with one of the following: intolerance to purine analogs refractory to initial purine analog-based therapy 1st relapse within 2 years of purine analog-based therapy ≥2 relapses. PI’s: Jae Park, Marty Tallman (Memorial Sloan Kettering Cancer); Open at Ohio State, Scripps, Northwestern, Dana Farber Cancer Center MRD assessment Monitor for disease recurrence If MRD+ continue 3 months more 6 months Daily vemurafenib x 3 months 3 months Jae Park, Martin Tallman

Phase II clinical trial of vemurafenib for R/R HCL 26 patients enrolled 24 patients are evaluable for toxicity with ≥ 1 month of study drug administration 24 patients are evaluable for response with ≥ 3 months of follow-up Median follow up: 12 months (5.6 – 22.1 months) Data cutoff date: 11/19/2014 Jae Park, Martin Tallman

Phase II clinical trial of vemurafenib for R/R HCL Number of Patients, N=24 Overall Response Rate (CR + PR) 24/24 (100%) Complete Response 8/24 (33.3%)* Partial Response¶ 16/24 (66.7%)§ * 2 patients achieved MRD negative CR (25%). ¶ All patients with PR achieved complete hematologic recovery. § Median % hairy cells in PR patients was 12.5% (range, 2-40%). 11 patients completed > 3 months of treatments (4-6 months). 2 patient experienced improvement of response. Jae Park, Martin Tallman

Summary BRAF inhibitors open up targeted treatment opportunities in HCL Integration into clinical care to be developed Trials currently open for vemurafenib / Trametinib+Dabrafenib Developments in other disease likely to influence HCL