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Spleen tyrosine kinase/FMS-like tyrosine kinase-3 inhibition in relapsed/refractory B-cell lymphoma, including diffuse large B-cell lymphoma: updated data with mivavotinib (TAK-659/CB-659)

Leo I. Gordon _, Reem Karmali, Jason B. Kaplan, Rakesh Popat, Howard A. Burris III, Silvia Ferrari, Sumit Madan, Manish R. Patel, Giuseppe Gritti, Dima El-Sharkawi, F. Ian Chau, John Radford, Jaime Pérez de Oteyza, Pier Luigi Zinzani, Swaminathan P. Iyer, William Townsend, Harry Miao, Igor Proscurshim, Shining Wang, Shilpi Katyayan, Ying Yuan, Jiaxi Zhu, Kate Stumpo, Yaping Shou, Cecilia Carpio and Francesc Bosch

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Oncotarget. 2023; 14:57-70. https://doi.org/10.18632/oncotarget.28352

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Abstract

Leo I. Gordon1, Reem Karmali1, Jason B. Kaplan1, Rakesh Popat2, Howard A. Burris III3, Silvia Ferrari4, Sumit Madan5,16, Manish R. Patel6, Giuseppe Gritti4, Dima El-Sharkawi2,17, F. Ian Chau7, John Radford8, Jaime Pérez de Oteyza9, Pier Luigi Zinzani10,11, Swaminathan P. Iyer12,18, William Townsend2, Harry Miao13, Igor Proscurshim13, Shining Wang13, Shilpi Katyayan13,19, Ying Yuan13, Jiaxi Zhu13, Kate Stumpo13, Yaping Shou13, Cecilia Carpio14 and Francesc Bosch14,15

1 Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA

2 Department of Haematology, NIHR/UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, UK

3 Drug Development, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN 37203, USA

4 Dipartimento di Oncologia ed Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy

5 Division of Hematology and Oncology, Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, TX 78229, USA

6 Drug Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL 34232, USA

7 Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, UK

8 NIHR Clinical Research Facility, The Christie NHS Foundation Trust and University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

9 Hematology, Hospital Universitario HM Sanchinarro, Madrid, Spain

10 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy

11 Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy

12 Department of Hematology and Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA

13 Oncology Clinical Science, Takeda Development Center Americas, Inc. (TDCA), Lexington, MA 02421, USA

14 Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

15 Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain

16 Current affiliation: Division of Hematology and Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ 85234, USA

17 Current affiliation: Department of Haematology, Royal Marsden Hospital, Sutton, Surrey, UK

18 Current affiliation: Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

19 Current affiliation: Biostatistics, Labcorp Drug Development, Princeton, NJ 08540, USA

Correspondence to:

Leo I. Gordon, email: [email protected]

Keywords: Non-Hodgkin’s lymphoma; DLBCL; relapsed/refractory; SYK inhibitor; TAK-659

Received: October 13, 2022     Accepted: January 16, 2023     Published: January 26, 2023

Copyright: © 2023 Gordon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report).

Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60–120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity.

A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%).

These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL.

Trial registration: ClinicalTrials.gov number: NCT02000934.


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