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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 57-70 |
| Number of pages | 14 |
| Journal | Oncotarget |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2023 |
Funding
LIG is on the Data Safety and Monitoring Board (DSMB) for Janssen and is a consultant for Ono Pharmaceuticals. RK received research support from Takeda. RP received honoraria and consultancy fees from Takeda, Janssen, BMS, GSK and Roche. HAB is employed by Sarah Cannon and HCA Healthcare; owns stocks/ shares at HCA Healthcare; holds a non-compensated consulting position for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, GRAIL, Incyte, Novartis, TG Therapeutics, Vincerx Pharma; and reports grants or funds paid to their institution from AbbVie, Agios, ARMO Biosciences, Array BioPharma, AstraZeneca, Bayer, BeiGene, BioAtla, BioMed Valley Discoveries, Boehringer Ingelheim, Bristol-Myers Squibb, CALGB, CicloMed, eFFECTOR Therapeutics, Lilly, EMD Serono, Roche/ Genentech, GlaxoSmithKline, Harpoon Therapeutics, Hengrui Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, Macrogenics, MedImmune, Merck, Millennium, Moderna, Pfizer, Revolution Medicine, Foundation Medicine, SeaGen, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals, Xbiotech, Zymeworks, Arch Oncology, Arvinas, Coordination Pharmaceuticals, NGM Biopharmaceuticals, Gossamer Bio, Ryvu Therapeutics, and BioTheryX. SM received honoraria from Karyopharm, GSK, BMS, Janssen and Oncopeptides. MRP reports leadership at ION Pharma; honoraria from Pfizer, Pharmacyclics, Bayer, Janssen, Genentech, and Adaptive Biotechnologies; consulting/advisory role at Pharmacyclics, Janssen, Pfizer, and EMD Serono; and speakers’ bureaus at Exelixis, Genentech, Roche, Taiho Pharmaceutical, and Celgene. GG reports participation in advisory boards for Roche, IQVIA, Kite-Gilead, Italfarmaco, Takeda, Ideogen, and Genmab; support for attending meetings from Roche, and Sandoz; and training activities for Roche, Takeda, Clinigen, Ideogen, Beigene, and Incyte; and individual scientific consultancy for Takeda. DES reports honoraria from AbbVie, AstraZeneca, Beigene, Janssen, Lily, Roche, and Takeda; consulting fees from AbbVie, ASTEX, AstraZeneca, Beigene, Janssen, and Kyowa Kirin; and financial support for conference/ travel from AbbVie, Novartis, and Roche. FIC reports participation in advisory council/committees for Eli-Lilly, Bristol Meyers Squibb, MSD, Roche, Merck-Serono, Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, Eisai, Daiichi-Sankyo, Taiho, Servier; honoraria from Eli-Lilly, Eisai, Servier, Roche; and grants or funds from Eli-Lilly, Janssen-Cilag. JPO reports participation in advisory council/committees for Janssen, Takeda, and Roche; and grants/funds from Takeda. PLZ reports participation in advisory council/committees for Takeda, MSD, AbbVie, BMS, and ADC Therapeutics; and honoraria from Takeda, MSD, BMS, Gilead, Novartis, Kyowa Kirin, Sanofi, Incyte, Roche, Eusapharma, Janssen, Incyte, and AstraZeneca. SPI reports honoraria from Curebio, MD Education, and Target Oncology; consulting fees from Seagen, Yingli, Legend, and Securabio; and grants/funds from Merck, Seagen, CRISPRx, Legend, Myeloid, Innate, Rhizen, Spectrum, Affimed, Takeda, Yingli, and Ono. WT reports participation in advisory council/committees for Roche, Incyte, and Takeda; honoraria and consulting fees from Roche, Incyte, Takeda, Gilead, and BMS. SK reports employment and ownership of stocks/shares at Labcorp Drug Development. KS reports ownership of stock at AstraZeneca and Teva Pharmaceuticals. HM, IP, SW, SK, YY, JZ, KS and YS are all employees of Takeda; IP and SW also report the ownership of stocks/shares at Takeda. CC reports honoraria and consulting fees from Takeda and Regeneron; and honoraria from BMS, AstraZeneca, Gilead, and Novartis. FB reports participation in advisory council/committees, honoraria, consulting fees, and grants or funds from Roche, Genentech, AbbVie, Janssen, Lilly, AstraZeneca, Novartis, Kite, BMS, Takeda, TG therapeutics, BeiGene, Advantage, Allogene, LAVA therapeutics, Enterome. SF, JBK, and JR report no conflicts of interest. This study was sponsored by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. We thank all of the patients and their families, and the investigators and staff at all clinical sites, for their participation in the trial. The authors acknowledge Tori Gordon, BSc, of Ashfield MedComms, an Inizio Company, for medical writing support for the development of this manuscript under the direction of the authors, which was funded by Takeda Pharmaceuticals U.S.A., Inc., and complied with the Good Publication Practice 3 ethical guidelines (Battisti WP, et al. Ann Intern Med 2015. 163: 461–4). R. Popat and W. Townsend acknowledge support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Keywords
- DLBCL
- Non-Hodgkin’s lymphoma
- SYK inhibitor
- TAK-659
- relapsed/refractory
ASJC Scopus subject areas
- Oncology