www.oncotarget.com Oncotarget, 2023, Vol. 14, pp: 57-70 Research Paper 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. 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: l-gordon@northwestern.edu 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). www.oncotarget.com 57 Oncotarget 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. INTRODUCTION aminotransferase (AST) elevations, pyrexia, and increased amylase, although abnormalities in clinical laboratory Diffuse large B-cell lymphoma (DLBCL) is an parameters were generally not associated with symptoms aggressive histologic subtype of non-Hodgkin’s lymphoma and were reversible upon treatment discontinuation. and is the most common adult lymphoid malignancy in Mivavotinib demonstrated anti-tumor activity in the Western world [1–4]. Although first-line R-CHOP patients with relapsed or refractory B-cell lymphomas treatment (rituximab plus cyclophosphamide, doxorubicin, across different histological subtypes, including DLBCL vincristine, and prednisone) is curative for an estimated [23]. The overall response rates (ORR) across all B-cell 60% of patients, outcomes are poor for those who are lymphoma subtypes in the intention-to-treat (ITT) refractory to initial treatment or who relapse [4–9]. population ranged from 20–50%. In patients with DLBCL Multi-agent salvage chemotherapy followed by (n = 53) the ORR was 23% in the ITT population (28% in autologous stem-cell transplant (ASCT) has been the the response-evaluable population), with a high proportion standard treatment for relapsed or refractory DLBCL [8, of those patients (19% of the response-evaluable population) 10–12]. However, many patients are either ineligible for achieving a complete response (CR). At the data cut-off this intensive approach or do not respond adequately. More (April 2018), the median treatment duration in patients with recently, several novel salvage therapeutic approaches, DLBCL was 14.3 months. The median duration of response including cellular therapies, antibody drug conjugates, (DOR) was not estimable (NE) due to ongoing responses in and bi-specific antibodies have been developed [13–17]. several patients. Based on these data, further evaluation was However, some of these novel therapies, particularly warranted, particularly in the DLBCL cohort [23]. CD19-targeted chimeric antigen receptor (CAR) T-cell The current analysis provides updated results for therapy, are associated with significant toxicities [14], and these lymphoma patients with extended follow-up. Also therefore additional novel options are needed. included are data for an additional cohort of patients with Mivavotinib (TAK-659/CB-659) is an DLBCL (n = 36) who were enrolled to expand testing of investigational, oral, reversible, potent dual inhibitor mivavotinib safety and efficacy prior to the opening of a of spleen tyrosine kinase (SYK) and FMS-like tyrosine planned phase II study (NCT03123393) [24]. Data from kinase 3 (FLT3) [18]. SYK is an essential component of these patients were not included in the initial analysis. the B-cell receptor signaling pathway; abnormal SYK Here, we report results for the complete DLBCL cohort signaling has been implicated in the pathogenesis of (n = 89), including data from both the original and DLBCL and several other B-cell malignancies [18–22]. additional DLBCL escalation and expansion cohorts, and The safety, tolerability, and preliminary efficacy updated data for all lymphoma patients in this first-in- of mivavotinib were investigated in a phase I first-in- human study. human dose escalation and expansion study conducted in patients with relapsed or refractory solid tumors or B-cell RESULTS lymphomas, including DLBCL [23]. The maximum tolerated dose (MTD) was determined to be 100 mg once daily (QD) Patients and anti-tumor activity was observed at doses of 60 mg to 120 mg QD. The most frequently occurring treatment- A total of 124 patients were enrolled; 17 patients emergent adverse events (TEAE) were isolated aspartate were enrolled in the dose escalation phase and received www.oncotarget.com 58 Oncotarget mivavotinib at the following doses: 60 mg QD (n = 4), Patient baseline demographics and disease 80 mg QD (n = 3), 100 mg QD (n = 11), and 120 mg QD characteristics for all lymphoma patients and all DLBCL (n = 1); 107 patients were enrolled in the expansion patients are shown in Table 1. The median age, both phase and received 100 mg QD. Overall, 89 patients had in all patients with lymphoma and within the DLBCL DLBCL (72%), 23 had indolent non-Hodgkins lymphoma subgroup, was 66 years (range 23–91). The median (iNHL) (19%), 6 had chronic lymphocytic leukemia time since diagnosis was 21.8 months (range 0.3–269.3) (CLL) (5%), 5 had mantle cell lymphoma (MCL) (4%), for all patients with lymphoma and 16.4 months (range and 1 patient had Epstein Barr virus-positive post- 0.3–269.3) for patients with DLBCL. Eighty-one patients transplant lymphoproliferative disorder (EBV+PTLD) with lymphoma (65%), including 60 patients with DLBCL (1%). The iNHL subgroup included 16 patients with (67%), were Ann Arbor stage III–IV at diagnosis, with follicular lymphoma, 2 patients with mucosa-associated 21% and 16%, respectively, having evidence of bone lymphoid tissue lymphoma, 2 patients with nodal marrow involvement at study entry. Disease was classified marginal zone B-cell lymphoma, 1 patient with B-cell as germinal center B-cell (GCB) in 47 patients, non-GCB lymphoplasmacytic lymphoma/immunocytoma, 1 patient in 18 patients, and unknown origin in 24 patients. The with B-cell small lymphocytic lymphoma and 1 patient median number of prior lines of therapy was 3 (range with splenic marginal zone lymphoma. 1–9) in all patients with lymphoma and within the DLBCL Of the patients with DLBCL, 12 were enrolled subgroup, with 17% and 15%, respectively, having during dose escalation, 41 were enrolled to the first previously undergone ASCT. Disease characteristics expansion cohort, and 36 were enrolled to the second for DLBCL patients by dose escalation and expansion expansion cohort. By data cut-off, treatment had been cohort are shown in Supplementary Table 1. The baseline discontinued in all 124 patients. Patient disposition is characteristics were generally similar between the two summarized in Figure 1. DLBCL expansion cohorts, with the exception of median Figure 1: Patient disposition flow diagram. www.oncotarget.com 59 Oncotarget Table 1: Baseline demographic and disease characteristics All DLBCL n = 89 All lymphomasa,b N = 124 Age (years), median (range) 66 (23–91) 66 (23–91) Gender (%), male/female 62/38 61/39 Race (%), white/other 97/2c 96/3c Disease characteristics Time since diagnosis (months), median (range) 16.4 (0.3–269.3) 21.8 (0.3–269.3) Tumor node metastases/Ann Arbor stage at diagnosis, n (%) 60 (67) 81 (65) I 3 (3) 4 (3) II 11 (12) 13 (10) III 19 (21) 22 (18) IV 41 (46) 59 (48) Bone marrow involvement at entry, n (%) 14 (16) 26 (21) Molecular/genetic classification (DLBCL only), n (%) GCB/non-GCB 47 (72d)/18 (28d) Double/triple hit 11 (16e) Treatment history Prior lines of therapy, median (range) 3 (1–9) 3 (1–9) Prior autologous transplant, n (%) 13 (15) 21 (17) a DLBCL (n = 89), iNHL (n = 23), CLL (n = 6), MCL (n = 5), EBV+PTLD (n = 1); bIncludes 36 additional patients with DLBCL and 2 additional patients with iNHL in addition to those included in the previously published analysis; cRace not reported for 1 patient; dPercentage of n = 65 patients with known molecular classification (n = 24 patients had unknown classification); ePercentage of n = 67 patients in whom genetic classification was assessed. time since diagnosis, which was slightly shorter in the Within the subgroup of patients with DLBCL second expansion cohort. (excluding those enrolled in dose escalation), 33 patients in the first expansion cohort were evaluable for response Efficacy and 25 in the second cohort were evaluable for response. The ORR was 24% (95% CI, 11.1–42.3) in the first Best overall responses to mivavotinib are shown in DLBCL cohort (18% with CR and 6% with PR) and 56% Table 2. A total of 95 patients with lymphoma (77%) were (95% CI, 34.9–75.6) in the second DLBCL cohort (20% evaluable for response; 19 patients (20%) achieved a CR with CR and 36% with PR). Considering all response- and 24 (25%) achieved a partial response (PR), resulting evaluable patients with DLBCL enrolled in the study (n = in an ORR of 45% (95% confidence interval [CI], 35.0– 69), 40 patients had GCB type DLBCL with an ORR of 55.8); 40 (42%) patients had a best response of progressive 28% (including 23% with CR), and 12 patients had non- disease (PD). Median time to response among all lymphoma GCB type DLBCL with an ORR of 58% (8% with CR); 17 patients was 1.8 months. The median DOR in patients with patients had unknown GCB type (ORR 47%; CR rate 24%) lymphoma achieving CR or PR was 28.1 months (95% (Supplementary Table 2). Responses were maintained at CI, 5.8–NE). Within the DLBCL subgroup, 69 patients data cut-off/last follow up in all responding patients with (78%) were response-evaluable; of these, 14 patients GCB type DLBCL (n = 11) and in 6/7 responding patients (20%) achieved CR and 12 (17%) achieved PR, resulting with non-GCB DLBCL; DOR was therefore NE. In the in an ORR of 38% (95% CI, 26.3–50.2). Thirty-five subgroup with unknown cell of origin, median DOR was (51%) patients with DLBCL had a best response of PD. In 6.3 months (95% CI, 1.9–NE). The ORR among DLBCL responding patients with DLBCL (n = 26), the median DOR patients with 1 vs. >1 prior lines of therapy was 50% vs. was NE (95% CI, 6.3 months – NE) (Figure 2), 8 patients 35%, while the ORR among DLBCL patients with prior (31%) had responses lasting >12 months and 5 patients transplant vs. without prior transplant was 33% vs. 39%. (19%) had responses lasting >24 months. Among DLBCL The median progression-free survival (PFS) in all patients with PR (n = 12), the median DOR was 5.7 months patients with lymphoma was 2.0 months (95% CI, 1.6– (95% CI, 1.9–NE); among patients with CR, no patients had 3.3); 86 patients (69%) experienced PFS events, of which a PD/relapse event, and data were censored with a range of 53 (62%) were due to progression and 33 (38%) were less than one month (1 day) to 63.0 months with responses due to death. In patients with DLBCL, the median PFS ongoing for all 14 patients at the time of data cut. was 1.6 months (95% CI, 1.5–1.9), and 67 patients (75%) www.oncotarget.com 60 Oncotarget Table 2: Best overall response DLBCL DLBCL DLBCL cohorts Response, n (%) DLBCL escalation All lymphomas cohort 1 cohort 2 (combined) ITT population, n 12 41 36 89 124 ORR (CR + PR) 4 (33) 8 (20) 14 (39) 26 (29) 43 (35) Response-evaluable population, n 11 33 25 69 95 ORR (CR + PR) 4 (36) 8 (24) 14 (56) 26 (38) 43 (45) 95% CI 10.9–69.2 11.1–42.3 34.9–75.6 26.3–50.2 35.0–55.8 Clinical benefit (CR + PR + SD) 6 (55) 14 (42) 14 (56) 34 (49) 55 (58) CR 3 (27) 6 (18) 5 (20) 14 (20) 19 (20) PR 1 (9) 2 (6) 9 (36) 12 (17) 24 (25) SD 2 (18) 6 (18) 0 8 (12) 12 (13) PD 5 (45) 19 (58) 11 (44) 35 (51) 40 (42) Percentages are based on the total number of patients in the response-evaluable population in each column. 2-sided 95% exact binomial CIs were used. Abbreviation: SD: stable disease. experienced PFS events; 41 (61%) were due to disease CI, 6.3–NE) in responding patients (n = 26 patients with progression and 26 (39%) were due to death (Figure 3). CR or PR), compared with 1.5 months (95% CI, 1.0–1.6) Median time to progression (TTP) was 3.7 months (95% in non-responders (n = 43). Median OS was not reached CI, 1.9–7.7) in the overall lymphoma group and 1.8 in responders (95% CI, 8.3–NE) and 3.3 months (95% CI, months (95% CI, 1.6–3.7) in the DLBCL subgroup. 2.1–3.9) in non-responders. Considering patient subgroups The median overall survival (OS) was 8.3 months based on cell of origin, median PFS was similar in patients (95% CI, 3.7–NE) in patients with lymphoma and 3.9 with GCB (1.6 months [95% CI, 1.3–2.1]), non-GCB months (95% CI, 2.1–NE) in patients with DLBCL. (1.7 months [1.1–3.7]) and unknown origin (1.6 months Overall, 52 patients with lymphoma (42%), including 42 [0.9–3.5]) DLBCL (Supplementary Figure 1A). However, patients in the DLBCL cohorts (47%), died within the time there was a higher proportion of PD events in GCB patients, period between the first dose and the last follow-up. while there were more deaths in non-GCB patients, and OS Within the DLBCL response-evaluable differed accordingly, with median OS 19.9 months (95% population (n = 69), median PFS was 19.9 months (95% CI, 2.4–NE) and 2.1 months (95% CI, 1.5–NE), respectively. Figure 2: Kaplan–Meier curve for estimated median DOR in the DLBCL combined cohort (response-evaluable population). DOR was defined as the time from the date of first documentation of PR or better to the date of first documentation of PD or relapse. Among patients with CR, no patients had a PD/relapse event, and data were censored with a range of less than one month (1 day) to 63.0 months with responses ongoing for all 14 patients at the time of data cut. Among patients with PR, 4 patients had a PD/relapse event, and data were censored for the remaining 8 patients. www.oncotarget.com 61 Oncotarget Table 3: Overview of TEAEs (safety population) Adverse event n, (%) DLBCL cohorts (combined) n = 89 All lymphomas N = 124 Any TEAEs 89 (100) 124 (100) Related 82 (92) 114 (92) Not related 88 (99) 122 (98) Grade 1 85 (96) 117 (94) Grade 2 83 (93) 112 (90) Grade ≥3 85 (96) 119 (96) Grade ≥3 related 65 (73) 94 (76) Leading to discontinuation 32 (36) 48 (39) Serious TEAEs 65 (73) 94 (76) Related 15 (17) 33 (27) Not related 58 (65) 79 (64) Leading to discontinuation 20 (22) 32 (26) Deaths 32 (36) 39 (31) Related 2 4 TEAEs are defined as any adverse event that occurs after administration of the first dose of study treatment through 28 days after last dose of study treatment, or until the start of subsequent antineoplastic therapy. Deaths occurred within 28 days of last treatment dose. Percentages are based on the number of patients in each treatment group for the designated population of this table. Median OS in the unknown origin subgroup was 3.7 months with DLBCL. Safety is summarized in Tables 3–5 for (95% CI, 1.2–NE) (Supplementary Figure 1B). the total patients with lymphoma and for the subgroup of patients with DLBCL. Safety was generally consistent Safety between the overall lymphoma population and the DLBCL subgroup and so is only described for patients All patients received at least one dose of with lymphoma. mivavotinib and were evaluable for safety. Patients All patients with lymphoma experienced at least received a median of 2 treatment cycles (range 1–68), one TEAE; 96% experienced a grade ≥3 TEAE, and and the median treatment duration was 6.8 weeks for 76% experienced a grade ≥3 TEAE considered by the all patients with lymphoma and 6.0 weeks for patients investigator to be related to mivavotinib (Table 3). Figure 3: Kaplan–Meier curve for estimated median PFS in the DLBCL combined cohort (safety population). PFS is defined as the time from the date of the first study treatment administration to the date of the first documentation of progressive disease or death. www.oncotarget.com 62 Oncotarget Table 4: Most frequent TEAEs occurring in ≥10% of patients by preferred term (safety population) Preferred term (n [%]) DLBCL cohorts (combined) n = 89 All lymphomas N = 124 Any TEAE 89 (100) 122 (98) AST increased 56 (63) 75 (60) Pyrexia 44 (49) 69 (56) Amylase increased 43 (48) 57 (46) Hypophosphatemia 34 (38) 51 (41) Anemia 35 (39) 50 (40) Blood CPK increased 37 (42) 50 (40) Diarrhea 33 (37) 48 (39) Lipase increased 34 (38) 45 (36) Fatigue 30 (34) 43 (35) ALT increased 32 (36) 39 (31) Neutropenia 29 (33) 39 (31) Nausea 25 (28) 37 (30) Cough 22 (25) 34 (27) Thrombocytopenia 24 (27) 33 (27) Asthenia 22 (25) 32 (26) Decreased appetite 20 (22) 28 (23) Periorbital edema 17 (19) 27 (22) Blood alkaline phosphate increased 19 (21) 26 (21) Constipation 19 (21) 26 (21) Vomiting 17 (19) 26 (21) Pneumonia 14 (16) 25 (20) Edema peripheral 17 (19) 24 (19) Hypokalemia 14 (16) 23 (19) Abdominal pain 18 (20) 22 (18) Headache 11 (12) 22 (18) Blood creatine increased 16 (18) 20 (16) Dyspnea 14 (16) 19 (15) Cytomegalovirus infection reactivation 14 (16) 18 (15) Urinary tract infection 10 (11) 17 (14) Blood lactate dehydrogenase increased 12 (13) 16 (13) Chills 8 (9) 16 (13) Gamma-glutamyltransferase increased 10 (11) 16 (13) Hypertension 12 (13) 16 (13) Stomatitis 10 (11) 16 (13) Back pain 10 (11) 15 (12) Night sweats 9 (10) 14 (11) Oral candidiasis 6 (7) 14 (11) Hyponatremia 8 (9) 13 (10) Rash maculo-papular 10 (11) 13 (10) TEAEs are defined as any adverse event that occurs after administration of the first dose of study treatment through 28 days after the last dose of study treatment, or until the start of subsequent antineoplastic therapy. Abbreviations: ALT: alanine aminotransferase; CPK: creatine phosphokinase. www.oncotarget.com 63 Oncotarget Table 5: Most common grade ≥3 TEAEs occurring in ≥10% of patients by preferred term (safety population) Preferred term, n (%) DLBCL cohorts (combined) n = 89 All lymphomas N = 124 Patients with grade ≥3 TEAE 85 (96) 119 (96) Increased amylase 28 (31) 36 (29) Neutropenia 26 (29) 34 (27) Hypophosphatemia 19 (21) 32 (26) Anemia 15 (17) 23 (19) Blood CPK increased 15 (17) 22 (18) Lipase increased 15 (17) 22 (18) Thrombocytopenia 13 (15) 19 (15) Pneumonia 7 (8) 14 (11) Pyrexia 8 (9) 13 (10) AST increased 11 (12) 12 (10) TEAEs are defined as any adverse event that occurs after administration of the first dose of study treatment through 28 days after the last dose of study treatment, or until the start of subsequent antineoplastic therapy. The most common TEAEs occurring in ≥10% of all was consistent with the previous report, with no new patients were increased AST (60%), pyrexia (56%), and signals identified. increased amylase (46%) (Table 4). The most frequent The ORR and CR rates reported here for all grade ≥3 TEAEs occurring in ≥10% of all patients patients with lymphoma including those with DLBCL are were increased amylase (29%), neutropenia (27%), and clinically meaningful, given the limited treatment options hypophosphatemia (26%) (Table 5). Granulocyte colony and poor outcomes for these patients with relapsed or stimulating factor (G-CSF) was administered to 28 patients refractory disease [1–4]. In addition, some of the patients for the management of grade ≥3 neutropenia. Overall, 39% were heavily pretreated with a median of 3 prior lines of patients with lymphoma experienced TEAEs resulting of therapy. Responses were also slightly improved in in mivavotinib discontinuation; the most common TEAEs the second DLBCL expansion cohort (56%) vs. the first leading to discontinuation were pneumonia (n = 6), expansion cohort (24%), which might be due to differences pneumonitis (n = 3), respiratory failure (n = 4), and in eligibility criteria (see Methods section) between the neutropenia (n = 4). Serious TEAEs were experienced by two cohorts. There was also a higher proportion of patients 76% of patients; 27% of patients had serious TEAEs which with non-GCB lymphoma in the second cohort (36% vs. were related to mivavotinib, and 26% had serious TEAEs 21%; Supplementary Table 1). However, baseline disease which resulted in discontinuation. Overall, 39 patients characteristics were generally consistent between the two with lymphoma died on study; 4 deaths were considered cohorts, except for a shorter median time since diagnosis related to mivavotinib and were due to complications from in the second. Similarly, the ORR was higher in patients pneumocystis pneumonia, multiorgan failure, respiratory with only 1 prior line of therapy (50%) vs. patients with failure and disseminated varicella (n = 1 each). >1 prior line of therapy (35%). Further research would be required to determine whether this reflects a higher benefit DISCUSSION of mivavotinib therapy earlier in the treatment paradigm. Meaningful response rates were observed in both Primary data from this phase I, first-in-human study GCB and non-GCB DLBCL subtypes, consistent with investigating the safety, tolerability, and preliminary the findings of our initial report [23]. There are known efficacy of SYK/FLT3 inhibitor mivavotinib, conducted biological differences between these two DLBCL in patients with advanced solid tumors or lymphoma subtypes, as activated B-cell-like DLBCL (which malignancies, were previously reported [23]. Here we comprises the majority of non-GCB) is known to be provide updated results for the total cohort of patients with more dependent on B-cell receptor (BCR) pathway lymphoma (N = 124) and present findings for an expanded signaling involving SYK than GCB DLBCL [2, 4, 25, subgroup of patients with DLBCL (n = 89). In this updated 26]. Although the patient numbers were small (n = 12 analysis, mivavotinib demonstrated encouraging efficacy patients with non-GCB subtype), there was a higher in patients with lymphoma and in the subgroup of patients response rate observed in patients with non-GCB DLBCL with DLBCL, with ORRs of 45% and 38%, respectively, (58% vs. 28%), which might have been a result of these and a CR rate of 20% in both groups. The safety profile biological differences; however, the majority were partial www.oncotarget.com 64 Oncotarget responses which did not translate into longer OS. In Several CD19-targeted CAR T-cell therapy agents have been contrast, patients with GCB subtype had a higher rate of approved for treatment, including axicabtagene ciloleucel CR (23% vs. 8%) and longer OS (19.9 vs. 2.1 months), [14], lisocabtagene maroleucel [36], and tisagenlecleucel which might have been expected since some studies have [37, 38]. Considering these recent developments, there may reported a more aggressive course with non-GCB DLBCL be a role for mivavotinib combinations in the treatment subtypes resulting in worse outcomes for patients [27]. pathway of patients with relapsed or refractory DLBCL, Given the differences in eligibility criteria and the known potentially as a bridge to CAR T-cell therapy or as an option heterogeneity of DLBCL pathogenesis and presentation, post-CAR T-cell therapy. further genomic analyses of non-GCB and GCB DLBCL Overall, safety findings were consistent with the subtypes to characterize markers for response to targeted primary analysis and toxicity was manageable despite treatment could enable the identification of patient a high proportion of patients experiencing grade ≥3 populations and DLBCL subtype(s) which may derive TEAEs (96% all cause, and 76% determined by the therapeutic benefit from a given treatment. For example, investigator as being related to mivavotinib). The most mutations in genes for key regulators of the B-cell and/ common grade ≥3 TEAEs were increased amylase, or Toll-like receptor pathways such as MYD88 or neutropenia and hypophosphatemia; other common grade CD79B [28] could suggest potential for modification by ≥3 TEAEs included elevations in clinical laboratory treatments targeting these pathways, including SYK/FLT3 investigations, including AST, amylase, lipase and inhibitors such as mivavotinib. blood creatine phosphokinase, which were largely Although population-level outcomes data are limited asymptomatic and reversible upon dose reduction or for patients with relapsed or refractory DLBCL, in the large discontinuation of the study drug, consistent with the retrospective SCHOLAR study of 636 patients, estimated initial analysis. The most common hematologic grade objective response rates were 26% with a CR rate of 7% ≥3 TEAE was neutropenia (27%), with most of these and a median OS of 6.3 months [29]. The response rates patients receiving G-CSF support to manage it; this was reported in the present study (38% ORR, including 20% largely expected due to the number of patients with bone CR) are improved compared with those estimated in this marrow involvement at study entry. Other hematologic retrospective study, despite the median OS of 3.9 months grade ≥3 TEAEs including anemia and thrombocytopenia being lower than what might be expected in this patient occurred in 19% and 15% of patients, respectively. population. In addition, agents which recently received The most common metabolic disorder of grade ≥3 was US Food and Drug Administration accelerated approval hypophosphatemia (26%). Serious TEAEs were reported for treatment of DLBCL based on encouraging response in 76% of patients; however, only 27% of patients had rates such as selinexor [30], polatuzumab vedotin (in serious TEAEs determined by the investigator as being several combinations), tafasitamab (in combination related to mivavotinib, and only 26% of patients had with lenalidomide), and CAR T-cell therapy such as serious TEAEs that led to discontinuation. There were axicabtagene ciloleucel and tisagenlecleucel [14, 31], have 39 on-study deaths among patients with lymphoma, 4 of achieved improved, or similar response rates than those which were considered related to mivavotinib and were reported with mivavotinib. However, a subsequent phase due to complications from pneumocystis pneumonia, II study of mivavotinib monotherapy, which enrolled 49 multiorgan failure, respiratory failure and disseminated patients with relapsed or refractory DLBCL (with similar varicella. The most common reasons for discontinuation eligibility criteria to the second expansion cohort) was were pneumonia and pneumonitis; further intervention terminated due to lack of efficacy [24]. Given the smaller to reduce the risk of opportunistic infection (e.g., number of patients in the study and perhaps because not Pneumocystis jirovecii pneumonia) or viral reactivation all patients started dosing at 100 mg QD, with 25 patients could further improve the safety profile of mivavotinib starting treatments at 60 mg to evaluate a ramp up dosing in future studies. schedule, it is possible that such differences contributed to In conclusion, the anti-tumor efficacy of mivavotinib the lack of efficacy observed. Altogether, these data suggest monotherapy observed in the primary analysis of this that a biomarker selection strategy, further dose refinement, study was confirmed in our analysis of patients with and combinations of mivavotinib with other agents in lymphoma, including an expanded cohort of patients DLBCL warrant further exploration. An ongoing phase I with relapsed or refractory DLBCL, with responses that study is investigating the safety and efficacy of mivavotinib were deep and durable. These findings support SYK as with R-CHOP as first-line treatment for patients with high- a potential therapeutic target for the treatment of this risk DLBCL [32], while a phase II study of mivavotinib population of patients. Further investigation of markers in patients with relapsed or refractory non-GCB DLBCL to predict response to SYK inhibition, and research into is investigating efficacy in subgroups defined according to possible mivavotinib treatment combinations, are needed genetic biomarkers [33]. to develop mivavotinib further, and to provide more CAR T-cell therapy is expected to become the new extensive therapy options for patients with relapsed or standard of care for relapsed or refractory DLBCL [34, 35]. refractory DLBCL who have limited treatment options. www.oncotarget.com 65 Oncotarget MATERIALS AND METHODS expansion cohort could also have been previously treated with BCR in-pathway inhibitors not directly targeting Study design SYK. For patients in both DLBCL cohorts, DLBCL cell of origin was determined by immunohistochemistry This was an open-label, multicenter, phase I, dose when available (local laboratory) and was classified escalation and expansion study of QD, oral, single-agent as GCB or non-GCB [40]. Cytogenetic profiling was mivavotinib in patients with advanced solid tumors performed using fluorescence in-situ hybridization where or lymphoid malignancies. The full study design and available, although this was not mandated, and patients methods have previously been reported [23]. Here we with multiple gene rearrangements (MYC and BCL2 and/ focus on aspects pertinent to patients with lymphoma, and or BCL6) were identified as having double- or triple-hit particularly those with DLBCL. lymphoma. Briefly, in the dose escalation phase, adults with a confirmed diagnosis of lymphoma for which no standard Assessments treatment was available were enrolled to receive escalating doses of oral mivavotinib (60 mg, 80 mg, 100 mg or 120 Efficacy endpoints including ORR, DOR, PFS, TTP mg QD) in an accelerated 3+3 dose escalation design. In and OS were analyzed for all patients with lymphoma, the expansion phase, patients with lymphoid malignancies including the additional DLBCL expansion cohort, and received mivavotinib 100 mg QD (the MTD from the dose for the full DLBCL subgroup (both expansion cohorts and escalation phase) in one of six disease-specific cohorts: the escalation cohort combined), based on data collected CLL, iNHL, MCL, EBV+PTLD and two separate up to June 29, 2021. This report includes extended follow- DLBCL expansion cohorts. All patients in the escalation up data for patients included in the initial analysis, as and expansion phases received oral mivavotinib at their well as data for additional DLBCL patients. DOR was assigned dosage in continuous 28-day cycles until disease also analyzed among the separate DLBCL cohorts, and progression or unacceptable toxicity. assessments of ORR were made in the GCB, non-GCB, or unknown GCB classified DLBCL subgroups. Patients Responses were assessed in patients who received at least one dose of study drug and had at least one Lymphoma patients enrolled in both the escalation post-baseline disease assessment (response-evaluable and expansion phases had histologically or cytologically population). Assessments were performed at cycles 2, 4, confirmed lymphoma, according to the modified 6, then every 3 cycles through cycle 24, and thereafter International Working Group (IWG) 2007 criteria for every 6 cycles (until disease progression or the start of malignant lymphoma [39], or the International Workshop alternative therapies). PFS, TTP and OS were evaluated on Chronic Lymphocytic Leukemia 2008 criteria. in the ITT population, based on the time from the date Patients in the expansion cohorts also had at least one of first study drug administration to the date of first site of measurable or evaluable disease confirmed by documentation of PD (PFS/TTP) or death (PFS/OS). computed tomography. Additional eligibility criteria The safety population was defined as all patients included an Eastern Cooperative Oncology Group in any lymphoma cohort receiving at least one dose of performance status of 0–1, adequate organ function, a study drug. Adverse events and toxicity were assessed life expectancy longer than 3 months, and recovery from continually during treatment and were graded in reversible effects of prior anti-cancer therapy. accordance with the National Cancer Institute Common Patients enrolled in the first DLBCL expansion Terminology Criteria for Adverse Events version 4.03. cohort had pathologically confirmed DLBCL with at Statistical analyses were primarily descriptive least one site of measurable disease based on IWG without formal hypothesis testing. Median DOR, PFS and criteria for malignant lymphoma [39], had relapsed or OS were estimated using the Kaplan–Meier method. refractory disease after at least one line of therapy, and were ineligible for or had progressed after receiving high- Data sharing statement dose chemotherapy/ASCT. Patients enrolled in the second DLBCL expansion cohort had histologically-confirmed Requests for de-identified datasets for the results DLBCL, including de novo DLBCL or transformed reported in this publication will be made available disease from iNHL, and had relapsed or refractory disease to qualified researchers following submission of a after ≥2 lines of chemotherapy (based on a standard of methodologically sound proposal. Data will be made care which included rituximab plus anthracycline [or available for such requests following online publication equivalent if contraindicated]) and an additional systemic of this article and for 1 year thereafter in compliance with chemotherapy as second-line salvage therapy (that may applicable privacy laws, data protection, and requirements have included ASCT), but had not failed >4 prior lines for consent and anonymization. Calithera does not share of therapy. Patients enrolled in the second DLBCL identified participant data or a data dictionary. www.oncotarget.com 66 Oncotarget Abbreviations CONFLICTS OF INTEREST ALT: alanine aminotransferase; ASCT: autologous LIG is on the Data Safety and Monitoring stem-cell transplant; AST: aspartate aminotransferase; Board (DSMB) for Janssen and is a consultant for Ono BCR: B-cell receptor; CAR: CD19-targeted chimeric Pharmaceuticals. RK received research support from antigen receptor; CI: confidence interval; CLL: Takeda. RP received honoraria and consultancy fees from chronic lymphocytic leukemia; CPK: creatine Takeda, Janssen, BMS, GSK and Roche. HAB is employed phosphokinase; CR: complete response; DLBCL: by Sarah Cannon and HCA Healthcare; owns stocks/ diffuse large B-cell lymphoma; DOR: duration of shares at HCA Healthcare; holds a non-compensated response; EBV+PTLD: Epstein Barr Virus-positive post- consulting position for AstraZeneca, Bayer, Bristol-Myers transplant lymphoproliferative disorder; FLT3: FMS- Squibb, Boehringer Ingelheim, GRAIL, Incyte, Novartis, like tyrosine kinase 3; GCB: germinal center B-cell; TG Therapeutics, Vincerx Pharma; and reports grants or G-CSF: granulocyte colony stimulating factor; iNHL: funds paid to their institution from AbbVie, Agios, ARMO indolent non-Hodgkin’s lymphoma; ITT: intention-to- Biosciences, Array BioPharma, AstraZeneca, Bayer, treat; IWG: International Working Group; MCL: mantle BeiGene, BioAtla, BioMed Valley Discoveries, Boehringer cell lymphoma; MTD: maximum tolerated dose; NE: Ingelheim, Bristol-Myers Squibb, CALGB, CicloMed, not estimable; ORR: overall response rate; OS: overall eFFECTOR Therapeutics, Lilly, EMD Serono, Roche/ survival; PD: progressive disease; PFS: progression- Genentech, GlaxoSmithKline, Harpoon Therapeutics, free survival; PR: partial response; QD: once daily; Hengrui Therapeutics, Incyte, Janssen, Jounce R-CHOP: rituximab plus cyclophosphamide, doxorubicin, Therapeutics, Kymab, Macrogenics, MedImmune, Merck, vincristine, and prednisone; SD: stable disease; SYK: Millennium, Moderna, Pfizer, Revolution Medicine, spleen tyrosine kinase; TEAE: treatment-emergent adverse Foundation Medicine, SeaGen, Tesaro, TG Therapeutics, events; TTP: time to progression. Verastem, Vertex Pharmaceuticals, Xbiotech, Zymeworks, Arch Oncology, Arvinas, Coordination Pharmaceuticals, Author contributions NGM Biopharmaceuticals, Gossamer Bio, Ryvu Therapeutics, and BioTheryX. SM received honoraria LIG, SM, IP, YS and FB were involved in the from Karyopharm, GSK, BMS, Janssen and Oncopeptides. conception and design of the study. LIG, RK, JBK, RP, MRP reports leadership at ION Pharma; honoraria from HAB, SF, MRP, GG, DES, FIC, JR, JPO, PLZ, SPI, WT, Pfizer, Pharmacyclics, Bayer, Janssen, Genentech, and HM, IP, SW, SK, YY, JZ, KS, YS, CC, and FB made Adaptive Biotechnologies; consulting/advisory role at substantial contributions to the acquisition, analysis and Pharmacyclics, Janssen, Pfizer, and EMD Serono; and interpretation of data. All authors drafted the work or speakers’ bureaus at Exelixis, Genentech, Roche, Taiho revised it critically for important intellectual content. Pharmaceutical, and Celgene. GG reports participation All authors approved of the final version to be published in advisory boards for Roche, IQVIA, Kite-Gilead, and agree to be accountable for all aspects of the work in Italfarmaco, Takeda, Ideogen, and Genmab; support for ensuring that questions related to the accuracy or integrity attending meetings from Roche, and Sandoz; and training of any part of the work are appropriately investigated and activities for Roche, Takeda, Clinigen, Ideogen, Beigene, resolved. and Incyte; and individual scientific consultancy for Takeda. DES reports honoraria from AbbVie, AstraZeneca, ACKNOWLEDGMENTS Beigene, Janssen, Lily, Roche, and Takeda; consulting fees from AbbVie, ASTEX, AstraZeneca, Beigene, Janssen, This study was sponsored by Millennium and Kyowa Kirin; and financial support for conference/ Pharmaceuticals, Inc., a wholly owned subsidiary of travel from AbbVie, Novartis, and Roche. FIC reports Takeda Pharmaceutical Company Limited. We thank all participation in advisory council/committees for Eli-Lilly, of the patients and their families, and the investigators Bristol Meyers Squibb, MSD, Roche, Merck-Serono, and staff at all clinical sites, for their participation in the Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer trial. The authors acknowledge Tori Gordon, BSc, of Ingelheim, Incyte, Astella, GSK, Sotio, Eisai, Daiichi- Ashfield MedComms, an Inizio Company, for medical Sankyo, Taiho, Servier; honoraria from Eli-Lilly, Eisai, writing support for the development of this manuscript Servier, Roche; and grants or funds from Eli-Lilly, under the direction of the authors, which was funded by Janssen-Cilag. JPO reports participation in advisory Takeda Pharmaceuticals U.S.A., Inc., and complied with council/committees for Janssen, Takeda, and Roche; and the Good Publication Practice 3 ethical guidelines (Battisti grants/funds from Takeda. PLZ reports participation in WP, et al. Ann Intern Med 2015. 163: 461–4). R. Popat advisory council/committees for Takeda, MSD, AbbVie, and W. Townsend acknowledge support from the National BMS, and ADC Therapeutics; and honoraria from Institute for Health Research University College London Takeda, MSD, BMS, Gilead, Novartis, Kyowa Kirin, Hospitals Biomedical Research Centre. Sanofi, Incyte, Roche, Eusapharma, Janssen, Incyte, and www.oncotarget.com 67 Oncotarget AstraZeneca. SPI reports honoraria from Curebio, MD B-cell lymphoma. Blood. 2011; 118:6342–52. https://doi. Education, and Target Oncology; consulting fees from org/10.1182/blood-2011-02-333773. [PubMed] Seagen, Yingli, Legend, and Securabio; and grants/funds 4. Chan A, Dogan A. Prognostic and Predictive Biomarkers in from Merck, Seagen, CRISPRx, Legend, Myeloid, Innate, Diffuse Large B-cell Lymphoma. Surg Pathol Clin. 2019; Rhizen, Spectrum, Affimed, Takeda, Yingli, and Ono. 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