Cheson, Bruce D.

Abstract BACKGROUND: SGN-40 is a humanized monoclonal antibody that targets CD40. Upon binding to CD40, SGN-40 triggers pro-apoptotic signal transduction pathways and mediates effector cell functions (ADCC and ADCP). SGN-40 demonstrated preliminary anti-tumor activity in a phase 1 study of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL) patients (ASH 2006, Abstract 695). METHODS: We conducted a multicenter, phase 2, open-label study to determine the overall response rate and toxicity profile of SGN-40 in patients with relapsed DLBCL. Tumor samples were assessed by a central lab for pathology confirmation and CD40 expression. Eligible patients had de novo or transformed DLBCL at diagnosis and were excluded if previously treated for indolent lymphoma. Required prior therapy consisted of combination chemotherapy with rituximab and, if eligible, autologous stem cell transplantation. Patients received 6 intravenous infusions of SGN-40 over 5 weeks (Cycle 1) with intra-patient dose loading (1 mg/kg on Day 1; 2 mg/kg on Day 4; 4 mg/kg on Day 8) and 8 mg/kg/wk thereafter. Responding patients and those with stable disease were eligible to continue therapy until disease progression or a maximum of 12 cycles. RESULTS: Forty-six patients (28 M, 18 F), with a median age of 72 years (range 17–85), were enrolled at 10 centers in the US. Patients were heavily pre-treated, with a median of 4 prior systemic chemotherapy regimens (range 1–10). Immunohistochemistry analysis of patient tumor samples demonstrated high expression of CD40 in all patients with the exception of 1 patient who was negative. Thirty-eight of the 46 patients met predefined criteria for evaluation (completed dose loading and had no major protocol violations). Best responses seen were CR (n=2, 5%) and PR (n=2, 5%), yielding an ORR of 10%. Furthermore, 9 (24%) patients had SD as best response. Reductions in tumor size were seen in approximately one-third of patients. Twenty (53%) patients had PD and 5 (13%) patients have yet to be assessed. Treatment with SGN-40 was generally well tolerated. Grade 3/4 events that occurred in more than 1 patient in the intent-to-treat population (N=46), regardless of drug attribution were thrombocytopenia (n=5); neutropenia (n=4); and anemia, fatigue, pneumonia, hyponatremia, DVT, and disease progression (n=2 pts each). Of these events, only fatigue (n=2) and neutropenia (n=2) were considered drug related by the investigator. CONCLUSION: Monotherapy with SGN-40 in DLBCL patients is well tolerated and resulted in objective responses consistent with the previous phase 1 experience. These data support further evaluation of SGN-40 in combination with chemotherapy in non-Hodgkin lymphoma; 3 combination clinical trials are ongoing. Retrospective correlation of clinical outcome and a gene signature that includes baseline CD40 activation status are planned.

Background Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) in adults. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) remains the standard of care for newly diagnosed DLBCL, with cure rates of 60-70%. However, more effective front-line options are needed to further improve outcomes, particularly in high-risk patients (Sehn LH, Gascoyne RD. Blood 2015;125:22). Approximately 15-20% of treatment-naïve patients with DLBCL have CD20-low expressing tumors, while CD19 is expressed in >90% of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. Blood 2009;113:3773; Prevodnik VK, et al. Diagnostic Pathol 2011;6:33). CD19 is a B-lymphocyte lineage-specific surface antigen that is widely expressed in mature B-cell malignancies, including DLBCL. CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation, and is, therefore, an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized anti-CD19 monoclonal antibody with an engineered constant region (Fc) that enhances Fc-γ receptor binding affinity on effector cells, thereby enhancing antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Preliminary data in DLBCL cell lines suggest that combined targeting of CD19 and CD20 with tafasitamab and rituximab, respectively, could have synergistic cytotoxic effects. Monotherapy with tafasitamab has shown clinical activity and acceptable safety in a Phase I study in relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (NCT01161511) and in a Phase IIa study in R/R NHL (NCT01685008). In patients with R/R DLBCL, treatment with single agent tafasitamab until progression led to a 26% objective response rate (ORR) with several long-term responses (Jurczak W, et al. Ann Oncol 2018; 29:1266). Preclinical in vitro and in vivo data have demonstrated increased combinatorial antitumor effects with tafasitamab and the immunomodulatory agent lenalidomide (LEN). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, treatment with tafasitamab/LEN achieved an ORR of 60%, a complete response (CR) rate of 42.5% and a median progression-free survival (PFS) of 12.1 months (Salles GA, et al. ICML 2019; Abstr 124). This combination received breakthrough therapy designation by the US Food and Drug Administration. Study design and methods First-MIND is a Phase Ib, open-label, multicenter, randomized trial of tafasitamab/R-CHOP or tafasitamab/LEN/R-CHOP in patients with newly diagnosed DLBCL (Figure 1). Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index 2-5). Key exclusion criteria include known double- or triple-hit lymphoma, and transformed or composite lymphoma. Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously [IV], on Days [D] 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) and LEN (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). The trial includes a safety run-in phase and a main phase. In the safety run-in phase, 12 patients will be enrolled in each arm. If no unexpected safety signals suspected to be related to the addition of tafasitamab ± LEN to R-CHOP are observed, an additional 18 patients will be enrolled in each arm in the main phase. The primary objective of the trial is to assess safety; secondary objectives include evaluation of efficacy (ORR and PET-assessed CR rate at end of treatment, PFS, overall survival, event-free survival, time to next anti-lymphoma treatment), long-term safety and pharmacokinetics, and immunogenicity of tafasitamab in each arm. Exploratory objectives will include the assessment of biomarkers in peripheral blood (natural killer [NK] cell count, cell-free circulating tumor DNA) and tumor tissue (DLBCL cell of origin, NK cell or macrophage count/gene expression profile, CD19 and CD20 expression) that may be relevant to the mechanism of action and/or response to study treatment. As this is a Phase Ib study to primarily explore safety, no formal statistical hypothesis is considered for the sample size calculation; approximately 60 patients will be recruited across Europe and the US. Disclosures Burke: Gilead: Consultancy; Roche/Genentech: Consultancy; Celgene: Consultancy. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: Travel grants, Research Funding; Roche: Other: Travel grants, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Cheson:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Consultancy, Research Funding; Kite: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Nowakowski:Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Rosenwald:MorphoSys: Consultancy. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Staber:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trněný:Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria. Westin:Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding. Brugger:MorphoSys: Employment; AstraZeneca: Equity Ownership. Fingerle-Rowson:MorphoSys AG: Employment. Klanova:MorphoSys AG: Employment. Würth:MorphoSys AG: Employment. Truemper:Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Roche: Research Funding; Mundipharma: Research Funding.