THE FIRST‐IN‐CLASS ANTI‐CD47 ANTIBODY HU5F9‐G4 + RITUXIMAB INDUCES DURABLE RESPONSES IN RELAPSED/REFRACTORY DLBCL AND INDOLENT LYMPHOMA: INTERIM PHASE 1B/2 RESULTS

Abstract

Introduction: Hu5F9-G4 (5F9) is a first-in-class IgG4 antibody targeting CD47, a macrophage immune checkpoint and “don't eat me” signal on cancers leading to phagocytosis of tumor cells. Pre-clinically, 5F9 synergizes with rituximab to eliminate lymphoma by enhancing antibody-dependent cellular phagocytosis. 5F9+rituximab had encouraging safety/efficacy in a Phase (Ph)1b dose escalation cohort in relapsed/refractory (r/r) DLBCL and FL patients that were rituximab-refractory (Advani et al., NEJM 2018). We report on extended follow up of this Ph1b cohort and preliminary Ph2 data. Methods: The Ph2 enrolled: 1) DLBCL: primary refractory or r/r to ≥ 2 prior therapies, ineligible for CAR-T therapy; and 2) indolent lymphoma (FL/MZL) r/r to ≥ 2 prior therapies. A 5F9 priming dose was used to mitigate on-target anemia; followed by weekly or Q2 week maintenance doses. Based on a potential dose-response seen in Ph1b, 5F9 maintenance doses of 30 and 45 mg/kg were tested with rituximab. Results: 100 patients (63 DLBCL, 35 FL, 2 MZL) have been treated in both Ph1b+2 cohorts. Median age (range) was 66 years (21-88) with 3 median prior therapies (range 1-10). 84% were rituximab-refractory and 72% refractory to their last therapy. 5F9+rituximab was well-tolerated at 5F9 doses up to 45 mg/kg with no maximum tolerated dose reached or significant dose-dependent toxicities. Treatment-related AEs (TRAEs) in >10% of patients included infusion reactions (38%), headache (34%), chills (30%), fatigue (30%), anemia (27%), nausea (24%), pyrexia (23%) vomiting (13%), and back pain (11%). The majority were G1/2 with 7% or lower being G3/4, except G3 anemia (15%) which was an expected transient first-dose effect. Treatment discontinuation from TRAEs occurred in only 4% of patients. As of Feb 2019, for Ph1b patients dosed from 10-30 mg/kg (n=22), at a median follow up of 12 months (DLBCL) and 18 months (FL), the median duration of response had not been reached (DLBCL range: 2.4 – 20+ months; FL range: 6.2 – 22.6+ months), including some durable CRs for > 20 months. Of 100 patients enrolled, 75 patients were efficacy evaluable, 8 were not, and 17 had first assessment pending. Pooled data from Ph1b+2 efficacy evaluable patients (n=75) show an objective response rate (ORR) and CR rate of 49% and 21%, respectively. In indolent lymphoma (n=28 FL, 1 MZL), the ORR and CR rate was 66% and 24%, respectively. In DLBCL (n=46), the ORR/CR rate was 39/20%. Median time to response for responding patients was rapid at 1.8 months. The ORR for patients treated with 30 mg/kg 5F9 (n=59) was 47% and at 45 mg/kg was 71% in a limited number (n=7). Accrual is ongoing and additional data at the 45 mg/kg dose will be presented. Conclusions: 5F9+rituximab is a novel immunotherapy blocking a key macrophage/cancer checkpoint. It is well tolerated with rapid and durable responses observed in heavily pre-treated DLBCL and indolent lymphoma patients. Ph2 enrollment is ongoing (NCT02953509). Funded by Forty Seven and the Leukemia and Lymphoma Society. Keywords: diffuse large B-cell lymphoma (DLBCL); indolent lymphoma; macrophages. Disclosures: Advani, R: Consultant Advisory Role: AstraZeneca, Autolous, Bayer Healthcare Pharmaceuticals, Cell Medica, Genentech, Gilead, Kite Pharma, Kyowa, Pharmacyclics, Seattle Genetics, Takeda; Research Funding: Agensys, Celgene, Forty Seven Inc., Genentech/Roche, Infinity, Janssen Pharmaceuticals, Kura, Merck, Millennium, Pharmacyclics, Regeneron, Seattle Genetics. Lynn, J: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc. Huang, J: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc. Agoram, B: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc. Volkmer, J: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc.; Other Remuneration: Intellectual property licensed to Forty Seven, Inc. Takimoto, C: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc. Chao, M: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc.; Other Remuneration: Intellectual property licensed to Forty Seven, Inc. Mehta, A: Consultant Advisory Role: Spectrum, Celgene, Kite, BMS; Research Funding: Incyte, Roche, Merck, BMS, Epizyme, Seattle Genetics, Kite, Forty Seven Inc, Takeda, Rhizen, Juno; Other Remuneration: Speaker's Bureau: Astra Zeneca, Kite, Spectrum, Kyowa Kirin, Seattle Genetics.