S867 THE FIRST‐IN‐CLASS ANTI‐CD47 ANTIBODY HU5F9‐G4 WITH RITUXIMAB INDUCES DURABLE RESPONSES IN RELAPSED/REFRACTORY DLBCL AND INDOLENT LYMPHOMA: INTERIM PHASE 1B/2 RESULTS
Authors: Advani R. , Bartlett N. , Smith S. , Roschewski M. , Popplewell L. , Flinn I. , Collins G. , Ghosh N. , LaCasce A. , Asch A. , Kline J. , Kesavan M. , Tran T. , Lynn J. , Huang J. , Agoram B. , Volkmer J.‐P. , Takimoto C. , Chao M. , Mehta A. 
Published: June 2019

Background: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 demonstrated encouraging safety/efficacy in a Phase (Ph)1b dose escalation cohort in patients with relapsed/refractory (r/r) DLBCL and FL that were rituximab‐refractory (Advani et al., NEJM 2018). Herein we report on extended follow up of this Ph1b cohort and preliminary Ph2 data.Aims:The primary objectives were to determine the safety/efficacy of escalating doses of 5F9+rituximab in patients with r/r DLBCL and indolent lymphoma.Methods:The Ph2 enrolled: 1) DLBCL: primary refractory or r/r to at least 2 prior therapies, ineligible for CAR‐T therapy; and 2) indolent lymphoma (FL and MZL) r/r to at least 2 prior therapies. A 5F9 prime/maintenance dose regimen 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:A total of 100 patients (63 DLBCL, 35 FL, 2 MZL) have been treated across 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. No significant dose‐dependent toxicities were observed. Treatment‐related AEs occurring 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 due to drug‐related AEs occurred in only 4/100 (4%) patients. As of February 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 and FL range: 6.2 – 22.6+ months), including some durable CRs for > 20 months. Of 100 total patients enrolled, 75 patients were evaluable for efficacy, 8 were not evaluable, and in 17 first response assessment is pending. Pooled efficacy results from Ph1b+2 efficacy evaluable patients (n = 75) show an objective response rate (ORR) and CR rate of 49% and 21%, respectively. For 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 in a small number of evaluable patients treated at 45 mg/kg (n = 7) was 71%. Accrual is ongoing and data on additional patients treated at the 45 mg/kg dose will be presented.Summary/Conclusion:5F9+rituximab is a novel immunotherapy blocking a key macrophage/cancer checkpoint. It is well tolerated with rapid and durable responses observed in both heavily pre‐treated DLBCL and indolent lymphoma patients. Ph2 enrollment is ongoing (NCT02953509). Funded by Forty Seven and the Leukemia and Lymphoma Society.