EHA 2019 | Anti-CD47 antibody, HU5F9-G4, with rituximab in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (iNHL)

On Saturday 15th June, Dr. Mark Roschewski, National Cancer Institute, Bethesda, MD presented at the 24th annual congress of the European Hematology Association (EHA), Amsterdam, NL. He reported the results of a phase Ib/II clinical trial using HU5F9-G4 (5F9) and rituximab combination therapy in DLBCL and iNHL. ¹

5F9 is a first-in-class antibody targeting CD47, a macrophage immune checkpoint that cancer cells exploit to avoid phagocytosis. The study aimed to determine the safety and efficacy of 5F9 and rituximab combination in patients with iNHL and relapsed/refractory (R/R) DLBCL. The initial dose escalation results in R/R DLBCL showed the objective (OR) and complete response (CR) rates of 40% and 33% respectively, and 71% and 43% in refractory FL, with good safety profile. The data presented at the session were a follow up of phase Ib cohort and a preliminary results from phase II.

Study design

Eligibility Criteria

• Phase Ib - patients with R/R B-cell NHL to ≥ 2 prior lines of therapy
• Phase II - patients
• DLBCL – primary refractory or R/R ≥ 2 prior lines of therapy; refractory to rituximab and ineligible for CAR-T cell therapy
• iNHL – follicular lymphoma (FL) or marginal zone lymphoma (MZL) R/R to ≥ 2 prior lines of therapy

Dosing

• Phase Ib - priming dose (1 mg/kg) of 5F9, followed by dose escalation up to 45 mg/kg + 375 mg/ml rituximab
• Phase II – 30 or 45 mg/kg 5F9 weekly in cycle 1 and 2, followed by every 2 weeks maintenance dosing + 375 mg/ml rituximab

Patient characteristics

• Patients from the phase II cohort were older compared to those in phase Ib (72 vs 61 years)
• Majority of patients (89%) in phase II were ineligible for CAR-T

Table 1. Phase Ib and II patient characteristics

Characteristics

All
N=115 (%)

DLBCL
N=70 (%)

iNHL N=45 (%)
FL n=41,
MZL n=4

Median age (range)

67 (21–88)

69 (21–88)

60 (28–87)

Medium number of prior therapies (range)

3 (1–10)

3 (1–10)

3 (1–9)

ECOG performance status

0

1

2

Missing

 

50 (43)

58 (50)

5 (4)

2 (2)

 

22 (31)

43 (61)

5 (7)

0

 

28 (62)

15 (33)

0

2 (4)

Stage at diagnosis

I–II

III–IV

Unknown

 

17 (15)

68 (59)

30 (26)

 

12 (17)

19 (56)

19 (27)

 

5 (11)

29 (64)

11 (24)

Rituximab refractory

Any regimen

Last regimen

 

98 (85)

83 (72)

 

62 (89)

52 (74)

 

36 (80)

31 (69)

Refractory to last regimen

82 (71)

49 (70)

33 (73)

Primary refractory

-

41 (59)

-

Prior autologous transplant

27 (24)

17 (24)

10 (22)

Key findings

Efficacy

• The median time to response was 1.8 months (1.6–7.3 months)
• ORRs were similar across different DLBCL subtypes (30–46%) and primary refractory (34%) patients, irrespective of prior lines of therapy 

Table 2. Efficacy in all patients

Response

Total
N=97

DLBCL
N=59

iNHL
FL n=35,
MZL n=3

Overall response rate (ORR)

44 (45%)

21 (36%)

23 (61%)

Complete response (CR)

18 (19%)

9 (15%)

9 (24%)

Partial response (PR)

26 (27%)

12 (20%)

14 (£7%)

Stable disease (SD)

16 (17%)

7 (12%)

9 (24%)

Progressive disease (PD)

37 (38%)

31 (53%)

6 (16%)

• ORR in DLBCL patients with ≥ 3 prior lines of therapy was 38%
• Phase II cohort had lower response rates compared to phase Ib patients (ORR 29% vs. 48%; CR 5% vs. 33%)
• The median duration of response (DOR) was not reached in phase Ib
• Median follow-up in DLBCL and FL were 13 and 21 months, respectively

Safety (N=115)

• Treatment discontinuation due to adverse effects (AEs) occurred in 8 patients (7%)
• Majority of AEs were grade 1 or 2 and followed the priming dosing during the first month, with minimal AEs thereafter
• Most common AEs included
• Infusion reactions and related symptoms (headache, fever, chills)
• Anemia (transient, mitigated by priming/ maintenance dosing)
• Fatigue
• Grade 4 events included thrombocytopenia and neutropenia
• Maximum toxicity dose (MTD) not reached with 5F9 up to 45 mg/kg
• No significant late safety concerns in patients treated long term (up to 24+ months)

Conclusions

The 5F9 and rituximab combination is well tolerated and shows efficacy in R/R DLBCL and refractory FL. The lower response rate in the phase II cohort of patients is likely to be due to heavy pre-treatment and predominance of R/R CAR T ineligible patients.  CD47 is highly expressed in DLBCL and FL patients and potential correlation analysis of the expression levels with the response are ongoing.