REGN1979 for relapsed/refractory B-cell non-Hodgkin lymphoma

REGN1979 is a bispecific antibody targeting CD20 and CD3 that is designed to cross-link and activate T-cells that express CD3 upon contact with CD20⁺ B-cells. This means tumor cells can be killed independently of T-cell receptor recognition. Rajat Bannerji, Rutgers Cancer Institute of New Jersey, New Jersey, US, presented updated results from the dose escalation phase of a first-in-human study of REGN1979, at the 61^st American Society of Hematology (ASH) meeting in Florida, US. This article summarizes the updated results presented at the ASH meeting; these data may supersede the ones in the published abstract.¹

Study design¹

The dose escalation portion of the study enrolled patients with B-cell non-Hodgkin lymphoma (B-NHL), whilst the expansion cohorts will enroll patients with relapsed/refractory (R/R) aggressive lymphoma, and follicular lymphoma (FL) grade 1–3a following two prior lines of therapy.

The primary objectives of the study were to assess safety, tolerability, and dose-limiting toxicities (DLTs) of REGN1979. The secondary objectives were to evaluate anti-tumor activity, pharmacokinetics, and immunogenicity. Dosing of REGN1979 was in an escalating dose schedule using an (1) initial, (2) intermediate, and (3) step-up dose with the target dose achieved at the end of four weeks. REGN1979 was administered weekly by intravenous injection, followed by every two-weeks for a further 12 doses (total: 36 weeks).

Patient characteristics (N= 110)¹

• Median age: 67 years (range: 30–88)
• 70% of patients were male
• Most patients had stage III–IV disease by Ann Arbor (85.5%) and were diagnosed with diffuse large B-cell lymphoma (DLBCL, 55.5%) or FL (28.2%)
• Median prior lines of therapy: 3 (range: 1–11)
• 80% of patients were refractory to last treatment
• Patients must have received a prior anti-CD20 therapy

At data cut-off on 3^rd September 2019, 31 patients remained in the study (28.2%) with 69 discontinuing (62.7%), predominantly due to progression/recurrence of disease (n= 35) or death (n= 13). In total, 10 patients (9.1%) completed the study.

Safety¹

The most common treatment-emergent adverse events (TEAEs) of any grade were pyrexia (80%) and cytokine release syndrome (CRS, 59.1%). Grade 3–4 TEAEs that occurred in 10% or more of patients are shown in Table 1 and were predominantly cytopenias. CRS grade ≥3 occurred in 6.4% of patients and no seizures or grade 4–5 neurologic events were observed.

Infections and infestations were reported in 50% of patients. Six patients discontinued due to TEAEs:

• Grade 1: cytomegalovirus infection (n= 1)
• Grade 3: hemolysis (n= 1), fatigue (n =1), pneumonia (n= 2), and toxoplasmosis (n= 1)

Six grade 5 TEAEs occurred during the study. Three deaths (due to cardiac arrest, multi-organ failure or acute renal failure) were considered unrelated to the study drug, whilst three deaths (due to gastric perforation, lung infection or pneumonia) were considered related to study treatment.

Table 1. TEAE grade 3–4 occurring in ≥10% of patients

TEAE, treatment-emergent adverse event

TEAE

n (N= 110)

%

Anemia

24

21.8

Hypophosphatemia

21

19.1

Neutropenia

21

19.1

Lymphopenia

21

19.1

Thrombocytopenia

15

13.6

Leukopenia

11

10.0

Infusion related reactions (IRRs) and CRS:

• Most IRRs and CRS events happened during weeks 1–3 and subsequently declined
• Grade 3 IRRs/CRS occurred in eight patients, with no grade 4 or 5 events reported
• No patient discontinued study due to IRR or CRS

DLTs and MTD

• No DLTs were observed during dose escalation
• MTD was not reached

Efficacy¹

Overall response rate (ORR), and rates of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) are given in Table 2, as of week 12.

In the FL cohort, 16/22 patients experienced complete metabolic response by PET scan. In the DLBCL cohort, the response rate was higher in patients who had not previously received chimeric antigen receptor (CAR) T-cell therapy. Survival rates and ongoing response rates are shown in Table 3 by diagnosis, dose of REGN1979, and prior CAR T therapy.

Table 2. Efficacy results by diagnosis and dose of REGN1979

CAR, chimeric antigen receptor; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease

Diagnosis

FL, n (%)

DLBCL, n (%)

DLBCL with prior CAR T therapy, n (%)

DLBCL without prior CAR T therapy, n (%)

Dose of REGN1979

≥5mg

≥80mg

≥80mg

≥80mg

N

22

19

12

7

ORR

21 (95.5)

11 (57.9)

6 (50.0)

5 (71.4)

CR

17 (77.3)

8 (42.1)

3 (25.0)

5 (71.4)

PR

4 (18.2)

3 (15.8)

3 (25.0)

0

SD

1 (4.5)

2 (10.5)

1 (8.3)

1 (14.3)

PD

0

3 (15.8)

2 (16.7)

1 (14.3)

Not available

0

3 (15.8)

3 (25.0)

0

Table 3. Median survival and responses by diagnosis, prior CAR T therapy and REGN1979 dosing

CAR, chimeric antigen receptor; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; NR, not reported; PFS, progression-free survival

 

Patients with FL

DLBCL with prior CAR T therapy

DLBCL without prior CAR T therapy

Dose of REGN1979

≥5mg

≥80mg

≥80mg

N

22

12

7

Median PFS, months (95% CI)

11.4

(6.7–not evaluable)

NR

NR

Median duration of follow-up, months (range)

6.8 (1.0–22.1)

2.6 (0.4–9.9)

5.3 (1.2–11.8)

Number of patients with ongoing response at last assessment

14/21

4/6

5/5

Number of patients with ongoing CRs at last tumor assessment

12/17

3/3

5/5

Conclusion¹

REGN1979 was found to have an acceptable safety profile with no DLTs observed during the dose escalation phase of the trial. Most AEs were mild to moderate with no significant neurotoxicity reported. No patient discontinued due to IRR/CRS. Additionally, REGN1979 demonstrated clinical activity in heavily pre-treated patients with R/R B-NHL in a dose-dependent manner. 

At data cut-off, one patient in the expansion cohort experienced grade 5 tumor lysis syndrome and enrolment in the expansion cohort was subsequently halted whilst a safety amendment was made to the study protocol. A global multi-arm phase II trial (NCT03888105) evaluating REGN1979 in patients with R/R FL is also underway.²