Emerging clinical activity of REGN1979 in relapsed/refractory B-cell non-Hodgkin lymphoma

On 15^th June 2019, at the 24^th European Hematology Association meeting in Amsterdam, NL, Rajat Bannerji, from Rutgers Cancer Institute of New Jersey, New Brunswick, US, presented a session on the emerging clinical activity of REGN1979 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL).

Despite many patients with follicular lymphoma (FL) achieving impressive outcomes with the introduction of immunochemotherapy, certain subgroups of patients still have a poor prognosis, and as such novel therapies are needed. CD20 remains one of the best studied antibodies, and as it is highly expressed on the surface of B cells, the facilitation of efficient target opsonization.  

REGN1979 is a bispecific, human, anti-CD20 x anti-CD3 IgG4 antibody, and is designed to cross-link and activate CD3-expressing T cells when in contact with CD20+ B cells. In turn, this destroys CD20+ tumor cells, independent of T-cell receptor recognition. Preclinical studies have shown potent anti-tumor activity of REGN1979.¹

The primary objectives of the phase I, open-label, multicenter study were to assess safety, tolerability and dose-limiting toxicities of REGN1979. The secondary objectives were to characterize the pharmacokinetic (PK)/pharmacodynamic (PD) profile, antitumor activity and immunogenicity.

Patient characteristics

• Eligibility criteria:
  • CD20+ B-NHL
  • Prior treatment with an anti-CD20 antibody
  • ECOG status <1
• N = 81 patients; median age, 67 years
• Median prior lines of therapy, 3, (1–11)
• Relapsed/refractory patients:
  • Relapsed, n=14 (17.3%)
  • Refractory, n=67 (82.7%)

Table 1. B-NHL subtypes FL, follicular lymphoma; Gr 1–3a, grade 1–3a; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma

B-NHL diagnosis

N=81
n (%)

FL Gr 1–3a

21 (25.9)

DLBCL

45 (55.6)

MCL

6 (7.4)

MZL

6 (7.4)

Other

3 (3.7)

Methods

Treatment consisted of 12 weekly intravenous doses of REGN1979, followed by 2-week dosing for 12 doses (total 36 weeks). Data cut-off for this analysis was 15 March 2019.

Key findings

Table 2. Results of patients with R/R FL Gr 1–3a ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; DoR, duration of response; NR, not reached

 

R/R FL Gr 1–3a

REGN1979 dose

<5mg
(n=7)

5–12mg
(n=5)

18–40mg
(n=6)

160mg
(n=1)

ORR n (%)

1 (14.3)

5 (100)

5 (83.4)

1 (100)

CR n (%)

1 (14.3)

4 (80)

4 (66.7)

0

PR n (%)

0

1 (20)

1 (16.7)

1 (100)

SD n (%)

4 (57.1)

0

1 (16.7)

0

PD n (%)

2 (28.6)

0

0

0

Median DoR (months)

5.3

NR

11.8

NR

Table 3. Results from patients with R/R DLBCL *1/2 patients with CR was a CAR T-cell therapy failure

 

R/R DLBCL

REGN1979 dose

<5mg
(n=15)

5–12mg
(n=11)

18–40mg
(n=11)

80mg
(n=2)

ORR n (%)

2 (13.3)

2 (18.2)

6 (54.5)

2 (100)

CR n (%)

0

1 (9.1)

2 (18.2)

2* (100)

PR n (%)

2 (13.3)

1 (9.1)

4 (38.4)

0

SD n (%)

4 (26.7)

4 (36.4)

3 (27.3)

0

PD

8 (53.3)

4 (36.4)

1 (9.1)

0

Median DoR, months

2.1

NR

4.4

NR

Table 4. Details of patients who discontinued the study, n = 52 AE, adverse event

 

N (%)

Progression recurrence of disease

27 (33.3)

Death

10 (12.3)

Subject decision

5 (6.2)

Physician decision

2 (2.5)

AE

1 (1.2)

Other

7 (8.6)

Immunohistological analysis

• Seven of eleven patients had CD20 antigen loss at progression
• Doses of REGN1979 ranged from 3mg to 160mg
  • One patient treated at 3mg had PD, one patient at 27mg had SD, one at 40mg had PD and one at 80mg had PD
  • Two patients treated at 80mg achieved CR, one at week 5, and one at week 9
  • One patient treated at 160mg achieved SD by week five, but subsequently progressed

Adverse Events

Tolerability of REGN1979 was observed at does up to 320mg weekly, with the majority of AEs being mild-to-moderate in severity. No demonstrated dose limiting toxicities (DLTs) were identified. The most frequent TEAEs affecting over 50% of patients were pyrexia (82.7%), cytokine release syndrome (56.8%) and chills (54.3%), with infections and infestations (49.4%), increased C-reactive protein (38.3%), fatigue (38.3%) and anemia (35.8%) affecting over 30% of patients.

Table 5. Grade 3–4 adverse events occurring in patients

Grade 3–4 TEAEs

Total (N=81)
N (%)

Anemia

17 (21)

Lymphopenia

16 (19.8)

Neutropenia

14 (17.3)

Infections and infestations

12 (14.8)

Thrombocytopenia

11 (13.6)

Hypophosphalemia

9 (11.1)

Cytokine release syndrome

6 (7.4)

Fatigue

6 (7.4)

Leukopenia

6 (7.4)

Hypotension

5 (6.2)

Table 6. Grade 5 adverse events occurring in patients

Grade 5 TEAEs

Total (N=81)
N (%)

Cardiac arrest (not related)

1 (1.2)

Gastric perforation (related)

1 (1.2)

Lung infection (related)

1 (1.2)

Multi-organ failure (not related)

1 (1.2)

Pneumonia (related)

1 (1.2)

Conclusions

Dr Bannerji concluded that REGN1979 was well tolerated and showed efficacy in heavily treated patients with R/R B-NHL, and even showed activity in patients where CAR T-therapy had not.

Doses of REGN1979 at 80mg or higher showed activity in more resistant tumors, such as in patients with R/R DLBCL. Patients with MCL and MZL also showed activity when treated with REGN1979 at doses above 5mg. Treatment did not show DLTs, and no significant neurological toxicity was observed.

Based on the results obtained from this study, a phase II trial in R/R FL Gr 1 – 3a, DLBCL and other B-NHL subtypes is planned.