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Preliminary results from phase I studies of CD20 × CD3 bispecific antibodies in R/R B-cell non-Hodgkin lymphoma

Mar 11, 2021
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Early phase studies of several novel bispecific antibodies are showing promising results for the treatment of R/R B-cell NHL. When considering bispecific antibody therapy, which characteristic/s would primarily drive your treatment choice?

Route of administration

13%

Safety

13%

Duration of treatment

8%

Efficacy

65%

23 votes

For patients with B-cell non-Hodgkin lymphoma (NHL) who relapse or become refractory to chemotherapy and anti-CD20 immunotherapy, there are limited treatment options and these often result in poor outcomes. Bispecific antibodies, which bind to two different epitopes, are currently undergoing phase I trials in such patients.

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, three abstracts were presented from ongoing phase I studies of bispecific antibodies in relapsed/refractory (R/R) B-cell NHL. Rajat Bannerji covered the updated preliminary safety and efficacy analyses of odronextamab (REGN1979; NCT02290951).1 Martin Hutchings presented early data on epcoritamab (NCT03625037),2 and from a subset of patients treated with step-up dosing of glofitamab (CD20-TCB; NCT03075696).3 These data on glofitamab supplement those from the wider cohort of patients included the trial, which were presented at the 25th European Hematology Association (EHA) Annual Congress.4

These bispecific antibodies bind to both CD3 on T cells and CD20 on malignant B cells, triggering T-cell-mediated cytotoxicity independent of T-cell receptor recognition. This article summarizes the data presented at the ASH meeting for these three novel drugs.

Study designs

Odronextamab1

Primary objectives were the evaluation of safety, tolerability, and dose-limiting toxicities. Secondary objectives were to assess antitumor activity (by Lugano criteria), pharmacokinetics, and to determine the recommended phase II dosing regimen (RP2DR). The dose regimen consisted of dexamethasone premedication and an initial split dose of odronextamab at Weeks 1 and 2, followed by a single intravenous (IV) infusion weekly for 12 weeks, then every 2 weeks until disease progression or discontinuation.

At data cut-off on September 18, 2020, 136 patients with R/R CD20+ B-cell NHL (including diffuse large B-cell lymphoma [DLBCL], follicular lymphoma [FL], mantle cell lymphoma [MCL], and marginal zone lymphoma [MZL]) who had previously received anti-CD20 therapy were enrolled. Of these, 24 patients (17.6%) remain in the study, 99 (72.8%) have discontinued, and 13 (9.6%) have completed. Chimeric antigen receptor (CAR) T-cell therapy had previously been given to 35 patients (25.7%).

Epcoritamab2

The primary objectives were maximum tolerated dose (MTD) and RP2DR. Safety, tolerability, and antitumor activity (Lugano criteria) were assessed as secondary objectives. In the dose escalation part of the study, patients received subcutaneous injection of a flat dose of epcoritamab (0.0128–60 mg) in 28-day cycles until disease progression or unacceptable toxicity.

At the data cut-off on October 10, 2020, 68 adult patients with R/R CD20+ B-cell NHL who had previously had anti-CD20 therapy were enrolled, including patients with DLBCL, FL, MCL, MZL, and small lymphocytic lymphoma. Six patients (9%) had received prior CAR T-cell therapy. Treatment in the study is ongoing for 17 (25%) patients, and 51 (75%) patients have discontinued.

Glofitamab3,4

Primary objectives included safety, tolerability, pharmacokinetics, antitumor efficacy (Lugano criteria), and determination of MTD and RP2DR. Patients received 1,000 mg obinutuzumab pretreatment 1 week prior to the first cycle to mitigate cytokine release syndrome (CRS). In the step-up dosing subset, patients were administered IV glofitamab on Days 1 (2.5 mg) and 8 (10 mg) of Cycle 1. Patients subsequently received the target dose (either 16 or 30 mg) on Day 1 of Cycle 2 and then every 3 weeks for up to 12 cycles. The wider study included patients on a fixed dose of ≥ 0.6 mg glofitamab every 2 or 3 weeks for a maximum of 12 cycles.

At the clinical cut-off date of August 3, 2020, 52 adult patients with R/R CD20+ B-cell NHL who had previously received ≥ 1 line of therapy were enrolled in the step-up dosing subset. Of these, 28 patients had aggressive NHL (aNHL; including DLBCL, FL Grade 3B, and MCL) and 24 patients had indolent NHL (iNHL; FL Grade 1–3A). Three patients had received prior CAR T-cell therapy. In the wider study, 190 patients were enrolled as of April 17, 2020, of which 156 received ≥ 0.6 mg glofitamab. Of these patients, 130 had aNHL and 24 had iNHL.

Efficacy

Odronextamab1

Overall response rate (ORR) and rate of complete response (CR) are shown in Table 1.

Table 1. Efficacy of odronextamab by diagnosis and prior CAR T-cell therapy1

 

FL
(n = 30)

DLBCL without prior CAR T-cell therapy
(n = 11)

R/R DLBCL with prior CAR T-cell therapy
(n = 24)

Dose, mg

5–320

80–320

80–320

Median duration of follow-up, months (range)

9 (1–44)

6 (1–24)

3 (0–22)

ORR, n (%)

27 (90)

6 (55)

8 (33)

CR, n (%)

21 (70)

6 (55)

5 (21)

Durability of CR,* %

81, ongoing up to 41 months

83, ongoing up to 21 months

100, ongoing up to 20 months

CAR, chimeric antigen receptor; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; ORR, overall response rate.
*Defined as CR lasting ≥ 3 months.

Epcoritamab2

Table 2 shows the rates of overall response, complete response (CR), and partial response (PR). All patients with DLBCL who received ≥ 12 mg and achieved CR remained in remission.

Table 2. Efficacy of epcoritamab by diagnosis2

 

     DLBCL (n = 46)

      FL (n = 12)

  MCL (n = 4)

Dose, mg

12–60

48–60

0.76–48

12–48

0.76–48

Evaluable patients

22

11

10

5

4

ORR, n (%)

15 (68)

10 (91)

9 (90)

4 (80)

2 (50)

CR, n (%)

10 (46)

6 (55)

5 (50)

3 (60)

1 (25)

PR, n (%)

5 (23)

4 (36)

4 (40)

1 (20)

1 (25)

Median time to response, months (range)

1.4 (1–3)

1.3 (1–3)

1.9 (1–4)

1.4 (1–1)

In remission at 6 months, % (95% CI)*

72 (34-90)

CI, confidence interval; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; PR, partial response.

*Not all patients have reached 6 months of follow-up.

Of the four patients who had previously received CAR T-cell therapy and for whom data were available, all had DLBCL and all responded to epcoritamab (two with CR and two with PR).

Glofitamab3,4

Efficacy results for patients with available data who received fixed and step-up dosing schedules of glofitamab are given in Table 3.

Table 3. Efficacy of glofitamab for all patients and stratified by diagnosis3,4

 

Fixed dosing*

Step-up dosing*

 

All patients
(n = 148)

aNHL
(n = 123)

iNHL
(n = 23)

All patients
(n = 52)

aNHL
(n = 28)

iNHL
(n = 24)

Median follow-up, months (95% CI)

10.2 (5.6–17.3)

10.2 (5.3–NE)

3.7 (3.5–5.6)

1.8 (1.4–3.5)

ORR, %

48.0

45.5

65.2

63.5

60.7

66.7

CR, %

33.8

30.9

52.2

53.8

53.6

54.2

PR, %

14.2

14.6

13.0

9.6

7.1

12.5

Ongoing CR, n

24

9

13

13

aNHL, aggressive non-Hodgkin lymphoma; CI, confidence interval; CR, complete response; iNHL, indolent non-Hodgkin lymphoma; NE, non-estimable; ORR, overall response rate; PR, partial response.

*Clinical cut-off date was April 17, 2020 for the fixed dosing cohort and August 3, 2020 for the step-up dosing cohort.

 

Safety

Treatment-emergent adverse advents (TEAEs) from the three studies are summarized in Table 4.

In the odronextamab study, the most frequent TEAEs classified as Grade 3 or above (occurring in 10% of patients or more) were anemia (24.3%), lymphopenia (20.6%), neutropenia (18.4%), and hypophosphatemia (18.4%).1 Of the 46 patients in the epcoritamab study who experienced serious adverse events, the most common were pyrexia (n = 21), disease progression (n = 11), and pneumonia (n = 8).2 With stepped-up dosing of glofitamab, the safety profile was consistent with that seen in the wider patient cohort,4 and the most frequent adverse events were CRS (61.0%), neutropenia (38.5%), pyrexia, and thrombocytopenia,3

Table 4. Summary of odronextamab, epcoritamab, and glofitamab TEAEs1–4

AE, n (%)

Odronextamab1
(N = 136)

Epcoritamab2
(N = 68)
Glofitamab
Fixed dosing4
(N = 156)
Step-up dosing3
(N = 52)

TEAE

135 (99.3)

151 (96.8)

51 (98.1)

Serious TEAE

84 (61.8)

46 (67.6)

96 (61.5)

31 (59.6)

TEAE ≥ Grade 3

110 (80.9)

87 (55.8)

29 (55.8)

TEAE leading to discontinuation

9 (6.6)

1 (1.5)

5 (3.2)

2 (3.8)

CRS

83 (61.0)

40 (58.8)

88 (56.4)

33 (63.5)

CRS ≥ Grade 3

10 (7.3)

0

5 (3.2)

2 (3.8)

TLS

2 (1.5)

1

Not reported

Not reported

Fatal TEAE

6 (4.4)

0

1 (0.6)

0

CRS, cytokine release syndrome; TEAE, treatment-emergent adverse event; TLS, tumor lysis syndrome.

Conclusion

Limited treatments are currently available for patients with R/R B-cell NHL, who have often undergone many lines of prior therapy and have aggressive disease histologies. Novel bispecific antibodies, which crosslink CD20 and CD3, could therefore offer potential new options for these patients. The authors of the phase I studies of odronextamab, epcoritamab, and glofitamab summarized here concluded that safety profiles were acceptable and high clinical response rates were demonstrated in heavily pretreated patients, including those who had received prior CAR T-cell treatment. Previously reported phase I/Ib trial data for mosunetuzumab has similarly shown tolerable and efficacious results for R/R NHL patients, including those exposed to prior CAR T-cell therapy. These bispecific antibodies are also off-the-shelf, offering faster availability than custom-manufactured CAR T-cell therapies. Furthermore, epcoritamab can be given subcutaneously, making it more convenient than IV administration. An expert opinion on these trials is available below.

Whilst these promising phase I studies are continuing, recruitment is currently underway for a phase II trial of odronextamab (NCT03888105), and several clinical trials are in progress investigating glofitamab and epcoritamab in combination with other therapeutics across B-cell NHL subtypes.

  1. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a human CD20 x CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Blood. 2020;136(Supplement 1):42-43. DOI: 1182/blood-2020-136659
  2. Hutchings M, Mous R, Clausen MR, et al. Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: updated dose escalation data. Blood. 2020;136(Supplement 1):45-46. DOI: 1182/blood-2020-133820
  3. Hutchings M, Carlo-Stella C, Bachy E, et al. Glofitamab step-up dosing induces high response rates in patients with hard-to-treat refractory or relapsed non-Hodgkin lymphoma. Blood. 2020;136(Supplement 1):46-48. DOI: 1182/blood-2020-136044
  4. Dickinson MJ, Morschhauser F, Lacoboni G, et al. CD20-TCB in relapsed or refractory non-Hodgkin lymphoma: Durable complete responses and manageable safety observed at clinically relevant doses in phase I dose escalation. Oral Abstract #S241. 25th EHA Annual Congress; Jun 12, 2020; Virtual.

Expert Opinion

It’s an exciting time in the field of T-cell-directed therapies for lymphoma. Blinatumomab, a CD19/CD3 bispecific, was clearly active in B-acute lymphoblastic leukemia but was disappointing in lymphoma. It did serve as proof of principle that T cells could be harnessed for lymphoma control through drug-induced CD3-engagement and T cell activation. Hot on the heels of the CAR T-cell story in lymphoma, we now have a series of very interesting new drugs that improve on blinatumomab in several ways.

The series of agents presented here with updated data at ASH, all target CD20 (rather than CD19) and all have a favorable half-life that enables intermittent dosing. There are other agents in development not listed here, including mosunetuzumab. Put into the context of CAR T-cells, which deliver a 35–40% complete remission (CR) rate at 12 months in relapsed DLBCL, the response rates reported here are tantalising. My eyes go straight to the CR rate in DLBCL in patients treated at target doses, because I believe CR is a requirement for clinical benefit in this histology. Allowing for the small numbers, the CR rate is >40% for odronextamab and glofitamab, and is heading in the same direction for epcoritamab. What was interesting about this update for me was that the odronextamab and glofitamab data now provide some evidence of durability in this patient population. Durable CRs were reported at around 80% in the relatively small number of patients followed beyond 12 months. At the very least, this is a promising start for these agents. Activity in other histological subtypes, less well-represented in this series of abstracts, is very hopeful.

How do the bispecifics compare to each other on safety? Well, it’s too soon to draw conclusions. Unlike blinatumomab in ALL or CAR-T in lymphoma, neurotoxicity appears to be less of a practical issue. Cytokine release syndrome (CRS) is a key barrier to delivery in day units and it becomes more complicated to treat at Grade 2 or above. Odronextamab reports a higher rate of Grade 3+ CRS (7.3%) and treatment discontinuation (6.6%) compared with the other agents presented here. We don’t know whether epcoritamab’s subcutaneous delivery contributes to the early suggestion of a favorable safety profile. To really understand why CRS varies in frequency and severity, clarity around differences in steroid pre-dosing regimens and the use of tocilizumab in management is needed.

When framed against the extraordinary clinical challenge of multiply-relapsed DLBCL where the toxicities and practical challenges of CAR-T have been deemed acceptable for a subset of patients, these early data are promising. The future is bright for the ‘bispecifics’ in NHL.

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