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Positive interim findings from the EQUATE trial, including the mechanism of action of itolizumab in patients with aGvHD

Apr 15, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in acute GvHD.

Acute graft-versus-host disease (aGvHD) occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is a leading cause of mortality. The CD6-activated leukocyte cell adhesion molecule (ALCAM) pathway plays an important role in inflammation and autoimmunity.1 Earlier studies have demonstrated that depletion of CD6+ T cells prior to allo-HSCT decreases the incidence of aGvHD, suggesting CD6 is a target relevant to aGvHD pathogenesis.2

Itolizumab, a humanized immunoglobulin G1 (IgG1) anti-CD6 monoclonal antibody, inhibits CD6 signaling, consequently decreasing T-cell activation and proliferation2. Itolizumab is currently being investigated in the EQUATE trial (NCT03763318), which is evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of itolizumab for first-line treatment of aGvHD. The GvHD Hub has previously reported on interim findings from the EQUATE trial and published an expert interview on the promising results obtained when targeting CD6+ T cells in patients with aGvHD.

During the 48th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Stephen Connelly1 presented the mechanism of action of itolizumab and pharmacokinetic data, while Corey Cutler2 presented the updated interim results from the EQUATE trial. Here, we summarize the key findings from these two presentations.

Mechanism of action

CD6-ALCAM pathway1,2

CD6 is a co-stimulatory receptor, predominantly expressed on T cells. CD6 binds to ALCAMs present on antigen presenting cells, and epithelial and endothelial cells present on various tissues, including skin, gut, and lung. The CD6-ALCAM pathway modulates T-cell activation, proliferation, and trafficking, and thus plays an integral part in inflammation and autoimmunity. Itolizumab binds to CD6 (at Domain-1) and causes shedding of the receptor. T cells with lower levels of CD6 exhibit reduced sensitivity to stimulation, including decreased activation, proliferation, and cytokine production (Figure 1).

Figure 1. Mechanism of action of itolizumab*

ALCAM, activated leukocyte cell adhesion molecule; APC, antigen presenting cell; CD6, cluster of differentiation-6; IFN-γ, interferon-γ; IL, interleukin; TNFα, tumor necrosis factor-α.
*Adapted from Connelly, et al.1 and Cutler, et al.2

EQUATE study design1,2

EQUATE is an ongoing phase Ib/II, open-label, dose-escalation, multi-center trial, evaluating the efficacy and safety profile of itolizumab in patients aged ≥18 years with Grade III–IV aGvHD, who have received their first allo-HSCT. Patients received itolizumab intravenously biweekly at doses 0.4 mg/kg, 0.8 mg/kg, and 1.6 mg/kg, and were followed up through Day 337 (Figure 2).

Figure 2. Treatment schema*

aGvHD, acute graft-versus-host disease; IV, intravenously.

*Adapted from Connelly, et al.1 and Cutler, et al.2

Enrollment continued at 0.8 mg/kg with ≤3 days of prior steroids; no further dose escalation >1.6 mg/kg was conducted.

The primary objectives included assessment of the safety and tolerability of itolizumab, as well as determination of the optimal does levels.

The secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of itolizumab and assessment of its clinical activity (aGvHD overall response rate [ORR], non-relapse mortality, chronic GvHD response, and durability)

Baseline characteristics2

All results presented are interim data for patients enrolled through 13 October 2021 and are subject to change.

A total of 25 patients were included; the median age was 59 years, and 64% and 32% of patients had Grade III and IV aGvHD, respectively (Table 1).

Table 1. Baseline patient characteristics*

Characteristic, % (unless otherwise stated)

Itolizumab
0.4 mg/kg
(n = 4)

Itolizumab
0.8 mg/kg
(n = 12)

Itolizumab
1.6 mg/kg
(n = 9)

Total
(N = 25)

Mean age, years

44

60

55

55

Male

100

58

56

64

White

100

75

89

84

Primary disease

 

 

 

 

              AML

50

50

22

40

              MDS

0

25

22

20

              Other

50

25

56

40

Graft source

 

 

 

 

              Peripheral blood

100

83

100

92

              Bone marrow

0

17

0

8

aGvHD grade

 

 

 

 

II

0

8

0

4

III

75

58

67

64

IV

25

33

33

32

Organ involvement

 

 

 

 

Skin

25

33

44

36

Liver

25

0

11

8

UGI

25

67

22

44

LGI

100

83

78

84

Minnesota high risk score

100

67

78

76

Ann Arbor Score 2 or 3

100

100

89

96

aGvHD, acute graft-versus-host disease; AML, acute myeloid leukemia ; LGI, lower gastrointestinal involvement; MDS, myelodysplastic syndrome; UGI, upper gastrointestinal involvement.
*Adapted from Cutler, et al.2
Highest clinical grade at screening or baseline.
Calculated at screening.

Results

Pharmacokinetics and pharmacodynamics1

An increase in itolizumab serum concentration levels was observed after the first dose and was proportional to the size of the dose.

The surface CD6 level on T cells following the first dose of itolizumab was reduced significantly (p < 0.001) and remained low throughout the treatment period. Of note, 0.4 mg/kg itolizumab was a suboptimal dose due to an increase in CD6 level trending towards baseline by Day 15. Itolizumab increased the ratio of regulatory T cells/effector T cells (compared with baseline) by Day 15 in the higher does cohorts (0.8 and 1.6 mg/kg) only, highlighting the potential for enhanced immune response. A decrease in protein death-1, CD25 (interleukin-2R), and CD95 was also observed over the dosing period. Patients who achieved a complete response (CR) on Day 15 showed higher trough concentrations of itolizumab in serum.

Efficacy2

Itolizumab demonstrated early responses at Day 15 in terms of CR rate and ORR (50% and 71%, respectively) and were maintained at Day 29 (52% and 64%, respectively). Patients receiving itolizumab within 72 hours of corticosteroids showed a higher CR rate and ORR of 61% and 67%, respectively, at Day 29 (Table 2). In addition, itolizumab also showed a durable response rate of 79% at Day 169 across all doses and the response rate was maintained in 55% of responders at Day 337. At 12 months, progression-free survival and overall survival in Day 29-responders was ~50% and >75%, respectively. The median steroid reduction for responders was 73% and 96% at Day 29 and Day 169, respectively.

Table 2. CR and ORR*

Itolizumab dose

Response at Day 15

Response at Day 29

Naïve response at Day 29

n

CR, %

ORR, %

n

CR, %

ORR, %

n

CR, %

ORR, %

0.4 mg/kg (n = 4)

4

50

75

4

50

50

4

50

50

0.8 mg/kg (n = 12)

11§

55

64

12

58

58

9

67

67

1.6 mg/kg (n = 9)

9

44

78

9

44

78

5

60

80

Total

24§

50

71

25

52

64

18

61

67

CR, complete response; ORR, overall response rate.
*Adapted from Cutler, et al.2
Treatment within ≤3 days of steroids.
ORR = complete response + very good partial response + partial response.

§Response data were not available for one patient.

Safety2

In total, 64% of patients presented with a serious adverse event (SAE), including 40% reporting an infection SEA and 8% reporting a treatment-related SAE. Six patients discontinued due to AEs, including three due to infections. There was one dose-limiting toxicity at the 1.6 mg/kg dose. A total of 11 patients died, including eight due to AEs leading to death. However, there were no treatment-related deaths (Table 3).

Table 3. AEs and SAEs*

AEs and SAEs, %

Itolizumab
0.4 mg/kg
(n = 4)

Itolizumab
0.8 mg/kg
(n = 12)

Itolizumab
1.6 mg/kg
(n = 9)

Total
(N = 25)

Any AE

100

100

100

100

              Infusion reaction AE

25

17

0

12

              Infection AEs

75

50

78

64

              CTCAE Grade ≥3 AE

50

75

100

80

Treatment discontinuation

 

 

 

 

              Any AEs

0

17

44

24

              Infection AEs

0

8

22

12

SAE

50

50

89

64

              Infection SAE

25

25

67

40

              Treatment-related SAE

0

8

11

8

Dose-limiting toxicity AE

0

0

11

4

Deaths

25

42

56

44

              AE leading to death

0

42

33

32

              Treatment-related mortality

0

0

0

0

AE, adverse event; CTCAE, common terminology criteria for adverse events, SAE, serious adverse event.
*Adapted from Cutler, et al.2
Defined as a ≥ Grade 3 infusion reaction or clinical finding associated with hypersensitivity or any ≥ Grade 3 AEs not related to underlying disease.

Conclusion

The updated interim findings from the EQUATE trial demonstrate that itolizumab is responsible for a rapid and durable decrease in cell surface CD6, including reduction in the ratio of activated effector T cells to regulatory T cells. A higher concentration of itolizumab in serum highlights the importance of achieving these concentrations earlier in the treatment period to maximize the efficacy. Itolizumab offers a deep and durable response, including a favorable risk profile. In a patient population with severe aGvHD, itolizumab showed tolerability across all doses. Based on these interim findings, a pivotal phase III study has been initiated to investigate the efficacy and safety of itolizumab versus placebo as first-line-therapy in patients with Grade IIIIV aGvHD (NCT05263999).  

  1. Connelly S. Itolizumab, a novel targeted anti-CD6 therapy, induces cleavage of cell surface CD6 and rapid onset of efficacy in subjects with newly diagnosed acute graft-versus-host disease. Oral abstract #OS10-02. 48th Annual Meeting of the European Society for Blood and Marrow Transplantation; Mar 23, 2022; Virtual.
  2. Cutler C. Updated Interim Results from The Equate Study: Preliminary Safety and Efficacy of Itolizumab, A Novel Targeted Anti-CD6 Therapy, In Newly Diagnosed Acute Graft-Versus-Host Disease. Oral abstract #OS10-04. 48th Annual Meeting of the European Society for Blood and Marrow Transplantation; Mar 23, 2022; Virtual.

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