Patients diagnosed with relapsed or refractory B-cell non-Hodgkin lymphoma have relatively few treatment options. Results from a first-in-human phase I/II study evaluating epcoritamab (DuoBody®-CD3xCD20), show that the investigational agent induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells.

Epcoritamab is a novel, highly selective, and potent bispecific antibody (also known as a dual-targeting molecule) created using Genmab’s DuoBody® technology, jointly owned by Genmab and AbbVie,

One of the unique features of bispecific antibodies is that they bind to two different epitopes, either on the same or on different targets. This may improve the antibodies’ specificity and efficacy in inactivating the disease target cells. In addition to these features, Genmabs’s DuoBody® molecules are unique in combining the benefits of bispecificity with the strengths of conventional antibodies, which allows DuoBody® molecules to be administered and dosed as other antibody therapeutics.

The investigational agent, epcoritamab, targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells. In this trial, subcutaneous epcoritamab was safely administered in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

With step-up dosing, prophylaxis with corticosteroids, and the subcutaneous route of administration the severity of cytokine release syndrome (CRS) was mitigated. The investigators reported a high response rates in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma.

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The findings of the study, supported by Genmab, were published online on September 8, 2021 in The Lancet by Martin Hutchings, MD, Ph.D., of the Phase I Unit, Department of Hematology, Righospitalet in Copenhagen, Denmark and colleagues.

The authors of the study wrote that despite recent advances in chemoimmunotherapy strategies, the management of relapsed or refractory B-cell non-Hodgkin lymphoma remains challenging. In addition to chimeric antigen receptor (CAR) T-cell therapy, antibody-drug conjugates, and targeted therapies such as Bruton’s tyrosine kinase inhibitors and PI3 kinase inhibitors, the development of bispecific immunological agents, which target both tumor cells and T-cells in patients with hematological malignancies, was initiated.

Validated therapeutic target
CD20 is a validated therapeutic target that is expressed in a wide variety of B-cell malignancies. Researchers at Genmab, in collaboration with AbbVie, initiated the development of bispecific antibodies that crosslink CD20 on malignant cells and CD3 on T-cells. In this study, the investigators aimed to establish the safety and recommended phase II dose of such bispecific antibody, epcoritamab.

Study design
In the dose-escalation part of this phase I/II study, the investigators enrolled adult patients with relapsed or refractory CD20-positive B-cell non-Hodgkin lymphoma at 10 institutions in Denmark, the Netherlands, the United Kingdom, and Spain. Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0.0128–60 mg).

Maximum tolerated dose
The study’s primary objectives were to determine the maximum tolerated dose and the recommended phase II dose. Safety, antitumor activity, pharmacokinetics, and immune biomarkers were also assessed. The dose-expansion part of this study is ongoing.
Between June 26, 2018, and July 14, 2020, the study team enrolled 73 patients with relapsed, progressive, or refractory CD20-positive mature B-cell non-Hodgkin lymphoma of whom 68 patients received escalating full doses (0.0128–60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase II dose.

All 68 patients received at least one dose of epcoritamab and were included in safety analyses. Common adverse events were pyrexia occurring in 47 patients (69%), primarily associated with CRS in 40 patients (59%), all were grade 1–2, and injection site reactions in 32 patients (47%) of which 31 were grade 1. There was no grade 3 or higher CRS event. There were no discontinuations due to treatment-related adverse events or treatment-related deaths.

Overall response rate (ORR) in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% confidence interval [CI] 45–86), with 45% achieving a complete response (CR) at full doses of 12–60 mg. At 48 mg, the ORR was 88% (95% CI 47–100), with 38% achieving a CR. Patients with relapsed or refractory follicular lymphoma had an ORR of 90% (95% CI 55–100), with 50% achieving a CR at full doses of 0.76–48 mg.
The study demonstrated that epcoritamab induced robust and sustained B-cell depletion, and CD4-positive and CD8-positive T-cell activation and expansion, with modest increases in cytokine levels.

Manageable safety profile
The investigators concluded that the dose-escalation part of this first-in-human phase I/II study showed that subcutaneous epcoritamab had a manageable safety profile, with no grade 3 or higher CRS events, and induced robust single-agent antitumour activity in heavily pretreated patients. The primary endpoint of the study was met. Coupled with the mechanism of action and ease of administration of epcoritamab, these findings are highly encouraging for patients with relapsed or refractory B-cell non-Hodgkin lymphoma. The clinical benefit of epcoritamab will be further validated in ongoing phase II and III studies.

In an accompanying comment, Professor Armin Ghobadi, MD, of the Department of Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine in St. Louis, MO, US, wrote that bispecific T-cell redirectors are anticipated to play an important role in improving outcomes for patients with B-cell non-Hodgkin lymphoma, especially if longer follow-up confirms durable remissions.

Bispecific redirectors might allow broader eligibility than CAR T-cell treatments, especially among patients with comorbidities or rapidly progressing disease, on the basis of its off-the-shelf technology and more favorable safety profile. These two platforms will probably have a complementary role in managing patients with relapsed or refractory non-Hodgkin lymphoma.

“These initial trial results are encouraging, and their publication in The Lancet speaks to the strong interest from the clinical community in this important area of study,” said Mohamed Zaki, M.D., Ph.D., vice president and head, global oncology development, AbbVie.

“We look forward to further study epcoritamab in B-cell lymphomas and other hematologic malignancies, and continued pursuit of potential new treatment options for patients.”

Results from this trial were also recently presented during an oral session at the 16th Annual International Conference on Malignant Lymphoma (ICML), held virtually June 18-22, 2021

Further development
In addition, the results from this study, epcoritamab is currently under investigation in multiple ongoing clinical studies including a phase 3 study for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). In addition, Phase 1/2 clinical studies in B-cell non-Hodgkin lymphoma (B-NHL) including chronic lymphocytic leukemia (CLL) and in combination with standard of care therapies for B-NHL are ongoing.

Clinical trials
Safety and Efficacy Trial of Epcoritamab Combinations in Subjects With B-cell Non-Hodgkin Lymphoma – NCT04663347
Safety and Efficacy Study of Epcoritamab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia – NCT04623541
A Phase 3 Trial of Epcoritamab in R/R DLBCL – NCT04628494
Trial of the Safety and Efficacy of Epcoritamab in Japanese Subjects With R/R B-NHL – NCT04542824
GEN3013 Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma – NCT03625037

[1] Hutchings M, Mous R, Clausen MR, Johnson P, Linton KM, Chamuleau MED, Lewis DJ, Sureda Balari A, Cunningham D, Oliveri RS, Elliott B, DeMarco D, Azaryan A, Chiu C, Li T, Chen KM, Ahmadi T, Lugtenburg PJ. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021 Sep 8:S0140-6736(21)00889-8. doi: 10.1016/S0140-6736(21)00889-8. Epub ahead of print. PMID: 34508654.
[2] Ghobadi A, Bartlett NL. CD3xCD20 bispecific T-cell redirectors for relapsed or refractory B-cell lymphoma. Lancet. 2021 Sep 8:S0140-6736(21)01070-9. doi: 10.1016/S0140-6736(21)01070-9. Epub ahead of print. PMID: 34508653.

Featured Image: Genmab’s Hybridoma and tissue Culture Laboratory. Photo courtesy: 2020 Genmab

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