Epcoritamab is a highly selective and potent bispecific antibody for CD3 and CD20 that induces T-cell-mediated cytotoxic activity against CD20-positive malignant B-cells. In a first-in-human phase I/II study 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. High response rates were observed in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. The study findings are published online on 8 September 2021 in The Lancet by Dr. Martin Hutchings of the Phase I Unit, Department of Haematology, Righospitalet in Copenhagen, Denmark and colleagues.
The authors wrote in the background 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, development of bispecific immunological agents, which target both tumour cells and T-cells in patients with haematological malignancies, was initiated.
CD20 is a validated therapeutic target in B-cell malignancies and the development of bispecific antibodies that crosslink CD20 on malignant cells and CD3 on T-cells was initiated. In this study the investigators aimed to establish the safety and recommended phase II dose of such bispecific antibody, epcoritamab.
In the dose-escalation part of this phase I/II study, the study team enrolled adults with relapsed or refractory CD20-positive B-cell non-Hodgkin lymphoma at 10 institutions in Denmark, the Netherlands, the UK, 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).
The study primary objectives were to determine the maximum tolerated dose and the recommended phase II dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. The dose-expansion part of this study is ongoing.
Between 26 June 2018 and 14 July 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 were no grade 3 or higher CRS events. No discontinuations occurred 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.
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.
The authors 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.
Prof. Armin Ghobadi of the Department of Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine in St. Louis, MO, US wrote in an accompanied comment 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 a 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 favourable safety profile. These two platforms will probably have a complementary role in managing patients with relapsed or refractory non-Hodgkin lymphoma.
This study was sponsored by Genmab.
Hutchings M, Mous R, Roost Clausen M, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. The Lancet; Published online 8 September 2021. DOI: https://doi.org/10.1016/S0140-6736(21)00889-8
Ghobadi A, Bartlett NL. CD3xCD20 bispecific T-cell redirectors for relapsed or refractory B-cell lymphoma. The Lancet; Published online 8 September 2021. DOI: https://doi.org/10.1016/S0140-6736(21)01070-9