A new bispecific antibody (epcoritamab) in combination with venetoclax (already approved) for the treatment of previously treated chronic lymphocytic leukemia (CLL or SLL)

Chronic lymphocytic leukemia (CLL) and small-cell lymphocytic lymphoma (SLL) are closely related blood cancers that are treated according to a common treatment regimen. In both chronic lymphocytic leukemia (CLL) and small-cell lymphocytic lymphoma (SLL), certain white blood cells—known as lymphocytes—undergo malignant changes. The main difference between the two diseases lies in the location of the tumor cells: In SLL, the abnormal cells are primarily found in the lymph nodes, whereas in CLL, the cancer cells are predominantly detected in the blood. Both diseases usually progress slowly over many years and are generally treated only when symptoms appear or certain risk factors are present. Today, specific medications are frequently used that specifically target and inhibit the metabolism of tumor cells (inhibitors). Since the disease can recur despite treatment (relapse) or the treatment may sometimes be ineffective (refractory), new drugs are being sought to address these situations.

Epcoritamab is a so-called bispecific antibody that is already used to treat another form of lymphoma. It can bind simultaneously to cancer cells and the body’s own immune cells to specifically activate the immune system against the tumor cells. To do this, it binds to surface receptors on tumor cells and immune cells (CD20 and CD3). Venetoclax blocks a protein called BCL-2, which is present in higher levels in the malignant cells of CLL/SLL and ensures their survival. It is already approved for the treatment of CLL/SLL.

The goal of the AETHER study is to investigate the combination of the novel drug epcoritamab with the established active ingredient venetoclax. The combination of both drugs is intended to effectively prevent the survival of tumor cells and specifically combat the disease. The study consists of two treatment arms to which patients are assigned at random (randomized). The treatment is open-label, meaning that both patients and the treating physicians know which therapy is being used. There is no control arm without study medications—all patients will receive the study medications in any case. One treatment group receives 6 cycles of epcoritamab and 26 cycles of venetoclax; the second group receives 12 cycles of epcoritamab and also 26 cycles of venetoclax. Administration is discontinued once the assigned number of cycles is reached, or earlier in the event of disease progression or a serious adverse event. The study is divided into two phases: In Phase 1, the optimal dosage of the medications is first determined (evaluation after approximately 12 months). Subsequently, in Phase 2, the efficacy of 6 versus 12 cycles of epcoritamab will be compared. This evaluation will take place approximately 29 months after the start of the study. In total, patients will be followed for up to six years as part of the study.

Eligible participants include women and men aged 18 and older with recurrent (relapsed) or treatment-resistant (refractory) CLL or SLL who have already received systemic therapy (e.g., chemotherapy) at least once. Patients who have received active CLL/SLL-specific treatment within the last 14 days or who have already been treated with a bispecific antibody against CD3xCD20 or with CAR-T cells are excluded from participation. Patients with a so-called Richter transformation (an aggressive form of CLL), a prior stem cell or organ transplant, or confirmed progressive multifocal leukoencephalopathy (PML) are also ineligible to participate. Also excluded are individuals with other active cancers that currently require systemic therapy or that have recurred following curative treatment.