In early results from a non-randomised study, the biologic agent epcoritamab, which leverages patients’ own immune systems to find and kill cancer cells, showed promise in patients with chronic lymphocytic leukaemia (CLL) that had come back or not responded to at least two prior treatments.

“In heavily pretreated CLL, single-agent epcoritamab had a high overall response rate and a manageable safety profile,” said principal investigator Alexey Danilov, MD, PhD, a professor in the department of haematology & haematopoietic cell transplantation at City of Hope National Medical Center in Duarte, California.

Two classes of targeted drugs known as BTK and BCL2 inhibitors are the standard of care for both previously untreated CLL and CLL that has come back after treatment, Dr. Danilov said. However, some patients do not respond well to these agents. Moreover, in almost all patients with CLL, these classes of drugs eventually stop working.

“To date, no treatments have been shown in randomised trials to be effective for patients whose CLL has worsened after treatment with both BTK and BCL2 inhibitors,” he said. “There is an unmet need for new treatment options for this group of patients.”

Epcoritamab, which is given as an injection under the skin, belongs to a class of drugs known as bispecific T-cell engagers. It works by attaching to proteins on the surfaces of both cancer cells and healthy T cells (cells in the immune system that help kill cancer cells). This brings the cancer cells and the T cells closer to each other, which enables the T cells to more effectively kill the cancer cells. Epcoritamab is approved by the U.S Food and Drug Administration to treat two types of lymphoma that have come back or not responded to at least two prior therapies.

“CLL cells have learned how to persist in the body by making themselves invisible to the patient’s immune system,” Dr. Danilov said. “Epcoritamab essentially works as a bridge between the body’s immune cells and the CLL cells, boosting the ability of the immune cells to find, attack, and kill the cancer cells.”

The ongoing EPCORE CLL-1 trial is testing the effectiveness of epcoritamab in patients with CLL and other blood cancers that have come back after treatment with at least two different agents, including a BTK inhibitor. The trial, which is being conducted in 12 countries, will enroll a total of 184 patients.

The current study reports early results for the first 40 patients (median age 71.5, mostly male) enrolled in the trial. Most had CLL with features that make it more challenging to treat, such as a mutation in the TP53 gene or a chromosomal abnormality known as 17p deletion. Everyone was treated with the same dose of epcoritamab, with the first group (the EXP cohort, 23 patients) receiving the drug in three gradually increasing doses, while the second group (the OPT cohort; 17 patients), who were enrolled later, received it in four increasing doses.

The primary endpoint for the EXP cohort was the overall response rate (ORR), defined as the proportion of patients in whom signs of cancer either completely cleared or reduced by at least half. Secondary endpoints included the time until patients’ cancer showed signs of worsening, overall survival, and minimal residual disease (MRD), which refers to cancer cells that remain in the blood or bone marrow at a level that can be detected only with highly sensitive tests. For the OPT cohort, the primary endpoints included the number and severity of new cases of common side effects.

In the EXP cohort, after a median follow-up period of 22.8 months, the ORR was 61%. Among responding patients, 39% had a complete response, meaning that signs of cancer completely cleared. For all patients in this cohort, the median time until their cancer showed signs of worsening was 12.8 months. After about 15 months of follow-up, an estimated 65% of patients (15 people) were still alive. Among 12 responding patients (52%) who underwent MRD testing, nine (75%) had undetectable MRD in tests based on the standard sensitivity level.

“The response rate was very impressive for a single agent, especially considering that most patients had already been treated with both BTK and BCL2 inhibitors without success and had disease features that are difficult to treat,” Dr. Danilov said.

Low blood counts were common in patients in the EXP cohort. However, most patients had low blood counts when they enrolled in the study, Dr. Danilov said, suggesting that the low counts were often caused by the cancer rather than by the study treatment. Cytokine release syndrome, or CRS (which includes symptoms like fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing), was the most frequent non-blood-related adverse effect, occurring in 96% of patients. In most cases, CRS was mild, Dr. Danilov said, and mostly occurred after the first full dose of epcoritamab. Other common side effects were diarrhoea, fatigue, and swelling in the hands or lower legs. Four patients in the EXP cohort (17%) died, all of causes other than CLL.

Follow-up for patients in the OPT cohort, who were enrolled in the study later than those in the EXP cohort, was just 2.9 months. Because of the brevity of follow-up to date, data on the effectiveness of epcoritamab treatment in this cohort are not yet available, Dr. Danilov said. Eighty-four percent of patients had mild CRS; none had severe CRS. To date, no patients in the OPT cohort have died. No patients in either cohort have discontinued treatment because of adverse effects, Dr. Danilov said.

He cautioned that these are early results from just 40 patients. “We will need to treat more patients, follow them for a longer period of time, and conduct randomised studies to validate these findings,” he said.

“We also want to test epcoritamab in patients with CLL who have had fewer prior therapies,” he said. “There is reason to believe it could be even more effective if used earlier in the disease course, when a patient’s immune system is less compromised.”

Source: ASH