Patients with heavily pretreated, relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) treated with epcoritamab, a bispecific antibody, had a high overall response rate (ORR) and complete response (CR) rate, as well as a high rate of undetectable measurable residual disease (uMRD). The therapy also had an acceptable side effect profile. These results, from the phase 1b/2 EPCORE CLL-1 trial, were presented at the 66th American Society of Hematology Annual Meeting and Exposition in San Diego.
“This is an innovative regimen that is very distinct from all currently approved therapies since the use of bispecific antibodies has no precedence in patients with CLL,” study author Alexey V. Danilov, MD, PhD, of the City of Hope National Medical Center in Duarte, California, told ASH Clinical News. “The treatment was highly effective in a very refractory group of patients who have progressed on prior BTK and BCL2 inhibitors and harbored high-risk genetic abnormalities, such as TP53 aberrations.”
Bispecific antibodies have been approved as therapies for R/R follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), including mosunetuzumab for FL and glofitamab for R/R DLBCL. Epcoritamab, approved by the U.S. Food and Drug Administration for adults with R/R FL and DLBCL, is a subcutaneously administered CD3 x CD20 T-cell–engaging bispecific antibody that activates T cells, directing them to kill malignant CD20+ B cells.
However, no bispecific antibodies are currently approved for CLL. “CLL is an incurable leukemia, and while BTK and BCL2 inhibitors have changed the treatment paradigm in CLL, resistance to these agents remains an unmet medical need. Thus, new therapies are needed to improve responses and address resistance in CLL,” Dr. Danilov said.
In the current EPCORE CLL-1 open-label study, patients with CD20+ R/R CLL or small lymphocytic lymphoma who had at least two prior therapies and no prior allogeneic hematopoietic cell transplant ramped up to a maximum dose of 48 mg of epcoritamab every four weeks. To mitigate cytokine release syndrome (CRS), patients received prophylaxis with dexamethasone in parallel with their first dose of epcoritamab. The primary endpoint was ORR.
Twenty-three patients were enrolled in the expansion cohort and were a median age of 72 years. Seventeen patients, with a median age of 68 years, were enrolled in the optimization cohort, which included an additional step-up epcoritamab dose prior to the full 48 mg dose and adequate hydration as prophylaxis in addition to dexamethasone. The overall patient group had a median of four prior treatments and as many as 10 prior treatments.
After a median of 22.8 months of follow-up, 17 (76%) of 21 evaluable patients in the expansion cohort achieved response, and nine patients (43%) had a CR. Ten (67%) of the 15 patients in the expansion cohort with a TP53 mutation achieved response including five (33%) with a CR. Among 19 patients double exposed to both a BTK inhibitor and BCL2 inhibitor, 10 patients (53%) responded, with seven patients (37%) achieving a CR.
Among 12 responder patients who could be evaluated for MRD, nine (75%) had uMRD, and seven of seven (100%) of responder patients who had a CR had uMRD.
The median progression-free survival among the expansion cohort patients was 12.8 months, and the median overall survival was not yet reached.
In the optimalization cohort, the median follow-up time was shorter, 2.9 months, with 10 evaluable patients at the May 28, 2024, data cutoff. Among these patients, six (60%) had a response, and one (10%) had a CR.
Ninety-six percent of patients in the expansion cohort experienced CRS of any grade, and four patients (17%) had grade 3 CRS. Among the 17 patients in the optimization cohort, 82% experienced grade 1-2 CRS, and no patient had grade 3 CRS. CRS did not lead to treatment discontinuation.
The incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) was 13% (n=3) in the expansion cohort, all grade 1-2, and no patient experienced ICANS in the optimization cohort.
“Epcoritamab was well tolerated with predictable side effects, namely CRS. We were able to successfully mitigate CRS by modifying the step-up dosing schema in the optimization cohort,” Dr. Danilov said.
The EPCORE CLL-1 trial is still enrolling patients in the expansion cohort as well as drug combination cohorts. According to Dr. Danilov, additional studies are being planned to compare epcoritamab with existing therapies in patients with CLL.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Danilov A, Fakhri B, Awan FT, et al. Epcoritamab monotherapy in patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL): results from CLL expansion and optimization cohorts of Epcore CLL-1. Abstract 883. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, California.
