Epcoritamab Monotherapy Induces Complete Responses in R/R CLL

Treatment with single-agent, subcutaneous epcoritamab-bysp (Epkinly) generated deep responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), regardless of the presence of high-risk features, according to findings from the CLL expansion and optimization cohorts of the phase 1/2 EPCORE CLL-1 study (NCT04623541; EudraCT: 2023-50428-25) that were presented during the 2024 American Society of Hematology Annual Meeting.¹

Results showed that in the expansion cohort, which had a median follow-up of 22.8 months, the overall response rate (ORR) in response-evaluable patients (n = 21) was 67%, and the complete response (CR) rate was 43%. In those with TP53 aberrations (n = 15), these rates were 67% and 33%, respectively; in the IGHV-unmutated group (n = 16), these were 63% and 44%. In patients who were double-exposed to both a BTK and BCL-2 inhibitor (n = 19), the ORR was 53%, and the CR rate was 37%.

In the cycle 1 optimization (C1 OPT) cohort, which had a median follow-up of 2.9 months among 10 evaluable patients, the ORR was 60%, and the CR rate was 10%.

Alexey Danilov, MD, PhD

“There was a comparable ORR between the expansion and C1 OPT cohorts, with limited follow-up for C1 OPT efficacy,” explained lead study author Alexey Danilov, MD, PhD, in a press briefing during the meeting. “Simple C1 OPT measures of an additional [step-up dosing], dexamethasone, and adequate hydration decreased the risk and severity of adverse events [AEs] of special interest.”

Danilov serves as the Marianne and Gerhard Pinkus Professor of Early Clinical Therapeutics, medical director of the Early Phase Therapeutics Program for the Systems Clinical Trials Office, co-director of the Toni Stephenson Lymphoma Center, and professor in the Division of Lymphoma of the Department of Hematology & Hematopoietic Cell Transplantation, all within City of Hope in Duarte, California.

Epcoritamab is a bispecific CD20-directed CD3 T-cell engager, which is currently approved by the FDA for the treatment of adult patients with relapsed/refractory follicular lymphoma following at least 2 prior lines of systemic therapy.²

In the expansion cohort of the Epcore CLL-1 trial (n = 23), patients were given a step-up dose schedule of 0.16 mg of epcoritamab on cycle 1, day 1; 0.8 mg on cycle 1, day 8; and then the first full dose of 48 mg on cycle 1, day 15.¹ Prophylaxis for cytokine release syndrome (CRS) with prednisone was also permitted. The data cutoff date was May 28, 2024, and the median follow-up was 22.8 months.

In the C1 OPT cohort (n = 17), CRS prophylaxis with dexamethasone and adequate hydration was given. This also included a step-up dose design of 0.16 mg on cycle 1, day 1; 0.8 mg on cycle 1, day 8; 3 mg on cycle 1, day 15; followed by the first full dose of 48 mg on cycle 1, day 22. Here, the data cutoff date was May 28, 2024, and the median follow-up was 2.9 months.

To be eligible for enrollment, patients must have had CD20-positive relapsed/refractory CLL, received at least 2 prior lines of systemic therapy, an ECOG performance status of 0 to 2, and measurable disease with at least 5 x 10⁹/L lymphocytes (expansion only). No prior allogeneic hematopoietic cell transplant was permitted.

The primary end point in the expansion cohort was ORR; in the C1 OPT cohort, this was incidence and severity of CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), and clinical tumor lysis syndrome (CTLS). Key secondary end points in the expansion cohort included CR rate, time to response, minimal residual disease (MRD), and safety and tolerability.

Investigators added that inpatient monitoring was required for the first 4 doses in cycle 1 to ensure patient safety and to better characterize CRS.

In the expansion and C1 OPT cohorts, respectively, the median age was 72 years (range, 55-83) and 68 years (range, 56-81); 74% and 82% of patients were male. The median time from initial diagnosis to first dose was 13 years (range, 6-19) and 11 (range, 6-18), respectively. The median number of prior lines of therapy was 4 (range, 2-10) in both arms; 61% and 53% received at least 4 prior lines of therapy. The median time from last treatment to first dose was 0.7 months (range, 0.1-49.4) and 1.6 months (–0.7 to –39.6), respectively. All patients in both arms previously received a BTK inhibitor; 83% and 88% of patients had received a BCL-2 inhibitor.

Further efficacy findings showed that, in the response-evaluable group of the expansion cohort, the partial response (PR) rate was 24%, the stable disease (SD) rate was 19%, and 5% of patients had progressive disease (PD). In those with TP53 aberrations, these rates were 33%, 13%, and 7%; in those with IGHV-unmutated disease, the rates were 19%, 19%, and 0%, respectively. In the double-exposed subgroup, these rates were 16%, 21%, and 5%, respectively.

In the C1 OPT cohort, the PR, SD, and PD rates were 50%, 20%, and 10%, respectively.

In the expansion cohort, the median time to response was 2.0 months (range, 1.6-3.8), and the median time to CR was 5.6 months (range, 1.6-11.1). The estimated 1-year progression-free survival (PFS) and overall survival (OS) rates were 52% and 70%, respectively; the median PFS was 12.8 months (95% CI, 5.4-17.1), and the median OS was not reached (NR; 95% CI, 8.6-NR).

Undetectable MRD4 (uMRD4) was only evaluated in patients who achieved a CR or PR. In overall responders, the uMRD4 rate was 75% (n = 9/12); 100% in all 7 patients who achieved a CR, and 40% (n = 2/5) in those who achieved a PR.

Additionally, Danilov noted that, in the C1 OPT cohort, the rate and severity of CRS was reduced, and there were no cases of ICANS or CTLS. Here, the overall CRS rate was 82% and was grade 1, 2, and 3 in 71%, 12%, and 0% of patients. In the expansion cohort, the CRS rate was 96% and was grade 1, 2, and 3 in 9%, 70%, and 17% of patients, respectively.

Tocilizumab (Actemra) was administered in 91% and 43% of patients in the expansion and C1 OPT cohorts, respectively. No such events led to treatment discontinuation, and all CRS cases resolved in both cohorts. The median time to resolution was 3 days (range, 1-16) in the expansion cohort and 3.5 days (range, 1-7) in the C1 OPT cohort.

In the expansion cohort, ICANS occurred in 13% of patients and were either grade 1 (4%) or 2 (9%); there was 1 case of CTLS, which was grade 2.

CRS events were also evaluated by dosing period. In the expansion cohort, these occurred at the first step-up dose (grade 1, 13.0%; grade 2, 21.7%), second step-up dose (grade 1, 36.4%; grade 2 13.6%), first full dose (grade 1, 18.2%; grade 2, 63.6%; grade 3, 18.2%); second full dose (grade 1, 10.5%; grade 2, 21.1%), and third full dose (grade 1, 6.3%; grade 2, 18.8%).

In the C1 OPT cohort, these also occurred at the first step-up dose (grade 1, 23.5%), second step-up dose (grade 1, 12.5%; grade 2, 6.3%), third step-up dose (grade 1, 31.3%), first full dose (grade 1, 46.7%; grade 2, 13.3%) second full dose (grade 1, 30.8%; grade 2, 7.7%) and third full dose (33.3%).

The phase 1/2 EPCORE CLL-1 trial is evaluating single-agent epcoritamab and as a combination regimen with various agents in patients with CLL and Richter’s transformation. It is currently recruiting patients.

Disclosures: Danilov listed consulting roles with AstraZeneca, AbbVie, BeiGene, Genentech, Nurix, MorphoSys, Incyte, TG Therapeutics, Bayer, ADCT, Bristol Myers Squibb, GenMab, and Janssen; and research funding support from AstraZeneca, Nurix, TG Therapeutics, Bayer, Takeda, MEI Pharma, Bristol Myers Squibb, Cyclacel, and GenMab.

References

1. 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. Blood. 2024;144(supplement 1):883. doi:10.1182/blood-2024-199708
2. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. FDA. News release. June 26, 2024. Accessed December 8, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-follicular-lymphoma