FDA Grants Accelerated Approval to Epcoritamab in R/R Follicular Lymphoma

The approval for epcoritamab was supported by findings from the phase 1/2 EPCORE NHL-1 trial (NCT03625037), in which investigators evaluated chemotherapy alone or in combination with epcoritamab for patients diagnosed with relapsed/refractory follicular lymphoma.

The News

The FDA has granted accelerated approved epcoritamab-bysp (Epkinly) as a treatment for patients with relapsed/refractory follicular lymphoma following at least 2 prior lines of therapy, according to a press release from the agency.¹

Supporting Data

The approval for epcoritamab was supported by findings from the phase 1/2 EPCORE NHL-1 trial (NCT03625037), in which investigators evaluated chemotherapy alone or in combination with epcoritamab for patients diagnosed with relapsed/refractory follicular lymphoma.

Topline data showed that the overall response rate (ORR) per independent review committee assessment was 82% (95% CI, 74.1%-88.2%) with epcoritamab. Additionally, a complete response (CR) occurred in 60% of patients. Median duration of response (DOR) was not reached [NR; 95% CI, 13.7-NR) after a median follow-up of 14.8 months among those with a response. Ongoing responses at 12 months occurred in 68.4% (95% CI, 57.6%-77.0%).

Investigators previously presented findings from this trial at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.²

The findings presented at ASCO showed that in the pivotal cohort (n = 128), the CR and partial response (PR) rates were 66% and 17%. The cycle 1 dose optimization (C1 OPT) cohort (n = 86) had CR and PR rates of 64% and 22%. Additionally, the minimal residual disease (MRD) negativity rate was 67% and 64%, respectively. The investigators noted a favorable trend between MRD negativity and progression-free survival (PFS) in all evaluable patients, as well as those in the cycle 3, day 1 landmark analysis.

Between the 2 cohorts, the median age was 65 years in the pivotal cohort vs 63.5 years in the C1 OPT cohort, 85% vs 92% of patients had stage III to IV Ann Arbor stage disease and 61% vs 51% had FLIPI between 3 and 5. Furthermore, 31% vs 20% had 4 or more prior lines of therapy, 52% vs 49% had progressive disease after 24 weeks, 70% vs 63% were double refractory, 54% vs 44% were primary, and 69% vs 57% were refractory to last prior systemic therapy.

In both cohorts, the median time to response was 1.4 months and the median time to CR was 1.5 months.

Expert Perspectives

“Compared with the standard dosing that was used in the prior protocol, this particular protocol [of dose optimization] had a response rate that was identical; it was in the upper 80s, and the CR rate in the 60s, with respect to this patient population. At the same time, the adverse effects [AEs] of cytokine release syndrome [CRS] as well as neurologic toxicity were markedly decreased by doing this kind of [step-up dosing]” Julie M. Vose, MD, MBA, said in an interview prior to ASCO with CancerNetwork^®.

Vose is the Division Chief and a Neumann M. and Mildred E. Harris Professor at the University of Nebraska Medical Center, and co-editor-in-chief of ONCOLOGY^®.

“This is a very effective therapy that we can use in a third-line setting or even in those patients who may have progression of disease after 24 months [of treatment],” Tycel Phillips, MD, stated in an interview with CancerNetwork® prior to the approval. “These [patients with] early progression tend to have poor outcomes, especially when given more cytotoxic agents like chemotherapy. Ideally, this treatment does not appear to be impacted by that sort of prognostic factor.”

Phillips is an associate professor in the Division of Lymphoma and Department of Hematology & Hematopoietic Stem Cell Transplantation at City of Hope in Duarte, California.

EPCORE NHL-1 Trial Design

In the trial, the primary objective of the pivotal cohort was to assess the ORR by an independent review committee. The data cutoff occurred on April 21, 2023, and the median follow-up was 17.4 months. The dosing regimen in the pivotal cohort included cycle 1, day 1, a 0.16 mg step-up dose of epcoritamab was administered; day 8 was a 0.8 mg step-up dose; and day 15 was a full dose of 48 mg. Required hospitalization occurred for 24 hours after the first full dose and CRS was treated prophylactically with prednisolone.

The primary objective of the C1 OPT cohort was to assess cytokine release syndrome, which was treated prophylactically with dexamethasone and recommended adequate hydration. The data cutoff was January 8, 2024, and the median follow-up was 5.7 months. On cycle 1, day 1, a 0.16 mg step-up dose of epcoritamab was administered; day 8 was a 0.8 mg step-up dose; day 15 was a 3 mg step-up dose; and day 22 was a full 48 mg dose.

Eligible patients had relapsed/refractory CD20-positive follicular lymphoma between grade 1 to 3A, an ECOG performance status between 0 to 2, and had received 2 or more prior lines of antineoplastic therapy including 1 or more treatments with an anti–CD20-positive monoclonal antibody. Furthermore, patients who received prior treatment with an alkylating agent or lenalidomide (Revlimid), and have prior CAR T-cell therapy and FDG-avid disease by PET/CT were included.

Adverse Effects

Common treatment-emergent adverse effects (TEAEs) occurred in 25% or more in all patients in both cohorts. In the C1 OPT cohort, grade 3 or greater TEAEs occurred in 53% of patients, with 3 instances of treatment discontinuation (3%; grade 2 bronchopulmonary aspergillosis [n=1] and pneumonitis [n=2]), and no fatalities.

No clinical tumor lysis syndrome was observed in either cohort. Additionally, an increased risk of morbidity and mortality due to infections was observed for patients with hematologic malignancies treated with B-cell-depleting therapies.

The C1 OPT cohort saw significant reductions in incidences and severity of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS). Observed cytokine release syndrome incidence among the pivotal and C1 OPT cohorts was 66% and 42%, respectively. Within the pivotal cohort, 41% of patients had grade 1, 25% had grade 2, and 2% had grade 3 cytokine release syndrome (CRS). Conversely, these rates were 40%, 9%, and 0%, respectively for the C1 OPT cohort.

Resolution rates were 100% in both cohorts, with the median time to resolution of 2 days between both cohorts (pivotal, 1-54; C1 OPT, 1-14). Additionally, no ICANS occurrence was observed in the C1 OPT cohort, as opposed to a 6% occurrence in the pivotal cohort.

Of the 82 patients in C1 OPT with no mandatory hospitalization, 54% had outpatient monitoring for CRS. Of the 30 patients with CRS following the first full dose, 77% experienced it in the outpatient setting, with successful CRS identification and treatment among all 30.

Most CRS occurred after the first full dose and was confined to the first cycle, with a median time of 2.5 days to cytokine release syndrome onset after the first full dose in C1 OPT.

References

1. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. News release. FDA. June 26, 2024. Accessed June 26, 2024. https://tinyurl.com/26s9myey
2. Vose J, Vitolo U, Lugtenburg P, et al. EPCORE NHL‑1 follicular lymphoma (FL) cycle (C) 1 optimization (OPT) cohort: expanding the clinical utility of epcoritamab in relapsed or refractory (R/R) FL. J Clin Oncol. 2024; 42(suppl 16):7015. doi:10.1200/JCO.2024.42.16_suppl.7015