New ASH results: subcutaneous epcoritamab for lymphoma

Arm 1 of the Phase 1b/II EPCORE NHL-2 multi-arm trial evaluates fixed-duration investigational epcoritamab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated high-risk DLBCL patients (n=46) with International Prognostic Index (IPI) scores of 3 to 5 (Abstract #581).  Results from this arm of the study showed an overall response rate (ORR) of 100% and a complete response (CR) rate of 87%. Among complete responders, an estimated 83% remained in remission after two years. Separately, three-year follow-up results from the Phase II EPCORE NHL-1 trial (Abstract #4480),  evaluating epcoritamab monotherapy in challenging-to-treat adult patients (n=157) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after two or more lines of systemic therapy showed that among the 41% of patients who achieved a CR, an estimated 52% were still responding at three years (median CR duration: 36.1 months).

DLBCL is the most common type of non-Hodgkin's lymphoma (NHL) worldwide, accounting for approximately 25-30% of all NHL cases. In the U.S., there are approximately 25,000 new cases of DLBCL diagnosed each year  DLBCL can arise in lymph nodes as well as in organs outside of the lymphatic system, occurs more commonly in the elderly and is slightly more prevalent in men.  DLBCL is a fast-growing type of NHL, a cancer that develops in the lymphatic system and affects B-cell lymphocytes, a type of white blood cell. For many people living with DLBCL, their cancer either relapses, which means it may return after treatment, or becomes refractory, meaning it does not respond to treatment. Although new therapies have become available, treatment management can remain a challenge.

"The results from these epcoritamab studies help provide confidence in our ongoing Phase II trials and highlight our commitment to advancing treatment standards for this challenging type of cancer," said Mariana Cota Stirner, M.D., Ph.D., vice president, therapeutic area head for hematology, AbbVie. "We remain dedicated to exploring epcoritamab both as a monotherapy and in combination with other therapies for earlier lines of treatment, as well as establishing it as a core therapy across B-cell malignancies."

EPCORE  NHL-2 Results in First-Line DLBCL (Abstract #581); The EPCORE NHL-2 trial enrolled 46 evaluable patients considered to have high-risk DLBCL, identified by International Prognostic Index (IPI) scores of 3 to 5, a range associated with poor long-term outcomes. The IPI is a key tool used by oncologists to predict the prognosis of aggressive B-cell lymphomas. At screening, 35% of patients (n=16) had bulky disease (>10 cm), and 21% (n=6/28) had double-hit/triple-hit DLBCL, which are aggressive subtypes caused by major genetic mutations. A minimal residual disease (MRD) analysis from blood samples (n=33) showed that 91% of patients achieved MRD negativity, indicating no detectable disease as defined by ctDNA.¹⁰

The most common treatment-emergent adverse events (TEAEs) were neutropenia (70%), anemia (69%), cytokine release syndrome (CRS 60%), fatigue (49%), nausea (47%), pyrexia (42%), and injection-site reaction (40%). Four patients (9%) discontinued epcoritamab due to TEAEs; fatal TEAEs occurred in two patients (COVID-19 and septic shock). CRS events were mostly low grade (45% Grade 1, 11% Grade 2, 4% Grade 3) and mainly occurred after the first full dose. All CRS cases resolved, and none led to discontinuation. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in two patients (one Grade 1; one Grade 2) and resolved in a median of 2.5 days without leading to discontinuation.

EPCORE  NHL-1 Results in Third-Line LBCL (large B-cell lymphoma) (Abstract #4480); Three-year follow-up results from the Phase II EPCORE NHL-1 trial evaluated epcoritamab monotherapy in 157 patients with R/R LBCL after two or more lines of prior therapy and showed that epcoritamab continues to deliver durable responses in challenging-to-treat patients. Additional data results include: i. The ORR was 59%, and CR was 41%.  ii. Median duration of response was 20.8 months (95% CI, 13.0-32.0) and median duration of CR was 36.1 months (95% CI, 20.2 to not reached [NR]). iii. A MRD analysis from blood samples (n=119) showed that 45.4% of patients achieved MRD negativity, as defined by ctDNA.

The most common TEAEs were CRS (51%; 32% Grade 1, 16% Grade 2, 3% Grade 3), fatigue (25%), and pyrexia (25%); CRS rates remained unchanged since prior reports. Fatal TEAEs were reported in 20 patients; 10 patients had Grade 5 COVID-19 (including COVID-19 pneumonia). 73% of patients who received epcoritamab for two or more years did not experience a Grade 3 or higher infection after two years (median follow-up after two years: 12.3 months). Incidence of Grade 3 or higher cytopenias was highest (27%) during the first eight weeks of treatment and rates were within 0-13% in subsequent 12-week time periods up to week 144. Immunoglobulin G levels decreased by a median of ~20% after the start of epcoritamab treatment (baseline median, 540.0 mg/dL) and remained stable over time. 

"More first-line treatments for diffuse large B-cell lymphoma are needed, especially for patients with aggressive disease markers that may impact the efficacy of current standard first-line therapies," said Lorenzo Falchi, M.D., Lymphoma Specialist, Department of Medicine, Memorial Sloan Kettering Cancer Center. "The durable responses observed in the study suggest significant potential for this first-line epcoritamab-based combination."

Epcoritamab (approved under the brand name Epkinly in the U.S. and Japan, and Tepkinly  in the EU) has received regulatory approval in certain lymphoma indications in several territories. Use of epcoritamab + R-CHOP in first-line DLBCL is not approved in the U.S. or in the EU or in any other territory. The safety and efficacy of epcoritamab for use as a combination therapy in DLBCL have not been established.

About the EPCORE NHL-2 Trial; EPCORE  NHL-2 is a Phase 1b/II open-label interventional trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics/biomarkers, immunogenicity, and preliminary efficacy of epcoritamab as a monotherapy and in combination with other standard of care agents in patients with B-cell non-Hodgkin's lymphoma (B-NHL). The trial consists of two parts: Part 1 (Dose Escalation) and Part 2 (Dose Expansion). The primary objective of Part 1 is safety, and it includes Arms 1-5 and Arm 10. Part 2 includes all 10 arms (Arm 1-10) and the primary goal of all arms, except Arm 7, is preliminary efficacy. The primary endpoint was overall response rate (ORR) based on best overall response per Lugano criteria. MRD negativity was assessed as a secondary endpoint. Arm 1 of the trial is epcoritamab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‑CHOP) in adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL). More information on this trial can be found at https://www.clinicaltrials.gov/ (NCT: 04663347). 

About the EPCORE NHL-1 Trial; EPCORE NHL-1 is an open-label, multicohort, single-arm, Phase 1/II trial of epcoritamab in participants with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL). The trial was conducted at 88 sites across 15 countries and consisted of three parts: a Phase 1 first-in-human, dose escalation part; a Phase IIa expansion part; and a Phase IIa dose optimization part. More information on this trial can be found at https://www.clinicaltrials.gov/ (NCT: 03625037).