Rationale for Requested Change: EPCORE NHL-2 trial, Arm 5 (NCT04663347) is a phase 1b/2, open-label trial in 103 adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL NOS, “double-” or “triple-hit” DLBCL, follicular lymphoma (FL) grade 3B or T-cell/histiocyte-rich DLBCL ineligible for autologous stem cell transplant (ASCT). [1] Patients received epcoritamab as a subcutaneous (SC) injection in combination with gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2, both administered intravenously (IV) for C1-4.1 Following step-up dosing, epcoritamab was administered once weekly for C1-3, every 2 weeks for C4-9 and every 4 weeks for C10+ until progression. GemOx was administered every 2 weeks at C1-4.
The primary endpoint was antitumor activity. Key secondary endpoints included duration of response (DOR), duration of complete response (DOCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and treatment-emergent adverse events (TEAEs). [1]
In the Arm 5 cohort, the median number of prior therapies was 2 (range, 1-6), with 38% receiving 1 prior therapy, 26% receiving 2 prior therapies, and 36% receiving 3 or more prior therapies.[1] Ten percent of patients had prior ASCT, and 28% had prior chimeric antigen receptor (CAR) T-cell therapy. Seventy percent of patients had disease refractory to last systemic therapy. Other baseline demographics are summarized in Table 1.
Table 1: EPCORE NHL-2 (Arm 5) Trial Baseline Patient Characteristics [1]
Arm 5 Cohort (N=103)
Median age (range), y 72 (20-87)
=75 y, n (%) 36 (35)
ECOG PS, n (%)
0 33 (32)
1 57 (55)
2 13 (13)
IPI, n (%)
<3 38 (37)
=3 65 (63)
Bulky disease by IRC assessment, n (%)
>10 cm 20 (19)
DLBCL type, n (%)a
De novo 75 (73)
Transformed 24 (23)
Median prior lines of therapy (range) 2 (1-6)
Prior lines of therapy, n (%)
1 39 (38)
2 27 (26)
=3 37 (36)
Primary refractory disease, n (%)b 54 (52)
Refractory to last systemic therapy, n (%)b 72 (70)
Refractory to =2 consecutive lines of therapy, n (%)b 38 (37)
Prior ASCT, n (%) 10 (10)
Relapsed =12 mo after ASCT, n/n (%) 5/10 (50)
Prior CAR-T therapy, n (%) 29 (28)
a De novo versus transformed status of 4 patients was missing
b Refractory disease is defined as disease either progressed during therapy or progressed within 6 mo of completion of therapy.
Abbreviations: ASCT: autologous stem cell transplant; CAR-T: chimeric antigen receptor; DLBCL: diffuse large B-cell lymphoma; ECOG PS: performance status: Eastern Cooperative Oncology Group performance status; IPI: International Prognostic Index; IRC: independent review committee
Patients initiated a median of 8 epcoritamab treatment cycles (range, 1–37) and received a median of 22 doses (range, 2–52).[1] All but one patient received the first full dose. Overall response and complete response (CR) rates were 85% and 61% by independent review committee (IRC) assessment, respectively (Table 2).
Table 2: EPCORE NHL-2 (Arm 5) Efficacy Endpoints in Patients with Relapsed or Refractory DLBCL Ineligible for ASCT [1]
Best Overall Response, n (%) Investigator Assessment (N=103)a IRC Assessment (N=103)b
Overall response rate 82 (80) 88 (85)
Complete response 60 (58) 63 (61)
Partial response 22 (21) 25 (24)
Median time to response (range), mo 1.5 (0.9-11.1) 1.5 (0.9-3.0)
Median time to complete response (range), mo 1.7 (1.3-10.7) 2.6 (1.3-22.1)
Data cutoff: December 15, 2023.
Abbreviations: ASCT: autologous stem cell transplant; DLBCL: diffuse large B-cell lymphoma; IRC: independent review committee
a Five patients were not evaluable for response per investigator.
b Four patients were not evaluable for response per IRC.
Median duration of response (DOR) among complete responders (n=63) was 25.4 mo (range, 2.2 to 31.9+) by IRC assessment. [1] CR rates were observed in patients with non–primary refractory disease, CAR T–naive patients, and 2L patients (CR rates by IRC assessment, 68%–74%).
Among complete responders by IRC assessment, percentage of patients with PFS and OS were 85% and 94% at 9 months, respectively, and 57% and 77% at 15 months, respectively. [1]
Epcoritamab labeling includes warnings and precautions for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections, cytopenias, and embryo-fetal toxicity, including boxed warnings for CRS and ICANS. [2]
The most common (=30%) treatment-emergent adverse reactions in the Arm 5 cohort were thrombocytopenia, neutropenia, anemia, CRS, diarrhea, nausea, fatigue, and hypokalemia. [1] CRS was primarily low grade; total CRS events observed were 52% (grade 1: 28%, grade 2: 23% events and grade 3: 1% events).1 Most CRS events occurred following the first full dose of epcoritamab (median time to onset after the first full dose, 2 d). Twenty-three percent of patients received tocilizumab and all CRS events resolved (median time to resolution, 2.5 d).
ICANS was reported in 3 patients (grade 1–3, n=1 each); all events resolved, and 1 patient discontinued treatment due to ICANS. [1] Events categorized as grade =3 for =20% of patients included thrombocytopenia, neutropenia and anemia. Seven patients had febrile neutropenia. In the overall population, the rate of serious infections, excluding COVID-19, was higher in the first 8 weeks of the study (15%) than during subsequent 12-week time intervals until week 72 (range, 1%–10%).
Based on the summary of the above data, we respectfully request your consideration of epcoritamab in combination with GemOx as a treatment option for adult patients with relapsed or refractory DLBCL with no intention to proceed to transplant.
