Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents
ATC code: L01FX27
Epcoritamab is a humanised IgG1-bispecific antibody that binds to a specific extracellular epitope of CD20 on B cells and to CD3 on T cells. The activity of epcoritamab is dependent upon simultaneous engagement of CD20-expressing cancer cells and CD3-expressing endogenous T cells by epcoritamab that induces specific T-cell activation and T-cell-mediated killing of CD20-expressing cells.
Epcoritamab Fc region is silenced to prevent target-independent immune effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).
Epcoritamab induced rapid and sustained depletion of circulating B-cells (defined as CD19 B-cell counts ≤10 cell/μl) in the subjects who have detectable B cells at treatment initiation. There were 21% subjects (n=33) with DLBCL and 50% subjects (n=56) with FL who had detectable circulating B-cells at treatment initiation. Transient reduction in circulating T cells was observed immediately after each dose in Cycle 1 and followed by T cell expansion in subsequent cycles.
In study GCT3013-01, following subcutaneous administration of epcoritamab at the recommended 2-step step-up dose schedule in patients with LBCL, transient and modest elevations of circulating levels of selected cytokines (IFN-γ, TNFα, IL-6, IL-2, and IL-10) occurred mostly after the first full dose (48 mg), with peak levels between 1 to 4 days post dose. Cytokine levels returned to baseline prior to the next full dose, however elevations of cytokines could also be observed after Cycle 1. In study GCT3013-01, following subcutaneous administration of epcoritamab at the recommended 3-step step-up dose schedule in patients with FL, median IL-6 levels associated with CRS risk remained consistently low after each dose in Cycle 1 and beyond, particularly after the first full dose, compared to patients who received the 2-step step-up dose.
Anti-drug antibodies (ADA) were commonly detected. The incidence of treatment-emergent ADAs with the 2-step step-up dose schedule (0.16/0.8/48 mg) in the combined population of DLBCL and FL was 3.4% (3.4 % positive, 93.9% negative and 2.7% indeterminate, N=261 evaluable patients) and 3.3% (3.3% positive, 95% negative and 1.7% indeterminate, N= 60 evaluable patients), in studies GCT3013-01 and GCT3013-04, respectively.
The incidence of treatment-emergent ADAs with the 3-step step-up dose schedule (0.16/0.8/3/48 mg) in the FL optimisation cohort was 7% (7% positive, 91.5% negative and 1.4% indeterminate, N=71 evaluable patients) in study GCT3013-01. A subject is classified as indeterminate if the patient is confirmed ADA positive at baseline but there is no confirmed positive on-treatment record or if confirmed ADA positive on treatment record titre are equal or lower than baseline.
No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited. Neutralising antibodies were not evaluated.
Study GCT3013-01 was an open-label, multi-cohort, multicentre, single-arm study that evaluated epcoritamab as monotherapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL). The study includes a dose escalation part and an expansion part. The expansion part of the study included an aggressive non-Hodgkin lymphoma (aNHL) cohort, an indolent NHL (iNHL) cohort and a mantle-cell lymphoma (MCL) cohort. The pivotal aNHL cohort consisted of patients with LBCL (N=157), including patients with DLBCL (N=139, 12 patients of which had MYC, BCL2, and/or BCL6 rearrangements i.e., DH/TH), with high-grade B-cell lymphoma (HGBCL) (N=9), with follicular lymphoma grade 3B (FL) (N=5) and patients with primary mediastinal B-cell lymphoma (PMBCL) (N=4). In the DLBCL cohort, 29% (40/139) of patients had transformed DLBCL arising from indolent lymphoma. Patients included in the study were required to have documented CD20+ mature B-cell neoplasm according to WHO classification 2016 or WHO classification 2008 based on representative pathology report, failed prior autologous hematopoietic stem cell transplantation (HSCT) or were ineligible for autologous HSCT, patients who had lymphocyte counts <5 × 109/L, and patients with at least 1 prior anti-CD20 monoclonal antibody-containing therapy.
The study excluded patients with central nervous system (CNS) involvement of lymphoma, prior treatment with allogeneic HSCT or solid organ transplant, chronic ongoing infectious diseases, any patients with known impaired T-cell immunity, a creatinine clearance of less than 45 ml/min, alanine aminotransferase >3 times the upper limit of normal, cardiac ejection fraction less than 45%, and known clinically significant cardiovascular disease. Efficacy was evaluated in 139 patients with DLBCL who had received at least one dose of epcoritamab SC in cycles of 4 weeks, i.e., 28 days. Epcoritamab monotherapy was administered at the recommended 2-step step-up dose schedule as follows:
Patients continued to receive epcoritamab until disease progression or unacceptable toxicity.
The demographics and baseline characteristics are shown in Table 8.
Table 8. Demographics and baseline characteristics of patients with DLBCL in GCT3013-01 study:
| Characteristics | (N=139) |
|---|---|
| Age | |
| Median, years (min, max) | 66 (22, 83) |
| <65 years, n (%) | 66 (47) |
| 65 to <75 years, n (%) | 44 (32) |
| ≥75 years, n (%) | 29 (21) |
| Males, n (%) | 85 (61) |
| Race, n (%) | |
| White | 84 (60) |
| Asian | 27 (19) |
| Other | 5 (4) |
| Not Reported | 23 (17) |
| ECOG performance status; n (%) | |
| 0 | 67 (48) |
| 1 | 67 (48) |
| 2 | 5 (4) |
| Disease stagec at initial diagnosis, n (%) | |
| III | 16 (12) |
| IV | 86 (62) |
| Number of prior lines of anti-lymphoma therapy | |
| Median (min, max) | 3 (2, 11) |
| 2, n (%) | 41 (30) |
| 3, n (%) | 47 (34) |
| ≥4, n (%) | 51 (37) |
| DLBCL Disease history; n (%) | |
| De Novo DLBCL | 97 (70) |
| DLBCL transformed from indolent lymphoma | 40 (29) |
| FISH Analysis Per Central labd, N=88 | |
| Double-hit/Triple-hit lymphoma, n (%) | 12 (14) |
| Prior autologous HSCT | 26 (19) |
| Prior therapy; n (%) | |
| Prior CAR-T | 53 (38) |
| Primary refractory diseasea | 82 (59) |
| Refractory to ≥2 consecutive lines of prior anti-lymphoma therapyb | 104 (75) |
| Refractory to the last line of systemic antineoplastic therapyb | 114 (82) |
| Refractory to prior anti-CD20 therapy | 117 (84) |
| Refractory to CAR-T | 39 (28) |
a A patient is considered to be primary refractory if the patient is refractory to frontline anti-lymphoma therapy.
b A patient is considered to be refractory if the patient either experiences disease progression during therapy or disease progression within < 6 months after therapy completion. A patient is considered relapsed if the patient had recurred disease ≥6 months after therapy completion.
c Per Ann Arbor Staging.
d Post hoc central lab FISH analysis was performed on available diagnostic baseline tumour tissue sections from 88 DLBCL patients.
The primary efficacy endpoint was overall response rate (ORR) determined by Lugano criteria (2014) as assessed by Independent Review Committee (IRC). The median follow-up time was 15.7 months (range: 0.3 to 23.5 months). The median duration of exposure was 4.1 months (range: 0 to 23 months).
Table 9. Efficacy results in study GCT3013-01 in patients with DLBCLa:
| Endpoint IRC assessment | Epcoritamab (N=139) |
|---|---|
| ORRb, n (%) | 86 (62) |
| (95% CI) | (53.3, 70) |
| CRb, n (%) | 54 (39) |
| (95% CI) | (30.7, 47.5) |
| PR, n (%) | 32 (23) |
| (95% CI) | (16.3, 30.9) |
| DORb | |
| Median (95% CI), months | 15.5 (9.7, NR) |
| DOCRb | |
| Median (95% CI), months | NR (12.0, NR) |
TTR, median (range), months 1.4 (1, 8.4)
CI = confidence interval; CR = complete response; DOR = duration of response; DOCR = duration of complete response; IRC = independent review committee; ORR = overall response rate; PR = partial response; TTR = time to response
a Determined by Lugano criteria (2014) as assessed by independent review committee (IRC)
b Included patients with initial PD by Lugano or IR by LYRIC who later obtained PR/CR.
The median time to CR was 2.6 months (range: 1.2 to 10.2 months).
Study GCT3013-01 was an open-label, multi-cohort, multicentre, single-arm trial that evaluated epcoritamab as monotherapy in patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. The study includes a dose escalation part, an expansion part and a 3-step step-up dose optimisation part. The expansion part of the study included an aggressive non-Hodgkin lymphoma (aNHL) cohort, an indolent NHL (iNHL) cohort and a mantle-cell lymphoma (MCL) cohort. The pivotal iNHL cohort, included patients with FL. Patients included in the study were required to have documented CD20+ mature B-cell neoplasm according to WHO classification 2016 or WHO classification 2008 based on representative pathology report with histologic confirmed FL 1-3A at initial diagnosis without clinical or pathological evidence of transformation. All patients had relapsed or refractory disease to the last prior line therapy and previously treated with at least 2 lines of systemic antineoplastic therapy, including at least 1 anti-CD20 monoclonal antibody-containing therapy and an alkylating agent or lenalidomide. The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or solid organ transplant, ongoing active infectious diseases, any patients with known impaired T-cell immunity, a creatinine clearance of less than 45 ml/min, alanine aminotransferase >3 times the upper limit of normal and cardiac ejection fraction less than 45%. Efficacy was evaluated in 128 patients who had received epcoritamab subcutaneously (SC) in cycles of 4 weeks, i.e., 28 days. Epcoritamab was administered as a monotherapy in a 2-step step-up dose schedule as follows:
Patients continued to receive epcoritamab until disease progression or unacceptable toxicity.
The median number of cycles initiated was 8 and 60% received 6 cycles.
The demographics and baseline characteristics are shown in Table 10.
Table 10. Demographics and baseline characteristics of patients with FL in GCT3013-01 study:
| Characteristics | (N=128) |
|---|---|
| Age | |
| Median, years (min, max) | 65 (39, 84) |
| <65 years, n (%) | 61 (48) |
| 65 to <75 years, n (%) | 50 (39) |
| ≥75 years, n (%) | 17 (13) |
| Males, (%) | 79 (62) |
| Race, n (%) | |
| White | 77 (60) |
| Asian | 7 (6) |
| Other | 2 (1.6) |
| Not Reported | 42 (33) |
| ECOG performance status; n (%) | |
| 0 | 70 (55) |
| 1 | 51 (40) |
| 2 | 7 (6) |
| Number of prior lines of therapies, n (%) | |
| Median (min, max) | 3 (2, 9) |
| 2 | 47 (37) |
| 3 | 41 (32) |
| ≥4 | 40 (31) |
| Ann Arbor Staging; (%) | |
| Stage III/IV | 109 (85) |
| FLIPI at baseline, n (%) | |
| 2 | 31 (24) |
| 3-5 | 78 (61) |
| Bulky Disease, n (%) | 33 (26) |
| Prior Therapy; n (%) | |
| Autologous stem cell transplant | 24 (19) |
| Chimeric antigen receptor (CAR)-T cell therapy | 6 (5) |
| Rituximab plus lenalidomide therapy | 27 (21) |
| PI3K inhibitor | 29 (23) |
| Progression of disease within 24 months of first systemic therapy | 67 (52) |
| Refractory to: | |
| ≥2 consecutive lines of prior anti-lymphoma therapy | 70 (55) |
| The last line of systemic antineoplastic therapy | 88 (69) |
| Prior anti-CD20 monoclonal antibody therapy | 101 (79) |
| Both anti-CD20 monoclonal antibody and alkylator therapy | 90 (70) |
Efficacy was established based on overall response rate (ORR) determined by Lugano criteria (2014) as assessed by Independent Review Committee (IRC). The median follow-up for DOR was 16.2 months. Efficacy results are summarised in Table 11.
Table 11. Efficacy Results in Study GCT3013-01 in FL Patients:
| Endpointa br>IRC assessment | Epcoritamabbr>(N=128) |
|---|---|
| ORRb, n (%) | 106 (83) |
| (95% CI) | (75.1, 88.9) |
| CRb, n (%) | 81 (63) |
| (95% CI) | (54.3, 71.6) |
| PRb, n (%) | 25 (20) |
| (95% CI) | (13.1, 27.5) |
| DORb | |
| Median (95% CI), months | 21.4 (13.7, NR) |
| DOCRb | |
| Median (95% CI), months | NR (21.4, NR) |
| 12-month estimate, % (95% CI) | 78.6 (67.3, 86.4) |
| TTR, median (range), months | 1.4 (1, 3) |
CI = confidence interval; CR = complete response; DOR = duration of response; DOCR = duration of complete response; IRC = independent review committee; ORR = overall response rate; PFS = progression-free survival; TTR = time to response
a determined by Lugano criteria (2014) as assessed by independent review committee (IRC)
b Included patients with initial PD by Lugano or IR by LYRIC who later obtained PR/CR.
The median time to CR was 1.5 months (range: 1.2 to 11.1 months).
The European Medicines Agency has deferred the obligation to submit the results of studies with epcoritamab in one or more subsets of the paediatric population in the treatment of mature B-cell malignancies, as per paediatric investigation plan (PIP) decision, for the granted indication (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The population pharmacokinetics following subcutaneous administration of epcoritamab was described by a two-compartment model with first order subcutaneous absorption and target-mediated drug elimination. The moderate to high pharmacokinetic variability for epcoritamab was observed and characterised by inter-individual variability (IIV) ranging from 25.7% to 137.5% coefficient of variation (CV) for epcoritamab PK parameters.
In patients with LBCL in study GCT3013-01, based on individually estimated exposures using population pharmacokinetic modelling, following the recommended 2-step step-up dose schedule SC dose of epcoritamab 48 mg, the geometric mean (% CV) Cmax of epcoritamab is 10.8 mcg/ml (41.7%) and AUC0-7d is 68.9 day*mcg/ml (45.1%) at the end of the weekly dosing schedule. The Ctrough at Week 12 is 8.4 (53.3%) mcg/ml.The geometric mean (% CV) Cmax of epcoritamab is 7.52 mcg/ml (41.1%) and AUC0-14d is 82.6 day*mcg/ml (49.3%) at the end of q2w schedule. The Ctrough for q2W schedule is 4.1 (73.9%) mcg/ml.The geometric mean (% CV) Cmax of epcoritamab is 4.76 mcg/ml (51.6%) and AUC0-28d is 74.3 day*mcg/ml (69.5%) at steady state during the q4w schedule. The Ctrough for q4W schedule is 1.2 (130%) mcg/ml.
Exposure parameters of epcoritamab in patients with FL were consistent with the exposure parameters seen in the patients with LBCL. Epcoritamab exposures are similar between FL subjects who received the 3-step step-up dose schedule and 2-step step-up dose schedule except for transiently lower trough concentrations, as expected, at Cycle 1 Day 15 after the second intermediate dose (3 mg) with 3-step step-up dose schedule compared first full 48 mg dose with 2-step step-up dose schedule.
The peak concentrations occurred around 3-4 days (Tmax) in patients with LBCL receiving the 48 mg full dose.
The geometric mean (% CV) central volume of distribution is 8.27 l (27.5%) and apparent steady-state volume of distribution is 25.6 l (81.8%) based on population PK modelling.
The metabolic pathway of epcoritamab has not been directly studied. Like other protein therapeutics, epcoritamab is expected to be degraded into small peptides and amino acids via catabolic pathways.
Epcoritamab is expected to undergo saturable target mediated clearance. The geometric mean (% CV) clearance (l/day) is 0.441 (27.8%). The half-life of epcoritamab is concentration dependent. The population PK model-derived geometric mean half-life of full dose epcoritamab (48 mg) ranged from 22 to 25 days based on frequency of dosing.
No clinically important effects on the pharmacokinetics of epcoritamab (Cycle 1 AUC within approximately 36%) were observed based on age (20 to 89 years), sex, or race/ethnicity (white, Asian, and other), mild to moderate renal impairment creatinine clearance (CLcr ≥30 ml/min to CLcr <90 ml/min), and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST) after accounting for differences in bodyweight. No patients with severe to end-stage renal disease (CLcr <30 ml/min) or severe hepatic impairment (total bilirubin >3 times ULN and any AST) have been studied. There is very limited data in moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST, N=1). Therefore, the pharmacokinetics of epcoritamab is unknown in these populations.
Like other therapeutic proteins, body weight (39 to 172 kg) has a statistically significant effect on the pharmacokinetics of epcoritamab. Based on exposure-response analysis and clinical data, considering the exposures in patients at either low body weight (e.g., 46 kg) or high body weight (e.g., 105 kg) and across body weight categories (<65 kg, 65 - <85, ≥85), the effect on exposures is not clinically relevant.
The pharmacokinetics of epcoritamab in paediatric patients has not been established.
No reproductive or developmental toxicity studies in animals have been conducted with epcoritamab. Effects generally consistent with the pharmacologic mechanism of action of epcoritamab were observed in cynomolgus monkeys. These findings included dose-related adverse clinical signs (including vomiting, decreased activity, and mortality at high doses) and cytokine release, reversible hematologic alterations, reversible B-cell depletion in peripheral blood, and reversible decreased lymphoid cellularity in secondary lymphoid tissues.
Mutagenicity studies have not been conducted with epcoritamab.
Carcinogenicity studies have not been conducted with epcoritamab.
Animal fertility studies have not been conducted with epcoritamab, however, epcoritamab did not cause toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses up to 1 mg/kg/week in intravenous general toxicity study of 5-week duration. The AUC exposures (time-averaged over 7 days) at the high dose in cynomolgus monkeys were similar to those in patients (AUC0-7d) receiving the recommended dose.
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