Dual target dilemma: navigating epcoritamab vs. glofitamab in relapsed refractory diffuse large B-cell lymphoma

KEYWORDS:

• DLBCL
• glofitamab
• epcoritamab
• bispecific antibodies
• CD20/CD3

1. Introduction

Despite more than 60% of patients with diffuse large B-cell lymphoma (DLBCL) achieving cure with frontline chemoimmunotherapy, patients with relapsed and particularly those with refractory (R/R) disease have poor outcomes with median overall survival (OS) of around 6 months [1–4]. The standard of care for eligible patients with R/R DLBCL currently consists of either chimeric antigen receptor (CAR) T-cell therapy or salvage chemotherapy followed by autologous stem cell transplantation (ASCT). Relapses after ASCT and CAR T occur in approximately 40–50% of patients; the poor prognosis of patients with R/R DLBCL has led to the development of novel treatment modalities, including bispecific antibodies (BsAbs) [1–4].

1.1. Anti-CD20 BsAbs

CD20 is an ideal target for therapies treating DLBCL, as it almost exclusively expressed on mature B-cells [5]. Anti-CD20 BsAb therapies utilize antigens on both the B-cell (CD20) and T-cell (CD3) to usher immune cells within the proximity of the malignant B-cell inducing T-cell activation and immune-mediated cytotoxicity. Epcoritamab-bysp and glofitamab-gxbm represent two recently approved CD20/CD3 BsAbs for the treatment of DLBCL [3,4]. Here, we review the relevant similarities and differences of these novel anti-CD20 BsAb products as well as offer a fair comparison of relevant characteristics related to use in real-world patient care. Given the ongoing uncertainty regarding the preference between the two products, we delve into pertinent factors related to patients, the disease, and product constructs, to provide valuable insights for providers in the management of patients with R/R DLBCL.

1.2. Epcoritamab

EPCORE NHL-1 (NCT03625037) was a single-arm, multicenter, open-label, phase I/II trial investigating dosing, safety, and efficacy of epcoritamab in 157 patients with R/R DLBCL. Patients received weekly subcutaneous (SQ) step-up doses of 0.16 mg on day 1, 0.8 mg on day 8, and a full 48 mg on day 15, followed by weekly thereafter until disease progression or unacceptable toxicity. Doses were administered once weekly for three 28-day cycles, every other week for six 28-day cycles, and then every 4 weeks from cycle 10 onward [3]. At a median follow-up of 10.7 months, 63.1% of patients achieved the primary outcome of overall response rate (ORR) (95% CI, 55–70.6) with 38.9% obtaining a complete response (CR).

Median progression-free survival (PFS) was 4.4 months (95% CI, 3–7.9), and median OS was not reached (95% CI, 11.3–not reached) [3]. Common grade ≥3 toxicities included neutropenia (14.6%), infections (14.6%), anemia (10%), and thrombocytopenia (5.7%). Among the patient population, 50% experienced cytokine release syndrome (CRS), while 6% encountered immune effector cell-associated neurotoxicity syndrome (ICANS). Severe (grade ≥3) toxicities were observed in less than 3% of the patients [3]. The US Food and Drug Administration (FDA) granted accelerated approved to epcoritamab in May 2023 for patients with R/R DLBCL after two or more prior lines of systemic therapy [6].

1.3. Glofitamab

NP30179 (NCT03075696) was a single-arm, multicenter, open-label, phase I/II trial investigating efficacy of glofitamab in 154 patients with R/R DLBCL. Patients received pre-treatment with a one-time 1000 mg obinutuzumab dose 7 days prior to receiving weekly intravenous (IV) glofitamab step-up doses of 2.5 mg on day 8, 10 mg on day 15, and a full 30 mg on day 1 of cycle 2. Patients then received the full dose of 30 mg every 21 days through cycle 12 [4]. At a median follow-up of 12.6 months, 52% of patients achieved the primary outcome of ORR (95% CI, 43–60) with 39% obtaining a CR (95% CI, 32–48) according to independent review committee [4]. Median PFS was 4.9 months (95% CI, 3.4–8.1), and estimated 12-month OS was 50% (95% CI, 41–58) [4]. Frequent severe (grade ≥3) toxicities included neutropenia (27%), infections (15%), anemia (6%), and thrombocytopenia (8%). Among the patient population, 63% experienced CRS, while 8% experienced ICANS. Severe (grade ≥3) toxicities were observed in less than 5% of the patients [4]. The US FDA granted accelerated approved to glofitamab in June 2023 for patients with R/R DLBCL after two or more prior lines of systemic therapy [7].

2. Discussion

Despite significant breakthroughs in the treatment landscape over the last 10 years, outcomes for patients with R/R DLBCL remain poor. Despite the increased use of CAR T-cell therapy or ASCT in the second line, 40–50% still relapse. Third-line and subsequent treatment remains challenge even with the recent approvals of polatuzumab vedotin, tafasitamab/lenalidomide, loncastuximab teserine, and selinexor [8–11]. Commercially approved BsAb therapy represents novel immunotherapy options which show similar effectiveness, boasting ORRs between 52% and 63%, and a median response duration of 12–18 months [3,4]. Although these two CD20/CD3-directed BsAbs target the same antigen with a similar mechanism of action and have been studied in heavily pretreated R/R DLBCL patients, significant distinctions exist, encompassing factors such as the route of administration, frequency and duration of treatment, as well as the specific patient demographics examined in the pivotal clinical trials for both. The characteristics outlined in Tables 1 and 2 potentially account for the variations observed in the effectiveness and safety profiles of the two treatments. Without a randomized controlled trial directly comparing them, it remains challenging to definitively declare one product’s superiority over the other.

Table 1. Comparison of available anti-CD20 bispecific antibodies for DLBCL.

	Epcoritamab (n = 157)	Glofitamab (n = 154)
Baseline characteristics
Median age (range)	64 years (20–83)	66 years (21–90)
Median prior lines (range)	3 (2–11)	3 (2–7)
Non-Hodgkin lymphoma subtype, %
DLBCL, not otherwise specified	74	71
Transformed	28.8	18
High-grade BCL	5.7	7
Primary mediastinal BCL	2.5	4
ECOG PS ≥ 2, %	3.2	0
Ann Arbor stage, %
I/II	24.8	22
III	13.4	20
IV	61.8	55
Missing data	0	2
International Prognostic Index, %
0–2	35	Not reported
≥3	52.2
Double/Triple hit per FISH analysis, %	13.1	Not reported
Prior ASCT, %	19.7	18
Prior CAR T-cell therapy, %	39	33
Primary refractory disease, %	61	58
Adverse events
CRS, all (grade ≥3)	50% (2.5%)	63% (4%)
Median onset of CRS, duration	20 hours, 48 hours	13 hours, 30 hours
ICANS, all (grade ≥3)	6% (0.6%)	8% (3%)
Infections, all (grades 3–4)	45% (15%)	38% (15%)
Neutropenia, all (grade ≥3)	21.7% (14.6%)	38% (27%)
Thrombocytopenia, all (grade ≥3)	13.4% (5.7%)	25% (8%)
Tumor lysis syndrome, all (grade ≥3)	1.3% (1.3%)	Not reported (1.9%)
Grade 5 adverse event	5.7%	5%
Efficacy
ORR	63%	52%
CR	39%	39%
MRD negativity rate	45.8%	Not reported
Median PFS	4.4 months (95% CI, 3–7.9)	4.9 months (95% CI, 3.4–8.1)
Median OS	NR (95% CI, 11.3–NR)	11.5 months (95% CI, 7.9–15.7)
Median time to best response (range)	2.7 months (1.2–11.1)	1.4 months (95% CI, 1.4–1.44)
Median duration of response (range)	12 months (0–15.5)	18.4 months (95% CI, 13.7–NR)

Key: ECOG PS, Eastern Cooperative Oncology Group Performance Status; ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; ORR, overall response rate; CR, complete response; MRD, minimum residual disease; PFS, progression-free survival; OS, overall survival; NR, not reached.

Table 2. Details of treatment regimens.

	Epcoritamab	Glofitamab
Mechanism of action	CD20/CD3 BsAb	CD20/CD3 BsAb
FDA approval	After failure of two or more lines of systemic therapy	After failure of two or more lines of systemic therapy
REMS requirement	No	No
Boxed warning	CRS and ICANS	CRS
Recommended admission duration during dose step-up	24-hour hospitalization after cycle 1 on day 15 (first 48 mg dose)	24-hour hospitalization during and after step-up dose 1 (cycle 1, day 8)
Cycle length and dosing schedule	Cycle length: 28 days Cycle 1: SQ dose step-up: Day 1: 0.16 mg Day 8: 0.8 mg Days 15, 22: 48 mg Cycles 2–3: 48 mg SQ days 1, 8, 15, 22 Cycles 4–9: 48 mg SQ days 1, 15 Cycles 10+: 48 mg SQ day 1	Cycle length: 21 days Cycle 1: IV dose step-up Day 1: obinutuzumab 1000 mg Day 8: 2.5 mg over 4 hours Day 15: 10 mg over 4 hours Cycle 2: 30 mg over 4 hours Cycles 3–12: 30 mg over 2 hours
Treatment duration	Until disease progression or toxicity	Until disease progression, toxicity, or up to 12 cycles
Required pre-medications	Antipyretic and antihistamine are recommended during cycle 1. Dexamethasone 15 mg oral/IV or prednisone 100 mg is recommended during cycle 1 and for 3 days following dose for subsequent cycles if prior grade 2/3 CRS until CRS grade <2	Antipyretic and antihistamine are recommended for all cycles. Dexamethasone 20 mg IV is recommended for cycles 1–3 and subsequently if prior CRS.
Renal dose adjustment	No	No
Hepatic dose adjustment	No	No
Infection prophylaxis	PJP and consider herpes zoster	Consider PJP, herpes zoster, and CMV

Key: BsAb, bispecific antibody; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; SQ, subcutaneous; IV, intravenous.

2.1. Treatment protocols

Both products are constructed as full-length IgG1 BsAbs specific for CD20 and CD3; however, glofitamab has a 2:1 tumor to T-cell binding configuration that confers bivalency for CD20 and monovalency for CD3 and is given intravenously [4]. Whether this is meaningful clinically remains unknown, especially considering response rates and safety outcomes between the two products are similar. Preferred route of administration may be important to consider for patients with a history of difficult IV placement, those who are obese, or those who are cachectic as obtaining IV access can be a challenge in these populations. Frequency and duration of treatment should also be considered when choosing between products. Although SQ administration with epcoritamab represents a shorter length of treatment and infusion chair time, more frequent travel may be a barrier for patients who are traveling substantial distances for treatment. Some prescribers and patients may prefer a treatment option with finite duration in glofitamab, which is completed after 12 cycles as opposed to indefinite treatment with epcoritamab, although this may not be relevant as the median number of cycles received in both trials was five. Although both trials included patients with heavily pretreated R/R DLBCL who were unresponsive to their previous line of therapy, the EPCORE NHL-1 trial had a higher proportion of patients with Ann Arbor stage IV disease and a history of prior CAR T-cell therapy compared to the NP30179 trial. This disparity might contribute to the variations observed in the depth and duration of response between the two treatments.

2.2. Safety

Although most patients (50–63%) developed CRS in the two trials, the vast majority of the events were grade 1 or 2 in severity and were managed with supportive care, corticosteroids, and tocilizumab. Differences in product route of administration (SQ vs IV), step-up dosing, and pre-/post-prophylactic medications may partially explain the difference in CRS risk between products. Hospitalization is recommended during and after the initial glofitamab dose, which may be a financial barrier for some institutions; however, the minimal incidence of severe CRS/ICANS could potentially allow for outpatient management of both products allowing for better reimbursement. To mitigate CRS with glofitamab, B-cell depletion with obinutuzumab is also required the week prior to the initial dose and should not be omitted as this was required as a part of glofitamab development. Patients who received glofitamab exhibited a higher frequency of grades 3–4 neutropenia and thrombocytopenia in contrast to those receiving epcoritamab. This raises the concern for an increased need for supportive measures such as anti-infective prophylaxis, transfusions, and growth factors. It is worth noting, however, that the incidence of infections, both of all grade and grade 3+, were similar between the two products. Infection prophylaxis is of utmost importance for patients receiving either product as approximately 40% of patients contracted an infection while on the trials. Prescribers should consider Pneumocystis jiroveci pneumonia (PJP) and herpes zoster prophylaxis as well as antimicrobial and antifungal prophylaxis during periods of prolonged neutropenia. IV immune globulin should also be considered if patients experience hypogammaglobulinemia. COVID-19 infections were seen in nearly 10% of each study population and in 30% in one real-world study; therefore, prescribers should encourage patients to stay up to date with SARS-COV-2 vaccinations and consider treatment if patients become infected [12–15]. Grade 5 adverse events occurred in approximately 5% of each study population. In the epcoritamab population, grade 5 events including COVID-19 occurred in two patients with one case each of myocardial infarction, hepatotoxicity, progressive multifocal leukoencephalopathy, loss of consciousness, general health deterioration, pulmonary embolism, and ICANS. In the glofitamab population, grade 5 events including COVID-19, sepsis, and delirium occurred in five, two, and one patients, respectively.

2.3. Real-world application

As previously observed with CAR T-cell therapy, real-world analyses utilizing data from consortia and registries will provide further insights into the safety and effectiveness of BsAb therapy for patients with R/R DLBCL. These analyses are likely to shed light upon on the potential role of BsAb therapy in patients that were excluded from clinical trials based on comorbidities, aggressive disease biology, and performance status. Atesoglu and colleagues recently published data of 43 patients who received glofitamab in a real-world setting [16]. They found lower ORRs, PFS, and OS which were attributed to a more heavily pre-treated patient population with poorer performance status at baseline. However, without a randomized controlled trial directly comparing the two products, it is impossible to establish the superiority of one BsAb product over another.

3. Where we stand

The introduction of two commercially approved BsAb therapy products is a breakthrough in the treatment landscape of R/R DLBCL. Both products offer notable effectiveness coupled with tolerable safety profiles. In the absence of a head-to-head comparison, selection of BsAb should be tailored to each patient after a thorough review of the safety and efficacy and perhaps more importantly, patient preference for time limited or indefinite therapy.

Declaration of interest

V Nachar has received advisory fees from Genmab and Genentech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A peer reviewer on this manuscript has received consultancy fees or honoraria from AbbVie, Roche, Novartis, Kyte/Gilead, Incyte, and Amgen. One peer reviewer is a consultant for both AbbVie and Roche. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.