Epcoritamab: the next frontier in the treatment of relapsed/refractory follicular lymphoma

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL) in adults, accounting for approximately 20% of all NHL (1,2). FL is a heterogeneous disease considered incurable in the advanced stage despite multiple advances in treatment. The incorporation of anti-CD20 monoclonal antibodies (mAbs) into backbone chemotherapy regimens has significantly improved the prognosis of FL patients (2,3). Most patients exhibit a high response rate to the first-line therapy; however, approximately 20% of patients will experience progressive disease (PD) within the first 24 months (POD24) of first-line treatment (4). These patients constitute a group that will not respond well to further chemo-immunotherapy based strategies. Overall, 20–30% of FL patients will succumb either from relapsed/refractory (R/R) FL or from transformed disease to a high-grade lymphoma (5), with R/R FL patients representing a challenging group to treat with no optimal or clearly defined therapy pathway. There remains, therefore, a continued unmet need to induce remission in such patients or those who run out of treatment options down the line of the therapeutic pathway. In addition, there is an urge to find therapies that combine efficacy and safety.

This unmet need has been met with the progress in recombinant deoxyribonucleic acid (DNA) technology and antibody engineering, resulting in the development of novel therapies which harness the potential of the immune system, including bispecific antibodies (BsAbs) and chimeric antigen receptor T-cells (CAR-T). The rationale of exploiting the properties of the immune system derives from the fact that FL growth is highly dependent on interactions with immune subsets within a complex tumor microenvironment (6). BsAbs have emerged as a very promising treatment modality in NHL and have now been shown to induce deep remissions in both diffuse large B-cell lymphoma (DLBCL) and FL, as well as other haematological malignancies such as B-acute lymphoblastic leukemia and multiple myeloma (7). BsAbs act as a bridge between a target antigen on malignant cells and a surface marker on host immune cells, usually T-cells. This engagement leads to direct T-cell activation in a major histocompatibility complex independent way, with subsequent immune-mediated cell cytotoxicity and tumour cell lysis. Bystander activation of the immune system is also triggered, both within the tumour microenvironment and systemically against the malignant cells, mainly through cytokine secretion and neoantigen formation (8,9). The overt activation of the immune system and release of cytokines may lead to adverse reactions such as the cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). To mitigate these adverse effects and to limit tumor lysis syndrome (TLS), most BsAbs are administered in an escalated step-up dosing manner during the first cycle (10-13).

Epcoritamab is a subcutaneously administered, anti-CD20 full-length humanized immunoglobulin G1 (IgG1) BsAbs with a silenced Fc domain to reduce nonselective T-cell activation. Preclinical data, both in tumor cell lines and cells derived from FL and other lymphoma patients, showed robust T-cell—mediated cytotoxicity. Due to delayed and lower peak cytokine levels compared to intravenous (IV) administration, a subcutaneous (SBC) formulation was developed (14,15). Following these encouraging findings, the efficacy and safety of epcoritamab monotherapy in the EPCORE NHL-1, the first-in-human multicohort, single-arm, phase 1–2 trial, was conducted at 88 sites across 15 countries (10).

The study investigated epcoritamab in histologically confirmed FL grade 1–3A patients with at least two previous lines of therapy (including an anti-CD20 mAb and an alkylating agent or lenalidomide) in 2 cohorts, the pivotal (dose expansion) and cycle 1 optimisation. The study excluded patients with central nervous system lymphoma involvement but did permit previous exposure to CAR T-cell therapies. Epcoritamab was administered SBC in 28-day cycles, once weekly during cycles 1–3, once every 2 weeks during cycles 4–9 and once every 4 weeks onwards until unacceptable toxicity or PD. Cycle 1 doses were administered in a step-up schedule. The pivotal cohort consisted of a 0.16 mg priming dose (day 1), a 0.80 mg intermediate dose (day 8) and subsequent 48 mg full doses with prednisolone 100 mg (or equivalent) given for 4 days with each cycle 1 dose for CRS prophylaxis. Patients were hospitalized for 24 hours after the first full dose for CRS monitoring. The cycle 1 optimisation cohort included a second intermediate dose of 3 mg (day 15) plus IV hydration and dexamethasone 15 mg for 4 days with each cycle 1 dose as CRS prophylactic measures. Hospitalization was not required for this cohort. The primary endpoint for the pivotal cohort was overall survival (OS) rate and for the cycle 1 optimisation cohort was the CRS rate of grade 2 and above. Measurable residual disease (MRD) (positive ≥10⁻⁶) was also evaluated on longitudinal peripheral blood mononuclear cell samples at prespecified timepoints using a next-generation sequencing assay and was correlated with response outcomes.

In total, 128 R/R FL patients were enrolled in the pivotal cohort and 86 in the cycle 1 optimisation cohort. In the pivotal cohort, the median age was 65 years. High-risk patients were included, with 60% having stage IV disease, 54% primary refractory disease, 42% POD24 from first-line chemoimmunotherapy, 31% had received 4 or more lines of therapy, while 5% had been previously treated with CAR T-cell therapies. The overall response rate (ORR) was 82% with 62.5% of patients achieving a complete response (CR). Median time to response was 1.4 months. Prespecified subgroup analyses showed no difference in response outcomes, including high-risk characteristics (age, sex, POD24, Follicular Lymphoma International Prognostic Index score). However, slightly lower response rates were seen in patients with 4 or more previous lines of treatment or those who were refractory to their last systemic therapy. At a median follow-up of 17.4 months, 37% remained on treatment with the most common cause of discontinuation being PD. Ninety-two (92%) of responders treated for 10 cycles or above maintained response at data cutoff. At 18 months, 49.4% were progression-free (73.8% of patients with CR) and 70.2% were alive. A sensitivity analysis adjusting for coronavirus disease 2019 (COVID-19) showed an improvement in progression-free survival (PFS) and OS. MRD was negative in 61/91 patients in whom MRD was evaluable and these patients had a better PFS compared to MRD-positive patients, irrespective of the presence of high-risk features. In the cycle 1 optimisation cohort, patient demographics, baseline characteristics, response rates and MRD negativity were similar to the pivotal cohort.

In terms of safety and toxicity profile, in the pivotal cohort, 66% of patients developed CRS with almost all events being grade 1–2 and only 2 patients had a grade 3 event. The majority of patients had CRS after the first full dose, with 24% needing tocilizumab and 13% extra steroids. All events resolved and none resulted in treatment discontinuation. In contrast, in the cycle 1 optimisation cohort, only 49% developed CRS with no grade 3 and above events, all of which resolved after tocilizumab and/or steroids (12% and 13%, respectively). Immune effector cell-associated neurotoxicity syndrome (ICANS) was extremely rare (6%) and of low-grade in the pivotal cohort, while no ICANS occurred in cycle 1 optimisation cohort, potentially due to prophylactic dexamethasone which has better CNS penetration than prednisolone. Cytokine levels in the cycle 1 optimisation cohort remained low. Other common adverse events (AEs) included injection-site reactions (57% in pivotal vs. 33% in cycle 1 optimisation cohort), COVID-19 infection (40% in pivotal vs. 21% in cycle 1 optimisation cohort), fatigue (30% in pivotal vs. 20% in cycle 1 optimisation cohort) and neutropenia grade 3–4 (26% in pivotal vs. 19% in cycle 1 optimisation cohort). Febrile neutropenia was extremely rare in the pivotal cohort (3%), all of which required treatment with granulocyte colony-stimulating factors. Treatment discontinuation due to AEs occurred in 19% of patients in the pivotal cohort, with 13% being due an infectious cause, including some fatal cases mainly due to COVID-19, given that the trial enrolment occurred during the peak of COVID-19 omicron prevalence. No TLS was observed.

Overall, epcoritamab monotherapy elicited deep MRD-negative and durable responses exhibiting potent antitumour activity in heavily pretreated, highly refractory FL patients with high-risk features, while in parallel demonstrated an acceptable toxicity profile, especially with the cycle 1 optimisation strategy. For patients receiving therapy at third-line, impressive CR rates were achieved compared to a historical rate of 40% with standard options (16). It should be acknowledged that, similarly with all phase 2 trials, the single-arm design of the EPCORE NHL-1 trial and the patient selection bias constitute a limitation in the generalizability of the results and the outcome of a phase 3 trial should be awaited. Based on the results of the EPCORE NHL-1 trial, epcoritamab has been licensed by the Food and Drug Administration (FDA) for the treatment of R/R FL, following licensing for another BsAbs mosunetuzumab, while glofitamab has not been approved yet. All of these BsAbs target the CD20 antigen on lymphoma cells, while there are experimental products under investigation that are directed against the CD19 antigen. The 2 FDA-approved products have been approved with the indication to treat multiply relapsed patients who have received at least 2 prior lines of systemic therapies. Currently, a fourth anti-CD20 agent odronextamab is under review.

Mosunetuzumab is the first-in-class T-cell engaging BsAbs approved with the indication to treat R/R FL. It is a humanized IgG1 molecule with a modified Fc domain to prevent FcγR and complement binding. It has been approved as a fixed-duration treatment for IV administration, while approval for SBC formulation is pending. Mosunetuzumab was investigated in the phase 2 GO29781 trial, showing an ORR and CR rate of 80% and 60%, respectively, with a median PFS of 21.1 months and median OS not reached (NR). In terms of CRS, 44% developed any grade of CRS with 2% grade 3 and above (11). Glofitamab is another humanized mouse-derived IgG1 molecule with a modified Fc domain but in contrast to mosunetuzumab, it has 2 anti-CD20 binding sites which can potentially increase the risk of cytokine release upon T-cell activation. For this reason, Obinutuzumab has been previously investigated to be given on day 1 of the first cycle as a B-cell depletion strategy. Glofitamab was administered IV as a fixed-duration treatment for 12 cycles (12). Odronextamab is a fully human IgG4 molecule with decreased immunogenicity and a longer half-life than other BsAbs. Both IV and SBC formulations have been developed, and similar to epcoritamab, it is administered continuously (13). Table 1 summarizes the characteristics of these 3 CD20 × CD3 BsAbs in terms of structural features, efficacy and safety outcomes as demonstrated in the relevant phase 2 trials. Overall, the efficacy and safety of epcoritamab monotherapy appear comparable to other CD20 × CD3 BsAbs in R/R FL, although caution must be made when making cross-trial comparisons due to inevitable heterogeneity in trial design, patient populations under investigation and different CRS prophylactic strategies.

Apart from the well-recognised cytokine-related AEs, tumor flare has been observed in 3–7% of patients treated with CD20-directed BsAbs in NHL due to T-cell penetration into the tumor sites, similar to the one observed after exposure to immunomodulators (17). Tumor flare can be presented as pseudoprogression clinically and radiologically, while steroids can be administered for local control of pain or pressure effects. It should be noted that the inflammatory milieu is not responsible only for CRS and ICANS, but it is believed that it causes a general suppression of hematopoietic cell maturation in the bone marrow microenvironment, contributing to cytopenias. In addition to supportive measures and growth factor administration, extending the dosing interval should be considered in severe cases. Infections can also constitute a major hurdle in BsAbs treatment impairing patients’ quality of life. The risk of infections can be multifactorial especially in the R/R setting, such as T-cell exhaustion, neutropenia, lymphopenia, B-cell aplasia and subsequent hypogammaglobulinemia. All patients should receive prophylactic antimicrobial and antiviral drugs, vaccinations and immunoglobulin replacement when indicated according to local institutional policies (18).

Despite the safety signals, CD20 × CD3 BsAbs have offered a paradigm shift in the treatment of R/R FL achieving impressive, rapid and durable responses with a manageable and acceptable safety profile in heavily pretreated and highly refractory patients. All approved CD20 × CD3 BsAbs are now being investigated in combination with other fixed-duration treatment schedules in phase 2 and 3 studies in R/R FL, such as standard of care chemotherapy, mAbs, immunomodulatory agents or targeted therapies, to maximize the efficacy (NCT04712097, NCT06149286). For example, epcoritamab is being evaluated in combination with rituximab and lenalidomide in the phase 3 EPCORE FL-1 trial (NCT05409066) and in combination with lenalidomide in the phase 2 REFRACT trial (NCT05848765). In addition, multiple trials are currently underway investigating CD20 × CD3 BsAbs as monotherapy or in combination with other regimes in earlier lines of treatment including the first-line setting (NCT06284122, NCT05994235, NCT05169658, NCT05783596, NCT06112847, NCT06097364). The field is rapidly expanding with early-phase clinical trials investigating other novel CD20 or CD19-directed T-cell engagers (19) or BsAbs beyond T-cell engagement, harnessing other immune cells within the microenvironment, e.g., macrophages (NCT05427812).

Choosing among approved CD20 × CD3 BsAbs overall remains a challenge. Given similar efficacy and toxicity profiles, preference could be put down to the method of administration and duration of treatment. SBC formulations, such as epcoritamab, seem more convenient and easier to administer in the outpatient setting, consuming fewer health-care resources compared to IV products. On the contrary, a fixed-term treatment duration may be preferable from a patient perspective, while reducing care and drug-associated costs. In addition, fixed-term therapies may prevent T-cell exhaustion from continues antigen stimulation, although this area has not been elucidated yet. However, given the incurable nature of FL, a more prolonged therapy may be required for effective tumour control. MRD-driven decision making on de-escalating or stopping treatment is an open field for clinical research in BsAbs, especially for those products given continuously, such as epcoritamab.

Another challenge constitutes the selection between BsAbs and CAR T-cell therapies and the optimal sequence of these therapies (Figure 1). Currently, there are 3 CAR T-cell products approved in the USA for R/R FL after 2 or more lines based on the results of phase 2 pivotal trials (axicabtagene ciloleucel ZUMA-5, tisagenlecleucel ELARA, lisocabtagene maraleucel TRANSCEND) (20-22). These trials have demonstrated startling CR rates up to 94% but with a safety profile less favourable than BsAbs with slightly higher CRS and ICANS rates, although there are to date no head-to-head comparison trials. It seems that toxicity rates are higher with axicabtagene ciloleucel than tisagenlecleucel and lisocabtagene maraleucel, although comparisons across products cannot be safely made in the lack of head-to-head comparison trials. Further, CAR T-cell trials have generally assessed a fitter group of patients than BsAbs trials rendering comparison even more challenging (20-22). BsAbs are therefore likely preferred in older and frailer patients with co-morbidities due to the lower risk of high-grade toxicities. In addition, BsAbs are readily offered to be utilised compared to CAR T-cells, which require a laborious and lengthy manufacturing and can be administered in non-specialised centres. Moreover, BsAbs may be more cost-effective therapies as the products are cheaper per se and treatment requires fewer days of hospitalisation. Therefore, it is likely that BsAbs may be adopted in earlier lines of treatment than CAR T-cells due to the ease of logistics. In terms of the optimal sequence of these therapies, this question is still under investigation and open to debate especially for products targeting the same antigen, taking into account immunological phenomena such as antigen escape and T-cell exhaustion. Enrolment in BsAbs trials permitted prior exposure to CAR T-cells exhibiting good efficacy. Further studies may shed more light on this field (NCT04889716).

Figure 1 Factors influencing the decision of choosing between BsAbs or CAR T-cell treatments. Choosing between these two classes of treatment requires an individualized approach taking into account product characteristics, such as effectiveness and toxicities. Multiple factors contribute to decision making, such as patient characteristics, disease features, including kinetics of progression, drug access in specialised centres and insurance coverage. BsAbs, bispecific antibodies; CAR, chimeric antigen receptor.

In conclusion, epcoritamab has been added to the treatment armamentarium of R/R FL, making this an exciting time for the field with plenty of chemotherapy-free treatment options gradually becoming available. However, managing relapsed or refractory patients after BsAbs exposure still remains a challenge, as very often there are limited therapeutic alternatives apart from experimental agents offered within the scope of clinical trials.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-264/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-264/coif). P.E.M.P. has received grants from Roche and Gilead; honoraria from Abbvie, Astra Zeneca, Beigene, Gilead, and Janssen; support for attending meetings from Abbvie, Janssen, and Beigene; and has participated on the Data Safety Monitoring Board or Advisory Board for Abbvie, Beigene, and Lilly. The other author has no conflicts of interest to declare.

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