https://orcid.org/0000-0001-7772-2747
In this issue of Blood, Falchi et al1 reported the results of arm 2 of EPCORE NHL-2 evaluating fixed-duration epcoritamab with rituximab and lenalidomide (R2) in relapsed/refractory (R/R) follicular lymphoma (FL) in an open-label, multicenter, phase 1b/2 study. The authors showed that the addition of epcoritamab to R2 was safe with promising signals of efficacy.
Epcoritamab is a subcutaneous CD3×CD20 bispecific antibody approved as monotherapy for R/R FL and R/R diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of therapy and administered until progression or unacceptable toxicity.2,3 Epcoritamab monotherapy showed an excellent overall response rate (ORR) of 82% in 128 R/R FL with a complete response (CR) rate of 62.5%. Efficacy of epcoritamab monotherapy was maintained across different subgroups including those with high-risk features. Responses appeared durable with 73.8% of CRs being progression-free at 18 months form treatment initiation and the safety profile was good.2
Preclinical data had shown potential synergy between epcoritamab and immunomodulatory agents due to enhanced T-cell cytotoxicity and activation as well as synergy with rituximab, that binds CD20 on a different epitope and exerts its function mainly through antibody dependent cytotoxicity rather than through T-cell activation.4 Based on this encouraging preclinical data, this study was conducted to assess safety and preliminary efficacy of epcoritamab plus R2. The study enrolled 108 patients with R/R FL from May 2021 to September 2024. The primary end point was ORR. Two key differences from the EPCORE NHL-1 study with epcoritamab monotherapy were 1) the use of a fixed-duration treatment of epcoritamab for up to 2 years with R2 for 12 cycles; and 2) enrollment of R/R patients predominantly at first relapse (57%) vs a more heavily pretreated population (≥2 previous line and 63% patients beyond third line).2 Notably, the study population included a substantial number of patients with high-risk features: FLIPI (Follicular Lymphoma International Prognostic Index) 3-5, 56.5%; progression of disease within 24 months, 50%; and primary or double refractory, 36% each. The efficacy appeared impressive: ORR 96% and CR 88% that were maintained even in patients with high-risk features. Minimal residual disease negativity rate was 86%. Survival outcomes at 2 years look favorable as well: remaining in CR for the duration of the study, 82%; progression-free survival (PFS), 76%; and overall survival (OS), 90%. These latter results should be taken cautiously because the median follow-up is still short for FL (28.2 months) where later relapses are common, thus limiting the interpretation of long-term outcomes of this study for now. Adverse events included neutropenia (63%, mainly grade 3-4), COVID-19 (59%), and cytokine release syndrome (CRS 51%, predominantly low-grade, predictable in kinetics since occurring at first full dose and none leading to treatment discontinuation). In the subgroup of patients aged >65 years, toxicity was not consistently increased, and CR rates were comparable to overall population.
Treatment of R/R FL has continuously evolved over the last decade, moving from second-line chemoimmunotherapy, including consolidation with autologous transplantation that ultimately was shown not to improve the outcome, to chemo-free approaches.5,6 R2 is currently considered one of the treatments of choice for second line FL, based on the results of the AUGMENT trial that showed CR in one-third of patients and a median PFS exceeding 3 years.7
Aiming at further improving efficacy, R2 has become the backbone platform for novel combinations. The addition of bispecific antibodies may represent a new weapon to further boost R2 activity, as shown in the EPCORE NHL2 trial. With the limitations of cross trial comparisons, other studies are evaluating similar strategies of combining bispecifics with lenalidomide and/or anti-CD20 monoclonal antibodies, showing favorable results in RR FL (mosunetuzumab + lenalidomide, glofitamab + obinutuzumab).8,9 Moreover, R2 was combined to the naked anti-CD19 monoclonal antibody tafasitamab in the phase 3 INMIND trial and compared to R2, showing a significant PFS and a CR benefit, with high tolerability and manageability (see table).10
Although the strategy of combining epcoritamab with R2 likely enhances treatment efficacy, it also raises concerns, particularly regarding infectious toxicity. Indeed, in the present trial a high incidence of COVID-19 (59%, including 24% grade ≥3, although it should be noted that the trial was conducted during the omicron wave that might have influenced the high frequency) and pneumonia (21%, 12% grade ≥3) was observed, along with hypogammaglobulinemia requiring immunoglobulin replacement in 34% of patients. Notably ∼1 out of 4 patients (24%) discontinued treatment prematurely due to adverse events. Given the typically indolent course and long survival associated with FL, minimizing toxicity and preserving quality of life are essential treatment goals. From this perspective, the high efficacy observed with the triplet supports the rationale for exploring shorter treatment durations, aiming at limiting immunosuppression and allowing a faster T-cell recovery. Indeed, in the present trial among the 34 patients in CR who discontinued treatment due to toxicity, the majority (85%) remained in CR, suggesting that prolonged therapy might not be necessary for durable remissions. This strategy is currently being explored in the randomized M20 638 trial comparing R2 vs R2 + epcoritamab administered for a fixed duration of only 12 cycles in RR FL.
Another open question is whether epcoritamab monotherapy employed in earlier lines could be as effective and potentially safer than epcoritamab given as part of combination therapies. Available data are insufficient to draw conclusions because the EPCORE NHL1 was conducted in a more heavily-treated population. Nevertheless, acknowledging the limitations of trial comparisons, the CR rate of epcoritamab + R2 when administered in ≥2 lines appeared higher (83%) compared to epcoritamab monotherapy in a similar setting (72%).1,2
In conclusion, the combination of epcoritamab and R2 has demonstrated encouraging efficacy and an acceptable safety profile in R/R FL. However, careful monitoring and proactive management of infectious complications (including growth factor support in case of neutropenia, immunoglobulin replacement, antimicrobial prophylaxis, and adherence to vaccination guidelines) are essential to mitigate treatment-related morbidity. Longer follow-up and the results of ongoing randomized trials (M20638 and M22-033) will be crucial to confirm the benefit-risk profile of this combination and may pave the way for its incorporation into the treatment algorithm of FL in the second-line and potentially in the frontline setting.
Conflict-of-interest disclosure: U.V. served on advisory boards for AbbVie, Genmab, Gilead, Incyte, Merck Sharp and Dohme (MSD), and Regeneron and received honoraria for talks from AbbVie, AstraZeneca, Genmab, Gilead, Incyte, MSD, and Sobi. F.B. served on advisory boards of AbbVie and AstraZeneca and received honoraria from AbbVie, Sobi, and Johnson & Johnson.
