Matching-Adjusted Indirect Treatment Comparison of Epcoritamab Versus Zanubrutinib Plus Obinutuzumab in Relapsed or Refractory Follicular Lymphoma

Introduction: Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL) and most common indolent NHL. Most patients requiring treatment achieve remission with first-line (1L) chemoimmunotherapy; however, many have relapsed or refractory (R/R) disease, supporting the need for development of new agents and regimens. Epcoritamab, a subcutaneously administered CD3xCD20 T-cell-engaging bispecific antibody, was recently approved in the US for the treatment of R/R FL after ≥2 lines of systemic therapy based on efficacy and safety demonstrated in the single-arm EPCORE NHL-1 trial (NCT03625037). The combination of the Bruton's tyrosine kinase inhibitor zanubrutinib with the second-generation anti-CD20 monoclonal antibody obinutuzumab (Z/O) has recently been approved in this patient population based on findings from the ROSEWOOD trial (NCT03332017). However, no head-to-head study has been performed comparing epcoritamab to Z/O, and evidence on the comparative efficacy of these regimens are needed to support treatment decision-making. Using a matching-adjusted indirect comparison (MAIC) approach, this study compared the efficacy outcomes of patients treated with epcoritamab in EPCORE NHL-1 to those treated with Z/O in ROSEWOOD.

Methods: Individual patient-level data from patients with FL treated with epcoritamab in EPCORE NHL-1 (April 2023 data cutoff) and aggregate data from patients with FL treated with Z/O in ROSEWOOD were used to conduct a MAIC. Propensity scores were used to weight the epcoritamab-treated patients to match the aggregate baseline characteristics of the Z/O patients. Characteristics included in the model represented relevant prognostic factors including age, Eastern Cooperative Oncology Group performance status, Follicular Lymphoma International Prognostic Index (FLIPI) score, and progression of disease within 24 months of 1L treatment (POD24), among others. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for epcoritamab vs Z/O. Because of the timing of trial enrollment and primary completion date with respect to the COVID-19 pandemic, base case survival analyses were adjusted for the impact of the pandemic on EPCORE NHL-1, with additional sensitivity analyses exploring adjustments for the impact on both trials.

Results: A total of 128 patients with FL treated with epcoritamab in EPCORE NHL-1 were compared to 145 patients with FL treated with Z/O in ROSEWOOD. Before match-adjustment, more epcoritamab patients were aged 65 or older, were refractory to last prior line of therapy, had POD24, and had a FLIPI score ≥3. Distributions of these baseline characteristics and others were balanced after match-adjustment, and the effective sample size was 37. After match-adjustment, epcoritamab showed a significantly higher ORR vs Z/O (94.6% vs 69.0%, odds ratio [OR] 7.9 [95% CI 3.5-18.1], P<0.001). Similarly, the CR rate was significantly higher with epcoritamab vs Z/O (71.4% vs 39.3%, OR 3.9 [95% CI 1.8-8.2], P<0.001). In the base case analysis, epcoritamab provided a significantly reduced risk of mortality vs Z/O, with a hazard ratio (HR) of 0.35 (95% CI 0.16-0.78, P=0.01), corresponding to a 65% reduction in the risk of mortality with epcoritamab. No significant difference in PFS was found between epcoritamab and Z/O (HR 0.64 [95% CI 0.34-1.2], P=0.167). Sensitivity analyses showed a significantly reduced risk of mortality with epcoritamab vs Z/O, with HRs ranging from 0.37 (95% CI 0.16-0.82, P=0.02) to 0.41 (95% CI 0.18-0.91, P=0.03) across the explored scenarios, corresponding to a 59-63% reduced risk of mortality with epcoritamab.

Conclusions: Epcoritamab provided superior overall and complete response rates and a significantly reduced risk of mortality vs Z/O in patients with R/R FL after ≥2 lines of systemic therapy. While the findings are subject to limitations inherent to comparisons outside of controlled trials, the results underscore the therapeutic benefits of epcoritamab over Z/O in patients with R/R FL after ≥2 lines of systemic therapy.

Cumings:Genmab: Research Funding. Chirikov:Genmab: Research Funding. Ding:Genmab: Current Employment, Current equity holder in publicly-traded company. Marques Goncalves:Genmab: Current Employment, Current equity holder in publicly-traded company. Heaps:Genmab: Current Employment, Current equity holder in publicly-traded company. Bains Chawla:Genmab: Current Employment, Current equity holder in publicly-traded company. Wang:AbbVie: Current Employment, Current equity holder in publicly-traded company, Other: stockholder of AbbVie. Atiya:Genmab: Current Employment, Current equity holder in publicly-traded company, Other: stockholder of Genmab. Rivas Navarro:Genmab: Current Employment, Current equity holder in publicly-traded company. Favaro:Genmab: Current Employment, Current equity holder in publicly-traded company. Hoehn:Genmab: Current Employment, Current equity holder in publicly-traded company. Mutebi:Genmab: Current Employment, Current equity holder in publicly-traded company, Other: stockholder.