Epcoritamab with R-CHOP Overcomes Poor Risk Features of High Total Metabolic Tumor Volume in High-Risk Large B-Cell Lymphoma

Introduction: Total metabolic tumor volume (MTV) is a robust prognostic factor across different lymphoma subtypes. In patients with large B-cell lymphoma (LBCL) treated with R-CHOP (rituximab with cyclophosphamide, adriamycin, vincristine, and prednisone), an MTV > 220ml with a threshold of 41% has been associated with shorter progression-free survival (PFS) and overall survival (OS) (Vercellino L, et al. Blood 2020). Furthermore, emerging data associates high MTV with a higher incidence of CRS (cytokine release syndrome) and ICANS (immune effector cell-associated neurotoxicity syndrome) with CD20xCD3 bispecific antibodies. In this study, we assessed the value of baseline MTV to predict survival and safety in patients with high-risk LBCL treated with epcoritamab with R-CHOP. Methods: We reviewed screening PET/CT images of patients enrolled in the EPCORE NHL-2 arm 1 trial (NCT04663347). MTV was obtained by adding the metabolic volumes of all individual lesions. A 41% SUVmax threshold was used to compare this regimen with previously reported results with R-CHOP; for the rest of the analysis, we used data obtained from SUV ≥4 threshold. SUVmax and MTV were calculated on screening PET/CT images by two nuclear medicine (R.K. and M.P.) radiologists using Hermes Affinity Viewer software. We tested if these quantitative metrics presented as dichotomous variables could predict treatment response, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Out of 47 subjects who received 48mg, forty screening images (85%) were available for centralized review. The median age was 66.5 years, with 20 (50%) being male. Most patients presented de novo LBCL (n=32; 80%), germinal center B-cell phenotype (n=23; 57.5%), bulky disease ≥7cm (n=22; 55%), advanced-stage disease (n=40; 100%), and IPI score ≥3 (n=40; 100%) at screening. Considering a cutpoint of 220ml to risk-stratify patients based on MTV, the response in those with high MTV (n=19) to epcoritamab with R-CHOP was an overall response rate (ORR) of 100% (n=19) with a complete response (CR) rate of 84.2% (n=16). Patients with low MTV (n=21) presented an ORR of 95.2% (n=20) with a CR rate of 81% (n=17). With a median follow-up of 26 (range, 0.8 to 33.1) months, the median DOR, PFS, and OS were not reached in both high MTV and low MTV groups. Furthermore, there was no statistically significant difference testing the 220ml cutpoint comparing low vs high MTV (DOR: HR=1.4, P=0.62; PFS: HR=1.39, P=0.62; OS: HR=0.62, P=0.59), underscoring the potential survival benefit of adding epcoritamab to the R-CHOP backbone. In the safety analysis, we observed a slightly higher incidence of all-grade CRS in patients with low (66.7%) vs. high (52.6%) MTV, which were primarily grade 1 (47.6% vs 47.4%). Three (14.3%) cases of grade 2 CRS occurred in the low MTV group compared to no case in the high MTV. One case of grade 3 CRS happened in each group. The incidence of ICANS in this study was low (n=2), which does not allow a meaningful analysis. Then, using an SUV ≥4 threshold, we identified a median of 677ml. We observed common responses between groups with an ORR and CR rate in the high MTV (n= 20) 100% (95%CI: 83.2-100%) and 85% (95%CI: 62.1-96.8%), and 95% (95%CI: 75.1-99.9%) and 80% (56.3-94.3%) in the low MTV (n= 20) groups. With an MTV cutpoint of 677ml, we observed numerical differences in DOR (HR=0.32, 95%CI 0.07-1.54) and PFS (HR=0.31, 95%CI 0.06-1.52) between patients with low and high MTV. However, we did not observe numerical differences in OS (HR=0.72, 95%CI 0.12-4.3) between low and high MTV, and a longer follow-up would be needed to observe these differences. Conclusions: At present follow-up, epcoritamab with R-CHOP overcomes poor survival previously reported in patients with high-MTV treated with R-CHOP. Using an MTV cutpoint of 220ml, we did not observe significant differences in CRS between groups, although the incidence of grade ≥2 was very low with this novel combination.Further MTV exploratory analysis will be presented at the meeting.