Mutebi, Alex

Background: Epcoritamab (epcor) is a first-in-class CD3xCD20 bispecific antibody (bsAb) approved for the treatment of 3L+ LBCL and follicular lymphoma. In the single-arm, phase 1/2, EPCORE NHL-1 trial (NCT03625037), epcor given until disease progression or unacceptable toxicity, demonstrated deep and durable responses, a median overall survival (OS) of 18.5 months, and a manageable safety profile in R/R LBCL. A second CD3xCD20 bsAb given as fixed-treatment duration, glofitamab (glofit), also demonstrated durable responses, conferring a median OS of 11.5 months in the pivotal study. Understanding how long-term outcomes compare among bsAb agents remains an important knowledge gap. With over 2 years of follow-up, in the absence of a head-to-head study, it is now relevant to compare the efficacy of these agents via indirect comparison. This study evaluated OS, progression-free survival (PFS), and duration of complete response (DoCR) of epcor vs glofit in R/R LBCL using data from the respective pivotal trials. Methods: Two analyses were conducted to compare the efficacy of epcor and glofit. First, a matching-adjusted indirect treatment comparison (MAIC) was conducted using published OS and PFS data from the full cohort of the glofit pivotal trial (12.6 months of follow-up, Dickinson et al, 2022) and the epcor pivotal trial (EPCORE NHL-1). Piece-wise hazard ratios (HRs) were calculated when proportional hazards assumptions were not met. Baseline characteristic prognostic variables were selected based on literature, clinical judgement, and empirical statistical testing and were adjusted between epcor and glofit cohorts. Second, in sensitivity analyses, indirect comparisons were conducted using an updated analysis of glofit with longer follow-up that included DoCR, together with OS and PFS data starting at cycle (C) 3 with 32 months of follow-up (Hutchings et al, ASH 2023). Sensitivity analyses with longer follow-up could not be adjusted because glofit pt baseline characteristics were not presented. Aggregate OS and PFS curves for glofit were derived from subgroups of pts with complete response/partial response/no response (CR/PR/NR) at C3 (Hutchings et al, ASH 2023). Aggregate epcor OS and PFS curves were similarly derived for pts with CR/PR/NR at C3 without prior disease progression. Weighted Cox proportional-hazards models were used to estimate the OS and PFS HRs between the 2 comparators. The DoCR comparison included all glofit and epcor pts achieving CR. All comparisons used EPCORE NHL-1 data with a median of 37.1 months of follow-up. Results: Pts enrolled into the pivotal trials of epcor and glofit were comparable by several key baseline characteristics before adjustment: age ≥65 y; male gender; Ann Arbor disease stage III-IV; primary refractory disease; refractory to most recent anti-CD20 therapy; previous chimeric antigen receptor T-cell therapy (CAR T); refractory to CAR T; and previous autologous stem cell transplant (ASCT). MAIC analysis revealed no significant difference in OS benefit from C1 until month 6 (HR 1.08, 95% CI 0.71, 1.64; P=0.72), but a demonstrable OS advantage from 6 months onward (HR 0.60, 95% CI 0.37, 0.98; P=0.04) in favor of epcor. An OS comparison starting at C3 with longer glofit follow-up demonstrated a consistent survival advantage in favor of epcor (HR 0.68, 95% CI 0.46, 1.01; P=0.05). The proportion of pts who received CAR T or ASCT subsequent therapy were similar for epcor and glofit (CAR T: 7.0% vs 8.9%; ASCT: 6.4% vs 6.3%) (National Institute for Health and Care Excellence Glofit Single Technology Appraisal, 2023). The MAIC analysis showed comparable PFS between epcor and glofit (HR 1.06, 95% CI 0.79, 1.41; P=0.71), although there was substantial censoring in the glofit PFS curve due to immature follow-up. With longer follow-up in the analysis starting at C3, with less censoring, the glofit PFS curve remained similar to the epcor PFS curve from C3 until month 6 (HR 0.67, 95% CI 0.42, 1.07; P=0.10), where separation of the PFS curves were observed favoring epcor (HR 0.56, 95% CI 0.33, 0.97; P=0.04). Median DoCR was longer for epcor (36.1 months) vs glofit (26.9 months). Conclusion: These indirect treatment comparisons suggest that epcor may provide an overall survival benefit over glofit through longer PFS with more mature follow-up, potentially driven by longer DoCR. Survival data with longer follow-up in the full glofit cohort are needed to confirm these findings.

Introduction: Epcoritamab (Epcor) is a novel subcutaneous CD3xCD20 bispecific antibody (bsAb) that is currently approved as monotherapy for the treatment of adults with relapsed or refractory (R/R) large B-cell lymphoma after ≥2 systemic therapies. The combination of Epcor with standard treatment regimens has been shown to be safe and efficacious; Epcor in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival outcomes in a transplant-ineligible R/R diffuse large B-cell lymphoma (DLBCL) patient (pt) population, of which 99% were from the US and Europe (EPCORE NHL-2; NCT04663347). Another CD3xCD20 bsAb, intravenous glofitamab, has been studied in combination with gemcitabine and oxaliplatin (Glofi+GemOx) in the randomized STARGLO trial (NCT04408638) and demonstrated benefit over rituximab plus GemOx (R-GemOx), despite not demonstrating superiority over R-GemOx in patients from the US and Europe. In the absence of head-to-head data, this study used matching-adjusted indirect comparisons (MAICs) to assess the comparative efficacy of Epcor+GemOx vs R-GemOx and vs Glofi+GemOx. Methods: Individual pt-level data from EPCORE NHL-2 arm 5 and aggregated data from pts in each of the STARGLO arms were used to conduct an MAIC. Logistic propensity score models were used to weight Epcor+GemOx-treated pts to create matched cohorts with the R-GemOx and Glofi+GemOx arms separately. Weighting was conducted based on the distribution of baseline characteristics and prognostic factors such as age, sex, Eastern Cooperative Oncology Group performance status, previous therapies, and primary refractory status. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx, and vs Glofi+GemOx. Results: A total of 103 pts treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 91 pts treated with R-GemOx and 183 pts treated with Glofi+GemOx (median follow-up: 20.7 months), although differences in median follow-up time limited comparisons of longer-term survival outcomes. Match-adjustment mitigated differences in baseline characteristics across the 3 cohorts. After adjustment, Epcor+GemOx demonstrated a significant 44.8% advantage in ORR over R-GemOx (85.4% vs 40.7%), with a 110% increase in the likelihood of achieving a response (odds ratio [OR] 2.1; 95% CI 1.6-2.8; P<0.0001). Epcor+GemOx also demonstrated a significant 43.2% advantage in CR rate over R-GemOx (68.5% vs 25.3%), with a 170% increase in the likelihood of achieving a CR (OR 2.7; 95% CI 1.8-4.1; P<0.0001). With the current follow-up, Epcor+GemOx demonstrated superior PFS vs R-GemOx (hazard ratio [HR] 0.37; 95% CI 0.22-0.63; P<0.001), corresponding to a 63% reduction in the risk of progression. Median OS was not reached [NR] for Epcor+GemOx vs 13.9 months for R-GemOx, corresponding to a 43% reduction in the risk of mortality (HR 0.57 [95% CI 0.33-0.98]; P=0.04). After adjustment, Epcor+GemOx demonstrated a significant 15% advantage in ORR over Glofi+GemOx (83.3% vs 68.3%), with a 20% increase in the likelihood of achieving a response (OR 1.2; 95% CI 1.0-1.4; P=0.021). Epcor+GemOx demonstrated a trend toward higher CR rate than Glofi+GemOx (66.8% vs 58.5%; OR 1.1; 95% CI 0.90-1.5; P=0.277). Adjusted median PFS and OS for Epcor+GemOx, with limited follow-up and substantial censoring, was 12.9 months and NR, respectively. For Glofi+GemOx with longer follow-up, PFS and OS were 13.8 months and 25.6 months, respectively. Conclusions: Results show significantly superior efficacy for all outcomes with Epcor+GemOx vs R-GemOx from STARGLO. Epcor+GemOx also provided superior ORR and a trend toward higher CR rates vs Glofi+GemOx, indicating potential for better long-term efficacy outcomes. The Epcor+GemOx survival data are still maturing given shorter follow-up time, preventing a robust comparison of survival vs Glofi+GemOx. Findings support the efficacy of Epcor+GemOx as an alternative therapeutic regimen in transplant-ineligible patients with R/R DLBCL.

Introduction: Epcoritamab, a novel subcutaneously administered CD3xCD20 bispecific antibody (bsAb) being developed as a core therapy across several lymphoma subtypes, is currently approved for the treatment of adults with different types of R/R LBCL after ≥2 systemic therapies. The combination of epcoritamab with standard treatments has been shown to be safe and efficacious; epcoritamab in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival benefits in a transplant-ineligible R/R DLBCL study population, of which 99% was from the United States and Europe (EPCORE NHL-2; NCT04663347). The rituximab plus gemcitabine and oxaliplatin (R-GemOx) regimen has been a widely used treatment for patients with R/R DLBCL ineligible for transplant, albeit with suboptimal efficacy outcomes. In the absence of direct comparisons of these regimens, this study assessed the comparative efficacy of Epcor+GemOx vs R-GemOx in patients with R/R DLBCL ineligible for transplant. Methods: Individual patient-level data (IPD) from EPCORE NHL-2 arm 5 were compared to 2 sources of clinical practice data for patients with R/R DLBCL treated with R-GemOx: published data from Cazalles et al (2021) and IPD from the US-based COTA electronic health record database. The Cazalles study reports the results of a large retrospective analysis of patients with R/R DLBCL treated in 2 academic centers in France. The COTA database includes de-identified IPD with demographic and clinical information from numerous academic and community clinical sites in the US. For the comparison to Cazalles, logistic propensity score models were used to weight the Epcor+GemOx cohort to create match-adjusted distributions of baseline characteristics with the R-GemOx cohort in Cazalles. For the comparison to COTA, inverse probability of treatment weighting was employed to balance covariates between the Epcor+GemOx and R-GemOx cohorts. Analyses were restricted to chimeric antigen receptor T-cell therapy (CAR T)-naive patients from EPCORE NHL-2, as the comparator cohorts did not include patients treated with CAR T. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx. Results: A total of 74 patients treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 196 R-GemOx-treated patients from Cazalles et al (median follow-up: 22 months). After match-adjustment, Epcor+GemOx (ORR 86.8%) demonstrated significantly higher ORR, corresponding to a 48.5% advantage over R-GemOx (ORR 38.3%) with an odds ratio (OR) of 2.3 (95% CI 1.8-2.9; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx vs R-GemOx (71.2% vs 32.7%; 38.6% difference; OR 2.2 [95% CI 1.6-3.0]; P<0.0001). Median PFS was significantly longer with Epcor+GemOx (26.7 months) vs R-GemOx (4.8 months; hazard ratio [HR] 0.38 [95% CI 0.22-0.67]; P<0.001). Median OS was not reached (NR) for Epcor+GemOx vs 10.0 months with R-GemOx (HR 0.54 [95% CI 0.29-1.0]; P=0.05), corresponding overall to a 62% reduction in the risk of a progression event and a 46% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx. A total of 72 patients were treated with R-GemOx in COTA (median follow-up: 7.5 months) and compared to 74 Epcor+GemOx patients. After adjustment, ORR was significantly higher with Epcor+GemOx vs R-GemOx (88.5% vs 35.6%; OR 2.5 [95% CI 1.8-3.4]; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx (63.9% vs 10.2%; OR 6.3 [95% CI 3.1-12.7]; P<0.0001). Adjusted median PFS was significantly longer with Epcor+GemOx (11.2 months) vs R-GemOx (2.4 months; HR 0.23 [95% CI 0.15-0.36]; P<0.0001). Adjusted median OS was also significantly longer with Epcor+GemOx (21.6 vs 8.3 months; HR 0.47 [95% CI 0.30-0.74]; P=0.002), corresponding overall to a 77% reduction in the risk of a progression event and a 53% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx. Conclusions: In this indirect treatment comparison analysis,Epcor+GemOx provided significantly superior efficacy benefits in terms of ORR, CR, PFS, and OS vs standard-of-care R-GemOx. While subject to the limitations of comparisons outside of controlled trials, findings indicate the compelling efficacy of Epcor+GemOx as a novel therapeutic option for transplant-ineligible patients with R/R DLBCL.

Aim: Patients with R/R LBCL after first-line treatment have poor prognosis. Multiple novel therapies have been approved for R/R LBCL in recent years, but CIT regimens are still commonly used. This study evaluated the effectiveness of CIT and novel therapies in 2L+ in patients with R/R LBCL and the association between patient clinical characteristics and real-world outcomes. Methods: This was a multi-site retrospective observational study of patients aged ≥18 years with R/R LBCL in the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) cohort (patients followed from 1/1/2015 to 2/15/2023) who were treated with CIT or novel therapy in 2L+. CIT regimens included salvage/palliative chemotherapy, lenalidomide, rituximab, or obinutuzumab, used alone or in combination. Novel therapies included polatuzumab vedotin plus bendamustine and rituximab or variations thereof (i.e., pola-based regimen), tafasitamab plus lenalidomide or variations thereof (tafa-based regimen), and loncastuximab tesirine (lonca). Patients' demographic and clinical characteristics were assessed from the first confirmed R/R disease diagnosis and initiation of 2L+ therapy. When multiple lines of therapy (LOTs) were eligible for inclusion in the analysis, one was randomly selected as the index LOT. Real-world outcomes, determined by investigators at each clinical site, including overall response rate (ORR), complete response (CR) rate, duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), and overall survival (OS) were described for all patients in each treatment group and for the subgroup of patients with prior chimeric antigen receptor (CAR) T-cell therapy. Multivariable Cox Proportional Hazards models were used to assess associations between select patient clinical characteristics and real-world outcomes. Results: The study population included patients treated with CIT (N=653), pola-based regimen (N=116), tafa-based regimen (N=55), and lonca (N=42) ( Figure 1A). The median (m) age at date of index treatment initiation across groups ranged from 63 to 74 years. Across groups, most patients had primary refractory disease-i.e., were refractory to the first LOT (69.5% CIT vs. 73.3% pola vs. 58.2% tafa vs. 71.4% lonca), whereas variable proportions had one prior LOT (65.5% vs. 17.2% vs. 43.6% vs. 7.1%) and prior CAR T-cell therapy (5.1% vs. 43.1% vs. 32.7% vs. 47.6%). In the CIT group, ORR was 33.8%, 15.5% of patients achieved CR, mPFS (95% CI) was 1.9 (1.7, 2.1) months, and mOS was 9.1 (8.1, 10.5) months. In the pola group, ORR was 42.2%, 24.1% of patients achieved CR, mPFS was 2.5 (2, 3.2) months and mOS was 7.8 (6.4, 11.8) months. In the tafa group, ORR was 25.5%, 14.5% of patients achieved CR, mPFS was 2.7 (2.1, 4.2) months, and mOS was 8 (5.3, 12.7) months. In the lonca group, ORR was 40.5%, 21.4% of patients achieved CR, mPFS was 3 (2.1, 5.1) months, and mOS was 4.7 (3.7, 10.8) months. Demographics and outcomes for all patients and those who received prior CAR T-cell therapy are summarized in Figure 1A. In the multivariable Cox regression analysis, International Prognostic Index (IPI) risk score ≥3, CIT as the index treatment type, and primary refractory status were significantly associated with time from response to progression/death (P<0.05; Figure 1B). IPI risk score ≥3, CIT as the index treatment type, and primary refractory status were significantly associated with worse PFS. IPI risk ≥3, ≥3 prior LOTs, and primary refractory status were significantly associated with OS. Conclusion: In this large clinical cohort of patients with R/R LBCL with high proportions having primary refractory disease, all common treatments were associated with modest ORR/CR and poor OS. Receiving CIT treatments, higher IPI score, primary refractory status, and higher number of prior LOTs were significantly associated with poor clinical outcomes. A study with larger sample size and longer follow-up may be warranted to further understand the clinical effectiveness of novel treatments. Thus, despite the availability of novel treatments during the study period, these findings highlight the need for more effective treatment alternatives beyond currently available options to improve outcomes.

e19530 Background: In large B-cell lymphoma (LBCL) trials, racial and ethnic representation is difficult to determine due to underreporting in some regions, or because some patients may not provide data. It is difficult to understand the full extent of any underrepresentation of specific races or ethnicities in these trials relative to the prevalence of LBCL in clinical practice. The objective of this study was to characterize racial and ethnic representation in LBCL real-world databases and recently published LBCL studies. Methods: Analyses of the distribution of different racial and ethnic categories were conducted across 6 real-world clinical practice databases from the United States (US): SEER-Medicare, COTA, Medicare, Optum Market Clarity, Optum CDM, and ConcertAI RWD. In addition, a targeted review of recently published studies in patients with LBCL was conducted to identify reported race and ethnicity distributions. Distributions were described using counts and percentages for each race (Asian, Black, White, and other/unknown/not reported) and ethnicity (Hispanic, non-Hispanic, and other/unknown/not reported) category. Results: Patients with LBCL from the databases included: COTA (N=5848), SEER-Medicare (N=102,548), Medicare (N=136,466), Optum Market Clarity (N=19,649), Optum CDM (N=22,175), and ConcertAI (N=1828). Race and ethnicity distributions are reported in the table. Across databases, Asian (2–6%) and Black (5–8%) races were substantially lower than White race (69–88%). Across various lines of therapy, distributions were similar: 3–5% Asian, 3–5% Black, and 78–82% White. Hispanic ethnicity (5–22%) was substantially lower than non-Hispanic ethnicity (70–91%). In the targeted review, 14 publications of LBCL therapies were identified; of these, 10 did not report racial/ethnic composition. In 4 publications (Salles et al, 2020; Sehn et al, 2020; Bannerji et al, 2022; and a real-world study by Shenoy et al, 2011), Asian, Black, White, and other/unknown/not reported represented 2–13%, 0–7%, 71–89%, and 1–11%, respectively. Conclusions: Information on racial and ethnic distributions in LBCL studies is underreported, particularly in global trials. If this information was reported and reflective of LBCL in clinical practice in the US, the numbers of Asian and Black patients would be low at ≤8%, and most patients would be expected to be White and non-Hispanic. [Table: see text]