Genmab and AbbVie’s Epkinly Combo Improves PFS in Second-Line DLBCL Trial

Genmab's Epkinly Combo Improves PFS in Second-Line DLBCL

Genmab and AbbVie announced that their Phase III EPCORE DLBCL-4 trial, investigating a fixed-duration combination of Epkinly (epcoritamab) and Bristol Myers Squibb’s Revlimid (lenalidomide), met its primary endpoint in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who had received at least one prior line of treatment. The trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care R-GemOx. The combination reduced the risk of disease progression and death by 60% in the US and 56% outside the US, with a safety profile consistent with individual agents. The companies plan to engage global regulatory authorities based on these positive topline data.

• The EPCORE DLBCL-4 trial (NCT06508658) evaluated a fixed-duration combination of Epkinly (epcoritamab), a bispecific T-cell engager, and Revlimid (lenalidomide) against standard-of-care rituximab plus gemcitabine plus oxaliplatin (R-GemOx). The study focused on adult patients with relapsed or refractory DLBCL who had undergone at least one prior line of treatment, aiming to establish the combination's efficacy in this challenging patient group.
• The trial successfully achieved its primary endpoint, showing a statistically significant and clinically meaningful improvement in progression-free survival (PFS). This outcome indicates a substantial benefit for patients, with the combination therapy reducing the risk of disease progression and death by 60% in the US and 56% in other regions, based on distinct censoring rules.
• The safety profile observed for the Epkinly and Revlimid combination was consistent with the known profiles of the individual agents, suggesting no new or unexpected safety concerns. Following these positive topline results, Genmab and AbbVie are preparing to engage global regulatory authorities to discuss the data and advance the program, with plans to present the full data at a future medical meeting.

Unpacking the EPCORE DLBCL-4 Trial Design and Endpoints

The EPCORE DLBCL-4 trial context is best understood against the broader landscape of pivotal DLBCL trial designs, which span phase II/III randomized controlled trials, real-world database studies, and retrospective cohort analyses. Across these studies, endpoints consistently center on overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS), with early molecular and metabolic biomarkers increasingly incorporated as exploratory or surrogate endpoints. The table below summarizes key trial design parameters and endpoints from the most clinically relevant studies in this space.

Epkinly's Position in the Evolving DLBCL Treatment Landscape

The DLBCL treatment landscape has undergone substantial transformation over the past five years, driven by regulatory approvals and accumulating clinical trial data across all lines of therapy. While R-CHOP remains the dominant first-line standard of care — achieving prolonged remissions in over 60% of patients, with 1-year and 3-year overall survival rates of 88.5% and 78.4%, respectively — its limitations are well established, with approximately 30–40% of patients experiencing relapsed or refractory disease. Novel first-line strategies have sought to improve upon this benchmark. Pola-R-CHP (polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone) has emerged as a new frontline option for non-low-risk IPI patients. In a phase 3 trial, zuberitamab plus CHOP (Hi-CHOP) demonstrated non-inferior objective response rates versus R-CHOP (83.5% vs. 81.4% in the full analysis set), with significantly higher complete response rates in the per-protocol set (85.7% vs. 77.3%; p=0.038) and statistically significant survival advantages in the germinal-center B-cell-like subtype. Meanwhile, R-DA-EPOCH showed a numerical but non-significant improvement in complete response rate over R-CHOP (46.0% vs. 36.7%; p=0.313) in high-risk patients, accompanied by substantially greater hematological toxicity, higher dose reduction rates (52.0% vs. 18.4%), and longer inpatient stays (7.1 vs. 4.9 days).

In the relapsed/refractory setting, the approval of polatuzumab vedotin with bendamustine and rituximab (Pola-BR), selinexor, and tafasitamab plus lenalidomide marked a meaningful expansion of options for later-line patients. Real-world data from five U.S. centers, however, tempered enthusiasm for Pola-BR, with a complete response rate of only 24% and a median progression-free survival of 2.0 months in a predominantly refractory population — notably inferior to pivotal trial results. More recently, the Pola-ZR/G combination (polatuzumab vedotin with zanubrutinib plus rituximab or obinutuzumab) demonstrated a best overall response rate of 70% and a complete response rate of 45% in 20 evaluable relapsed/refractory patients, with a median PFS of 8.3 months and median OS not yet reached at a median follow-up of 16.1 months. Real-world treatment pattern analyses underscore the steep attrition across lines: among 1,347 eligible DLBCL patients, only 25.2% proceeded to second-line therapy, with 1- and 3-year OS from second-line initiation declining to 62.4% and 46.4%, respectively. In third- and fourth-line settings, conventional chemotherapy and chemoimmunotherapy yielded complete response rates of only 9.4% and 6.3%, respectively, with median OS of 7.7 and 4.4 months.

The most consequential paradigm shift in relapsed/refractory DLBCL has been the advent of cellular and T-cell–redirecting immunotherapies. Three CAR-T cell products have received FDA approval, demonstrating durable complete response rates of 40–60% and median progression-free survival of 11–12.5 months — outcomes that far exceed those of conventional salvage regimens, with median OS not yet reached in cell-based therapy recipients. Bispecific antibodies, including epcoritamab, glofitamab, and mosunetuzumab, have further expanded the immunotherapy landscape, offering off-the-shelf availability and an outpatient-compatible safety profile. BTK inhibitor combinations, particularly zanubrutinib-based regimens in MCD-subtype DLBCL, have shown compelling early efficacy (ORR 100%, CRR 94.4%, 1-year PFS 88.9% with BTKi plus R-CHOP versus 70%, 52.9%, and 41.2% in controls). Consolidation strategies are also under active investigation, with atezolizumab post-R-CHOP achieving a 2-year disease-free survival of 87.9% in high-IPI patients achieving complete metabolic remission — significantly better than historical controls. Collectively, these advances reflect a field rapidly stratifying treatment by molecular subtype, line of therapy, and transplant eligibility, with ongoing unmet need in post-CAR-T progression and broadly refractory disease.

Epkinly's Second-Line Success: Reshaping R/R DLBCL Treatment

The recent announcement regarding the Phase III EPCORE DLBCL-4 trial represents a pivotal moment for patients battling relapsed or refractory diffuse large B-cell lymphoma (DLBCL). For a disease characterized by aggressive progression and often poor outcomes, especially after initial treatment failure, the prospect of a new, highly effective second-line option is significant. Epkinly, a CD3xCD20 bispecific antibody, has already demonstrated efficacy in later lines of therapy. Its success in combination with Revlimid in patients who have received at least one prior line of treatment suggests a potential paradigm shift, moving this innovative therapy into an earlier and broader patient population.

The trial's achievement of a statistically significant and clinically meaningful improvement in progression-free survival, reducing the risk of disease progression or death by a substantial margin compared to standard R-GemOx, underscores the combination's therapeutic potential. This positions Epkinly and Revlimid as a formidable contender in the second-line setting, offering a fixed-duration treatment option that could improve patient outcomes and potentially alter the treatment sequencing landscape. The consistent safety profile observed, aligning with the known profiles of the individual agents, is also a crucial factor for physician adoption and patient tolerability.

However, as with any emerging therapy, certain considerations remain. While the topline data are compelling, the full dataset, including detailed overall survival and comprehensive safety analyses, will be essential for regulatory bodies and clinicians to fully assess the long-term benefits and risks. The competitive landscape for R/R DLBCL is dynamic, with other novel therapies and CAR T-cell options available or in development. Therefore, the combination's differentiation and real-world effectiveness against these alternatives will be key to its sustained success. Nevertheless, the positive results from EPCORE DLBCL-4 offer renewed hope and a promising new avenue for patients in urgent need of more effective treatment strategies.