A bold insight: combining epcoritamab with a reduced-dose R-mini-CHOP regimen shows promise for elderly patients facing newly diagnosed DLBCL, delivering deep responses with manageable safety. But here’s where it gets controversial: could this approach redefine treatment for a historically high-risk group, even as questions about long-term durability and real-world safety linger?
A rewritten overview of the EPCORE NHL-2 arm 8 data reveals that fixed-duration epcoritamab-bysp, when paired with dose-attenuated rituximab and R-mini-CHOP, was generally well tolerated and produced strong responses in elderly, high-risk patients with newly diagnosed DLBCL. In this phase 1b/2 study (NCT04663347), 28 participants received subcutaneous epcoritamab at 48 mg weekly for the first two cycles, then every three weeks through cycle 6, with intravenous R-mini-CHOP (rituximab 375 mg/m2, cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, vincristine 1 mg/m2, prednisone 100 mg/day on days 1–5 of each cycle), followed by epcoritamab every four weeks for cycles 7–8. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival (PFS), overall survival (OS), MRD negativity, and safety.
Key efficacy findings at a median follow-up of 33.4 months (range 2.8–41.1): an ORR of 93% across all patients, with CR in 86% and partial response in 7%. Time to response averaged 1.4 months, and time to CR averaged 1.6 months. At two years, 79% remained in response and 79% remained in CR. Among the 22 patients who completed therapy, 20 achieved CR at end of treatment (91%), and at a median 22.6 months post-treatment, 90% of those remained in CR. Two-year PFS and OS were 76% and 82%, respectively, with median PFS and OS not reached regardless of International Prognostic Index (IPI).
MRD assessment (n=21 evaluable) showed a striking 95% negativity rate overall, with 80% negative at the first assessment (day 1 of cycle 3). Of the MRD-positive cases at that point, most converted to MRD negativity by day 1 of cycle 6, though two patients later progressed. MRD negativity persisted across subgroups, including bulky disease and higher IPI scores.
Commenting on the potential role of adding epcoritamab to R-mini-CHOP, Chan Cheah, MD, emphasized that even though R-mini-CHOP is an established standard of care for patients unable to tolerate full-dose R-CHOP, outcomes remain suboptimal. The data suggest that epcoritamab can enhance efficacy, potentially offering meaningful benefit when full-dose chemotherapy isn’t feasible. Epcoritamab has previously shown activity as a monotherapy and in combination with standard regimens in newly diagnosed DLBCL.
Why consider this combination?
- R-mini-CHOP remains the SOC for frail patients who cannot receive full-dose R-CHOP, yet outcomes are limited. The addition of epcoritamab may boost response depth and durability without substantially increasing toxicity.
- Prior EPCORE DLBCL-3 results demonstrated durable responses with single-agent epcoritamab in elderly patients with comorbidities, while EPCORE NHL-2 arms reported high ORR and CR rates for the elderly when epcoritamab was added to R-mini-CHOP.
Study design and patient population
The open-label, phase 1b/2 trial enrolled newly diagnosed DLBCL patients (including DLBCL not otherwise specified, T-cell/HRS variants, high-grade B-cell lymphoma, or grade 3B follicular lymphoma) who were 75 or older, or 65 or older with comorbidities, and unable to tolerate full-dose R-CHOP. Participants had ECOG performance status 0–2. Twenty-eight patients received the described regimen.
Safety profile and notable toxicities
Most adverse events were mild to moderate. The most frequent grade ≥3 TEAEs were neutropenia (43%), serious infections (32%), and anemia (14%), with the majority of serious infections occurring during cycles 1–6 when R-mini-CHOP was coadministered. The predominant TEAE was cytokine release syndrome (CRS), affecting 61% of patients (grade 1 in 32%, grade 2 in 29%), typically beginning around day 16 and resolving within a median of 2 days after treatment with tocilizumab or corticosteroids. Only one CRS event led to treatment discontinuation. Importantly, no cases of ICANS or TLS were reported. Epcoritamab discontinuation occurred in 3 patients (11%), including one fatal event, and R-mini-CHOP discontinuation occurred in 6 patients (21%). Most CRS events occurred in cycle 1.
Implications and ongoing questions
The updated EPCORE NHL-2 data in Arm 8 are encouraging for an older, high-risk population, suggesting that fixed-duration epcoritamab plus R-mini-CHOP can achieve deep, durable remissions with manageable safety signals. These results, alongside data from other trial arms, hint at the potential for integrating epcoritamab with standard-of-care therapies across diverse patient groups.
However, questions remain about durability beyond the observed follow-up, long-term safety in broader real-world populations, and how this approach compares to other emerging first-line strategies for elderly DLBCL. Could this regimen become a new standard for patients who cannot tolerate full-dose R-CHOP, or will long-term outcomes temper enthusiasm? Share your thoughts on whether this strategy should influence current treatment guidelines and how it might be implemented in practice.
