Epcoritamab with rituximab + lenalidomide (R2) and epcoritamab maintenance deliver deep and durable remissions in previously untreated (1L) follicular lymphoma (FL): 3-year outcomes from epcore NHL-2 arms 6 and 7

Abstract Introduction: Most patients (pts) with newly diagnosed FL receive chemotherapy (chemo)-containing regimens. While R² offers a chemo-free option in the 1L setting, it failed to improve results over chemoimmunotherapy. Thus, newer chemo-free options that provide more durable responses and improve long-term outcomes are needed. Epcoritamab (epcor) is a CD3×CD20 bispecific antibody approved as monotherapy for relapsed/refractory FL after ≥2 prior lines of treatment (tx) based on the results of the EPCORE® NHL-1 trial. In the phase 1b/2 EPCORE NHL-2 trial (NCT04663347), tx with fixed-duration epcor + R² in 1L FL (Arm 6) or epcor monotherapy maintenance post-standard of care (SOC) induction (Arm 7) resulted in sustained responses with manageable safety. We report updated results with median follow-up (mFU) of ~3 years in both arms. Methods: In Arm 6, pts with CD20+ FL grade (Gr) 1–3A received SC epcor 48 mg (QW, cycles [C]1–2; Q4W thereafter for ≤2 years) with IV rituximab 375 mg/m2(QW, C1; Q4W, C2–6) and oral lenalidomide20 mg(QD, days 1–21, C1–12). In Arm 7, pts in complete (CR) or partial (PR) response after 1–2 prior lines of SOC received epcor 48 mg maintenance monotherapy (QW, C1 [28 days]; Q8W, C2–13 [56-day cycles]) for up to 2 years. Primary endpoints were overall response rate (ORR) per Lugano criteria (Arm 6) and safety (Arm 7). Results: At data cutoff (DCO; Apr 9, 2025), 41 pts received epcor+R² (Arm 6) and 19 epcor monotherapy maintenance (Arm 7). In Arm 6, median age was 57 years, 90% had Ann Arbor stage III–IV, 39% had FLIPI score 3–5, and 32% had bulky disease ≥7 cm. At DCO, 56% completed tx; most common reason for discontinuation (d/c) was AEs (n=14), generally after ≥6 tx Cs (8/14). With a mFU of 35.9 months, best ORR and CR rates were 95% and 88%. Median duration of response (mDOR), duration of CR (DOCR), PFS, and OS were not reached (NR). 33-month estimated DOR and DOCR were 89% and 93%; 36-month estimated PFS and OS were 86% and 88%. Of 36 pts in CR, 10 d/c tx for reasons other than progressive disease or death, had response measurement post d/c, and had CR at end of tx (EOT; median tx duration: 13.2 months). With a mFU for DOCR of 20.0 months post-tx, CR was maintained in 9 of these 10 pts (90%) at DCO. Of 23 pts who completed tx per protocol, 21 had CR at EOT and 20 maintained CR at DCO. With mFU for DOCR of 12.5 months post-tx, median DOCR was NR. All pts evaluable for minimal residual disease (MRD; n=26) were MRD-negative (10-6) by clonoSEQ. With ~13 months additional FU, no new safety signals were reported (Falchi L, et al. HemaSphere 2024;8:P1146) and treatment-emergent AEs (TEAEs), including Gr≥3 TEAEs, declined over 2 years of tx. Two new TEAEs (both pneumonia) led to d/c. Of 13 pts (32%) with serious infections, 7 had events in the first 24 weeks of tx. Since the prior DCO, 1 patient experienced a new Gr3 TEAE of COVID-19. Rates of neutropenia were highest during the first 24 weeks of the combination tx. No febrile neutropenia was reported. One additional death, non-TEAE related, was reported. In Arm 7, median age was 56 years and most pts (84%) received epcor maintenance after 1 prior line of therapy; median time from last SOC dose to 1st epcor dose was 2.8 months. Eleven (58%) pts in CR and 8 (42%) in PR started epcor monotherapy; all 8 PR pts converted to CR during tx. Median DOR, DOCR, and OS were NR; 30-month estimated DOCR and OS were 88% and 84%. All 10 pts who completed tx per protocol had CR at EOT. With mFU of 12.2 months post-tx, all 10 remained in CR at DCO, and median PFS and OS were NR. Safety in Arm 7 was largely consistent with the prior report. Of 8 serious infection events, 6 occurred in the first year of epcor maintenance and none were reported after completion of epcor maintenance (week 96). After the last DCO, 1 patient experienced a new Gr3 TEAE of COVID-19. Neutropenias primarily occurred in the first 48 weeks of tx and rates decreased thereafter; no febrile neutropenia was reported. One additional death, non-TEAE-related, was reported. Conclusions: Fixed-duration epcor + R² induced deep, durable remissions in 1L FL with 88% CR rate and 33-month estimated DOCR of 93%. Epcor monotherapy as maintenance further deepened and consolidated tx response post SOC induction with no relapses and manageable safety. The favorable efficacy and manageable long-term safety of these regimens reinforces the versatility of fixed-duration epcor in FL.