Rituximab and epcoritamab as first-line therapy for patients with high-tumor burden follicular lymphoma: Results of a multicenter phase II trial

Abstract Introduction For patients (pts) with high-tumor burden follicular lymphoma (FL), chemoimmunotherapy remains the standard first-line treatment. However, the role of chemotherapy could be challenged by emerging CD3xCD20 bispecific antibody (BsAb)-based treatment regimens, which may delay or obviate the need for chemotherapy and its many potential side effects. Epcoritamab (epcor) is a CD3xCD20 BsAb that achieves a high overall response rate (ORR) as a single agent and is approved for third-line or later treatment of FL. We hypothesized that debulking treatment with 4 weekly doses of rituximab (R) before initiation of full dose epcor would lower cytokine release syndrome (CRS) risk and deepen responses based on R's distinct mechanism of targeting CD20. Here we present response results for all pts enrolled in the initial cohort of a phase 2 trial (NCT05783609) of time-limited therapy with R+epcor. Methods Eligibility criteria include previously untreated grade 1-3A FL, age≥18, stage II-IV, requirement for therapy based on modified GELF criteria, ECOG PS 0-2. In cycle 1 (C1), pts received 4 weekly doses of R (D-14, -7, 1, 8) and subcutaneous epcor on D1 (0.16 mg), D8 (0.8 mg), and D15/D22 (48 mg). After 26 pts enrolled, a 3rd epcor step-up dose (SUD) (D15, 3 mg) was added and inpatient observation for the first full dose of epcor was no longer required. Epcor was continued for a total of 9 cycles, dosed weekly in C2-3 and biweekly in C4-9. Responses are evaluated using PET-CT based on Lugano 2014 criteria after 2, 5, and 9 cycles. Results From 7/2023-3/2025, 35 pts were enrolled. Median age was 58 (range 28-78). At study entry, 34 pts (97%) had stage III/IV, 10 (29%) bulky disease (≥7 cm), 7 (20%) grade 3A FL, and 20 (57%) a FLIPI score of 3-5. The best ORR and complete metabolic response (CMR) rates were 97% (95CI 85-100%) and 91% (95CI 77-98%), respectively. Responses occurred rapidly with 34/35 pts responding after 2 cycles (30 CMRs, 4 partial metabolic responses [PMRs]). Among 4 pts with a PMR, 2 have converted to a CMR and 1 had an ongoing PMR at the next restaging scan, while 1 has not yet been restaged. The only non-responder had progressive disease at the first response assessment with a biopsy confirming CD20+ histologic transformation. No other pt has progressed. With a median follow-up of 8.6 months(m) (3.2-22.4), the 9m PFS is 97% (95CI 91-100%). CRS occurred in 15 pts (43%; G1 37%, G2 6%). CRS was less frequent among the 9 pts who received 3 SUDs (11%; G1 11%) than among the 26 pts who received 2 SUDs (54%; G1 46%, G2 8%) (p=0.03). Infections occurred in 19 pts (54%; G1 11%, G2 34%, G3 9%). G3 infections include bacteremia, COVID-19, and lung infection. In each case, the AE resolved and the pt completed study treatment. Other common treatment-related (tr)AEs included fatigue (43%), headache (43%), injection site reaction (43%), and myalgias (31%). G3+ trAEs included neutropenia (20%), lymphopenia (9%), anemia (3%), eosinophilia (3%), and elevated AST (3%). Serious AEs beyond the 60-day safety window include G3 bacteremia (n=1), G3 autoimmune encephalitis (n=1), and G3 avascular necrosis (n=1), each deemed possibly related to study treatment. 4 pts discontinued treatment early due to persistent low-grade infections (n=2), G3 eosinophilia (n=1), and pt preference (n=1). All 4 pts were in CMR at treatment discontinuation and at last follow-up. Flow cytometry was performed to characterize circulating T-cell, NK-cell, and B-cell populations at screening, C1D1, C1D8, C1D15, and progression (if relevant). 5 pts were selected based on CRS and response. Pre-treatment with R induced near complete depletion of CD19/CD20+ B cells by C1D1 and was associated with potentially favorable changes in T-cell populations, including increases in helper and naïve T cells and a decrease in T cells with an exhausted phenotype. The non-responder had increased exhaustion (PD1/TIM3) and cytotoxic markers (Granzyme B) on CD8+ cells at progression. Conclusion R+epcor achieves rapid and deep responses in pts with high tumor burden FL. Debulking therapy with R appears to lower the risk of CRS, particularly when used in combination with 3 epcor SUDs. Based on these encouraging results, a 65-pt expansion cohort is currently enrolling, which includes 2 changes to improve the convenience and tolerability of treatment: less frequent (every 4 week) dosing of epcor in C4-C9 and less intensive steroid premedication during epcor SUD.