Phase II investigator-initiated trial of epcoritamab-lenalidomide in treatment naïve follicular lymphoma Free

Background Bispecific antibodies offer chemotherapy-free, time-limited options with reduced toxicity and durable responses for frontline follicular lymphoma (FL). In the phase 1/2 trial (NCT04663347), epcoritamab plus lenalidomide and rituximab demonstrated high complete response (CR) rates in the 1L and R/R settings. Yet rituximab is associated with increased risk of infections, infusion related reactions, and costs. Here we present interim analysis results of a phase 2 single arm study (NCT06112847) evaluating the efficacy and safety of epcoritamab + lenalidomide (E-len) in treatment-naïve FL.

Methods Adult patients (pts) with treatment naïve CD20+ histologically confirmed classic FL grade 1-3A and in need of systemic treatment by meeting GELF criteria received E-len. Epcoritamab was dosed subcutaneously weekly in cycle (C) 1-3, with 2 step-up doses in C1, and every 4 weeks starting at C4. Len 20 mg was given orally on days 1-21 of a 28-day cycle. Pts continued treatment until unacceptable toxicity, disease progression or a total of 12 cycles, whichever occurred first. Response was assessed per Lugano 2014 criteria. The primary objective was to assess efficacy by complete response rate (CR) of this combination and secondary objectives included overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR), as well as safety of the combination. A Simon two stage Minimax design was used (N=25; H₀ 45%, H_A 70%, power 80%, alpha level 0.05; stage 1= 12 pts).

Results Twenty-six pts were enrolled between 01/2024 and 07/2025. Median age was 60 years (range, 35-80), 15 (58%) were male, 7 (27%) Hispanics, 24 (92%) had advanced stage (III/IV) disease, 16 (62%) had FLIPI 3-5. Median number of cycles was 7.5 (range, 1-12). Nine completed 12 cycles; 2 terminated due to MD decision, and 15 were still on treatment. Three pts (12%) experienced cycle delay(s) due to bradycardia, grade 4 neutropenia, and PE/DVT respectively. Two pts (8%) started reduced dose of len due to renal dysfunction and 8 pts (31%) required a dose reduction of len during study treatment. Five pts (19%) required permanent discontinuation of len due to: Grade (G) 3 orbital angioedema and exfoliation (n=1), G3 rash (n=1), G3 venous thromboembolism (VTE)/pulmonary embolism (PE) (n=2), and insurance issue (n=1).

Twenty-six pts were evaluable for toxicities. The most common treatment-related adverse events were injection site reaction (69%), rash (69%), fatigue (62%), constipation (50%), anemia (42%), diarrhea (42%), neutropenia (42%)) and fever (38%). The most frequent treatment related G3-4 adverse events were neutropenia (31%), maculopapular rash (23%) and lymphopenia (8%). Cytokine release syndrome (CRS) of any grade was observed in 18 (69%) pts, 12 (46%) pts with G1, 5 (19%) pt with G2, and 1 (4%) pts with G3 CRS. Infection was observed in 4 (17%) pts, all low grade, and no ICANS or febrile neutropenia was observed.

Of the 26 enrollments, 2 pts received < 1 cycle due to treating provider decision (one had concern for underlying transformation and the other had G3 CRS after first dose) and were deemed non-response evaluable and replaced. Out of the other 24 pts, 6 are pending response evaluation. Eighteen pts were evaluable for response; ORR was 100% and CRR was 89% (16/18). All responses were observed at time of first disease assessment (following C4). With a median follow-up of 9.7 months (range 3.7-14.5) among the 18 response-evaluable pts, there were no cases of progression or death.

We conducted RNA-Seq analysis of PBMCs from 4 responding pts obtained at baseline and after 3 and 6 cycles of therapy. We observed an increase in absolute numbers of CD4+ and CD8+ T cells and decrease in B-cell numbers over time. Gene set enrichment analysis revealed upregulation of MYC targets in CD8+ T cells, accompanied by downregulation of E2F and G2M checkpoint genes in CD4+ and CD8+ T cells, possibly reflecting diminished proliferation. Focused gene analysis did not reveal an increase in T-cell exhaustion markers following 3 or 6 months of therapy. Analysis of additional samples will be presented at the meeting.

Summary/Conclusion Our results indicate that E-len is a safe and effective frontline chemotherapy-free regimen for treatment naïve FL pts, resulting in early and high CR rates. Longer follow-up will be needed to evaluate the durability of these responses.