Subcutaneous Epcoritamab in Combination with R ² (Rituximab and Lenalidomide) in Patients with Relapsed or Refractory Follicular Lymphoma: Preliminary Results from a Phase 1/2 Trial

Background: Patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL) develop increasingly aggressive disease and are at increased risk for histologic transformation, death, or both. The combination of rituximab and lenalidomide (R ²) is a highly effective therapy for pts with R/R FL, but most pts eventually relapse, and better treatment options are needed. Epcoritamab (DuoBody ^®-CD3×CD20) is a subcutaneously administered bispecific antibody that binds to CD3 on T cells and CD20 on B cells and induces conditional T-cell-mediated killing of malignant B cells. Single-agent epcoritamab demonstrated manageable safety and substantial antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the phase 1/2 EPCORE NHL-1 trial (NCT03625037). Among heavily pretreated pts with R/R FL (median, 5 prior lines of therapy) treated with epcoritamab (dose, 0.76-48 mg), the overall response rate was 90% (9/10), with 50% (5/10) achieving complete response (Hutchings, Lancet, in press). Treatment with R ² has immunomodulatory properties that may potentiate the activity of epcoritamab, suggesting that combining R ² with epcoritamab may be beneficial. The encouraging data from the EPCORE NHL-1 trial supported initiation of the EPCORE NHL-2 trial (NCT04663347), a phase 1/2 trial evaluating epcoritamab in combination with various standard of care therapies in pts with B-cell NHL. Herein, we present preliminary results from arm 2 of this trial, which is evaluating epcoritamab in combination with R ² in pts with R/R FL.

Methods: Adults with histologically confirmed R/R CD20+ FL received epcoritamab in a dose-escalation phase followed by an expansion phase at the recommended phase 2 dose in combination with R ² for 12 cycles (28 days/cycle). Step-up dosing and corticosteroids during cycle 1 were used to mitigate cytokine release syndrome (CRS). Responses were evaluated by position emission tomography-computed tomography per the 2014 Lugano classification criteria.

Results: As of June 29, 2021, 16 pts were treated with the combination of epcoritamab + R ² (3 pts treated with epcoritamab 24 mg and 13 with 48 mg). Five pts completed at least 6 weeks of therapy and were evaluable for efficacy. A median of 3 cycles per pt have been administered. Fourteen (88%) pts remain on treatment. Median age was 68 years (range, 52-81), 10 (63%) pts were female, and 11 (69%) had 1 prior line of therapy (range in all 16 pts, 1-3 prior lines). All pts received prior immunochemotherapy, and 6 (38%) had disease progression ≤2 years after initial treatment (POD24). CRS occurred in 31% of pts (5/16) and all cases were of grade 1/2. The median time to onset of CRS was 15 days (study day 16; range, 5-16) and median time to resolution was 2 days; no pt required tocilizumab. Other adverse events (AEs) reported in >15% of pts were injection-site reaction (25%; 4/16), constipation (19%; 3/16), cough (19%; 3/16), diarrhea (19%; 3/16), and stomatitis (19%; 3/16), all grade 1/2. No immune effector cell-associated neurotoxicity syndrome events or fatal AEs were observed. Five (31%) pts required hospitalization due to 6 serious AEs (grade 1 CRS related to epcoritamab in 3 pts; unrelated grade 2 mania in 1 pt; unrelated grade 3 pneumonia in 1 pt; and unrelated grade 3 atrial flutter). All 5 response-evaluable pts achieved an objective response by week 7, with 4 achieving complete metabolic response. All 5 responders had stage IV disease at baseline, 3 had an FL International Prognostic Index of 4/5, 3 had received >2 prior lines of therapy, and 2 had POD24 with first-line therapy.

Conclusions: These data from a small population of pts suggest that epcoritamab can be safely combined with R ² with a manageable toxicity profile, with no new safety signals or unexpected AEs. The novel chemotherapy-free combination showed encouraging preliminary activity with early responses in all evaluable pts by week 7, including a majority of pts with high-risk features. Enrollment is ongoing. Additional data will be presented.