Epcoritamab (epco) with gemcitabine + oxaliplatin (GemOx) in patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) induces high response rate even in pts failing CAR T therapy.

Abstract

7527 Background: Pts with R/R DLBCL who fail or are ineligible for ASCT have very poor outcomes with standard palliative chemotherapy. Rituximab + GemOx had a complete response rate of 33% (Cazelles et al, Leuk Lymphoma 2021); novel approaches are needed. Epco is a subcutaneously administered bispecific antibody targeting CD3 on T cells and CD20 on B cells. In the EPCORE NHL-1 dose-escalation trial, epco had manageable safety and antitumor activity in heavily pretreated B-cell NHL including DLBCL. EPCORE NHL-2 is a phase 1/2 trial evaluating epco + standard B-cell NHL therapies; shown here are results from arm 5 (NCT04663347). Methods: Adults with R/R CD20+ DLBCL who failed or were ineligible for ASCT received epco (QW, cycle [C] 1–3; Q2W, C4–9; Q4W, C≥10) and GemOx (Q2W, C1–4) until disease progression or unacceptable toxicity (28 d/C). Step-up epco dosing and prophylactic corticosteroids were required in C1 to mitigate CRS. Response was assessed by PET-CT per Lugano 2014 criteria. Results: As of Dec 1, 2021, 27 pts (median age, 71 y; range, 47–87 y) had received epco + GemOx (epco 24 mg, n=3; 48 mg, n=24). Most were stage IV (56%), primary refractory (56%), and refractory to last therapy (70%). Median number of prior therapies was 2 (range, 1–13). Median follow-up was 6.0 mo (range, 1.0–11.1), with treatment (Tx) ongoing in 16 pts (59%). The most common Tx-emergent AEs were CRS (70%), thrombocytopenia (70%), neutropenia (56%), anemia (52%), and infections (52%). CRS events were all grade (G) 1/2, with most cases occurring in C1; all cases resolved. One pt had ICANS (G3); 1 pt had tumor lysis syndrome (G3). Six pts (22%) had G5 AEs; investigator could not rule out contribution of epco in 2 pts: small bowel perforation in pt (72 y) with transformed DLBCL and extensive gastrointestinal involvement (had complete metabolic response [CMR]); acute hepatitis/multiorgan failure in pt (68 y) with transformed DLBCL and liver involvement (had CMR). Of 4 pts with fatal AEs unrelated to epcoritamab by investigator, 2 (87 y) had primary refractory disease and 2 (74 y) had multiple comorbidities. Response is shown in the Table. At the time of data cut, 65% of responders remained in response with the longest duration of response 6.9 mo. All 3 pts with prior CAR T remained on Tx and in response (2 CMR and 1 partial metabolic response [PMR]). Conclusions: When considering individual safety profiles of epco or GemOx, no unexpected safety findings were observed for epco + GemOx. In this R/R population with high unmet need, these initial data are encouraging and warrant further clinical evaluation. Clinical trial information: NCT04663347. [Table: see text]

Bispecific antibodies for the treatment of B-cell lymphoma: promises, unknowns, and opportunities

“…Glofitamab and epcoritamab have been integrated into standard-of-care platinum-based chemoimmunotherapy platforms for the treatment of patients with R/R aNHL. Clinical results have been promising (eg, ORR and CR rate of 100% and 86%, respectively, for epcoritamab-R-DHAX, 62 and 92% and 60%, respectively, for epcoritamab-gemcitabine, oxaliplatin 63 ) and registration-directed phase 3 trials are being launched (supplemental Table ).…”

The evolving therapy of DLBCL: Bispecific antibodies

“…These include combinations with platinum‐based chemoimmunotherapy for r/r aggressive B‐cell lymphomas, including DLBCL. Clinical results are so far quite favourable, with manageable toxicity and response rates of 90%–100% for the combinations of epcoritamab + R‐DHAX (rituximab, dexamethasone, cytarabine, oxaliplatin), 24 epcoritamab + GemOx (rituximab, gemcitabine, oxaliplatin), 25 as well as glofitamab + R‐GemOx. A randomised phase 3 study of GemOx +/− glofitamab is ongoing as well as a randomised phase 3 study of epcoritamab versus standard of care (R‐GemOx or R‐bendamustine) 26,27 .…”

Bispecific Antibodies in Hematological Malignancies: A Scoping Review

“…Tnb-486, a novel CD3xCD19 BiAb, demonstrated a complete response in 91% of RRFL patients in a phase 1 trial and had a lower incidence of ICANS and CRS compared to blinatumomab [ 119 , 121 , 123 ]. Mechanistically, the lower incidence of ICANS and CRS associated with Tnb-486 is likely due to its unique anti-CD3 moiety, designed to bind CD3 on T cells with low affinity, thereby attenuating the release of pro-inflammatory cytokines [ 124 ]. The higher incidence of ICANS observed with CD19xCD3 BiAbs when compared to CD3xCD20 BiAbs may be due to potential on-target off-tumor toxicity associated with targeting CD19, which is expressed on the pericytes and vascular smooth muscles that line the blood–brain barrier (BBB); therefore, the use of anti-CD19 BiAbs such as blinatumomab may impair the integrity of the BBB [ 125 ].…”

“…In this regard, gemcitabine can upregulate CD20 on DLBCL cells in vitro, which enhances the antitumor activity of rituximab [ 127 ]. A recent phase Ib/II trial demonstrated that epcoritamab + GemOx (gemcitabine, oxaliplatin) in RR DLBCL displayed a higher ORR than epcoritamab monotherapy (92% vs. 63%) [ 111 , 124 ]. Moreover, ameliorating antigen escape through targeting multiple antigens simultaneously in NHL may provide a novel approach to enhance their efficacy [ 113 , 128 ].…”