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7524 Background: R/R FL is associated with poor prognosis and less frequent, shorter responses with each line of treatment (Tx). Although R2 is an effective regimen in R/R FL with an acceptable safety profile, FL remains incurable; thus, better Tx options are needed. Subcutaneous epcoritamab is a bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells. In the dose-escalation part of the phase 1/2 EPCORE NHL-1 trial, single-agent epcoritamab (0.76–48 mg) resulted in an overall response rate of 90% and a complete response rate of 50% in R/R FL. The distinct mechanisms of action of epcoritamab and R2 may combine to increase antitumor response, with generally non-overlapping toxicity profiles. We present updated data for epcoritamab with R2 in R/R FL (EPCORE NHL-2 arm 2; NCT04663347). Methods: Adults with R/R CD20+ FL received epcoritamab + R2 for 12 cycles (C) of 28 d; epcoritamab was administered at 24 or 48 mg in dose escalation and 48 mg in expansion. During C1, step-up epcoritamab dosing and corticosteroids were required to mitigate CRS. Response was assessed by PET-CT. The epcoritamab regimen for these pts was: Q1W, C1–3; Q2W, C4–9; Q4W, C≥10 up to 2 y. Results: As of December 1, 2021, 30 pts (median age, 68 y) had received epcoritamab + R2 (24 mg, n=3; 48 mg, n=27), 21 pts (70%) had stage IV disease, and 20 pts (67%) had FLIPI scores 3–5. Median (range) number of prior lines of therapy was 1 (1–5), 30% had primary refractory disease, and 40% had disease progression within 24 mo after starting first-line Tx (20% within 24 mo after starting immunochemotherapy). At a median (range) follow-up of 5.1 mo (0.8–12.3), 25 pts (83%) remained on Tx; 5 pts discontinued Tx due to progression (n=2), AEs (n=2), or consent withdrawal (n=1). Common Tx-emergent AEs (TEAEs) of any grade (G) included infections (57%), injection-site reactions (50%), constipation (37%), fatigue (37%), and neutropenia (37%). CRS was seen in 15 pts (50%; G1/2 43%, G3 7%), with most events in C1. All CRS events resolved with standard management, including tocilizumab in 3 pts, and 1 pt discontinued Tx due to CRS. One pt experienced G2 ICANS. No fatal TEAEs occurred. Antitumor activity is shown in the Table. As of the data cut, all responders remained in response, with the longest duration of response being 7.0+ mo and ongoing. Conclusions: Subcutaneous epcoritamab+ R2 exhibits promising efficacy, including a high CMR rate, in pts with R/R FL. The safety profile was consistent with prior data, and CRS events were generally low grade and in C1. Updated data with an additional 30 pts will be presented. Clinical trial information: NCT04663347. [Table: see text]

7536 Background: Relapsed/refractory (r/r) DLBCL patients (pts) are characterized by poor prognosis. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor, with modest single-agent activity in unselected DLBCL pts. Here we report the treatment effect of copanlisib in r/r DLBCL pts with regards to cell of origin (COO) and molecular biomarker profiles (NCT02391116). Methods: Patients with r/r DLBCL and ≥1 prior lines of therapy were eligible. Copanlisib (60 mg IV infusion) was administered on days 1, 8 and 15 of a 28-day cycle. Tumor samples were evaluated for COO, CD79B mutations and > 400 genes by next generation sequencing (NGS). The primary endpoint was objective tumor response rate (ORR; per Lugano Classification, 2014) by COO and CD79B status. Results: The full-analysis (FAS) and per-protocol sets (PPS; ≥3 doses, post-baseline scans and NGS/COO data) included 67 and 40 pts, respectively. Pts were 58% male, median age 69 (range 25-93), ECOG status 0/1/2 22%/57%/21%, and heavily pretreated (median prior lines = 3, range 1-13). In the PPS, COO (and mutant CD79B status) analysis identified 22 GCB DLBCL (2 mutant), 16 ABC DLBCL (6 mutant), and 2 unclassifiable. The ORR in the PPS was 25% (10 of 40), with 5 complete responses (CR) and 5 partial responses (PR); stable disease in 12 pts. The ORR was 13.6% with 1 CR in GCB pts and 37.5% with 4 CRs (25%) in ABC pts. Response to copanlisib was 25% in pts with (2/8) and without (8/32) CD79B mutations. Five of 10 ABC DLBCL-wtCD79B pts and one GCB DLBCL-mCD79B responded (ongoing > 17 cycles). NGS analysis in 54 pts detected 348 mutations; BCL2 (54% of pts), TP53 (41%), BCL6 (30%), MYC (22%), CD79B (19%)/A (6%), MYD88 (19%), TNFAIP3 (17%), CARD11 (13%), and NFKBIA (9%). Response to copanlisib was not significantly different based on BCL2, BCL6, MYC, and MYD88 mutations. With a median of 6 cycles (range 1-29), the most common AEs (% all grade/gr3+4) were diarrhea (36/2), nausea (31/2), fatigue (31/3), fever (21/2) and transient hypertension (40/33) and hyperglycemia (34/31). There were 14 gr5 AEs (none drug-related). Conclusions: Copanlisib treatment of r/r DLBCL pts resulted in encouraging responses, especially in the ABC subtype, with a manageable toxicity. Clinical trial information: NCT02391116.