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FDA Clearance: EPKINLY® (epcoritamab-bysp) is indicated for the treatment of: Diffuse Large B-cell Lymphoma and High-grade B-cell Lymphoma - adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy. Follicular Lymphoma -adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. These indications are approved under accelerated approval based on response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Rationale for Requested Change: EPCORE NHL-2, Arm 4 (NCT04663347) is a phase 1b/2, open-label trial consisting of escalation (n=8) and expansion (n=21) in adults with relapsed or refractory DLBCL, including DLBCL NOS, “double-” or “triple-hit” DLBCL, FL grade 3B or T-cell/histiocyte-rich DLBCL eligible for R-DHAX/C and high-dose therapy autologous stem cell transplant (HDT-ASCT). [1] Of the 29 patients enrolled, 18 (62%) had primary refractory disease and 24 (83%) progressed within 12 months of initial therapy (referred to as high-risk patients). [1] Patients received epcoritamab as a subcutaneous injection in combination with R-DHAX/C. Following step-up dosing, epcoritamab was administered once-weekly for C1-4, every 2 weeks for C5-9 and every 4 weeks for C10+ until HDT-ASCT or disease progression (whichever is earlier). Cycles 1-4 were 21 days and Cycles 5+ were 28 days. [1] R-DHAX/C was administered at C1-3. The primary endpoint of the expansion portion was ORR per Lugano criteria. Median follow-up was 27.7 months (range, 2.0+ to 33.8). [1] For the 29 patients in the full analysis set, overall response and complete response (CR) rates were 76% and 69%, respectively. Response rates were observed regardless of high-risk status defined as patients with primary refractory disease or who relapsed within 12 months of initial therapy. Overall, the median time to response was 1.4 months (range, 1.2-4.2) and median time to CR was 1.5 months (range, 1.2-15.5). [1] An estimated 74% of complete responders (n=20) and 88% of high-risk patients proceeding to ASCT (n=12) remained in CR at 24 months. Additionally, the estimated rates at 24 months for progression-free survival (PFS) for the overall population (n=29) and high-risk patients proceeding to ASCT (n=13) were 60% and 100%, respectively. The estimated rates for overall survival (OS) were 86% and 100%, respectively, for the above populations. [1] Of the 16 patients who proceeded to HDT-ASCT, 12 (75%) remained in remission as of data cut-off (January 31, 2024). Six patients received epcoritamab monotherapy and did not proceed to transplant; of these, one patient remained in CR at data cut-off. [1] The most common (>30%) treatment emergent adverse events (TEAEs) included thrombocytopenia, anemia, neutropenia, nausea, cytokine release syndrome (CRS), fatigue and diarrhea. Grade 3 and 4 TEAEs included mostly thrombocytopenia (Grade 3 – 24% and Grade 4 - 45%), anemia (Grade 3 – 28%) and neutropenia (Grade 4 - 38%). [1] One patient had Grade 2 ICANS event, which resolved. Cases of CRS were primarily confined to Cycle 1. Of 13 (45%) CRS events, 11 (38%) were Grade 1 and 2 (7%) were Grade 2. There were no Grade =3 CRS events. CRS resolved in all patients within a median time of 2 days (range, 1-7). No CRS events led to discontinuation of epcoritamab. [1]