Odronextamab plus chemotherapy in patients with previously untreated follicular lymphoma: First results from part 1 of the Phase 3 Olympia-2 study

Abstract Introduction Odronextamab (Odro), a CD20×CD3 bispecific antibody, showed promising efficacy as first-line monotherapy for patients (pts) with previously untreated follicular lymphoma (FL) in Part 1 of the ongoing Phase 3 OLYMPIA-1 study (NCT06091254). OLYMPIA-2 (NCT06097364), a Phase 3, randomized, open-label, multicenter study, is the first to assess whether Odro + chemotherapy (CHOP/CVP) induction ± Odro maintenance is superior to standard-of-care rituximab (R) + CHOP/CVP induction + R maintenance in pts with previously untreated FL (Part 2). The study comprises Part 1A (dose escalation) and Part 1B (dose optimization). Here, we report first results from Part 1A. Methods Part 1A included pts aged ≥18 years with previously untreated CD20+ Grade (Gr) 1–3a FL, Stage II bulky or Stage III/IV disease, a FLIPI-1 score of 3–5, and an ECOG performance status of ≤2. In Part 1A, Odro-CHOP/CVP was administered in 6 × 21-day induction cycles. Odro was administered intravenously with weekly step-up dosing (0.7/4/20 mg) starting on Cycle (C)1 Day (D)8, followed by full doses on C2 (D8 and 15), C3–4 (D1, 8, and 15), and C5D1, and 2 × full dose on C5D8 and C6 (D1 and 15). Odro full doses of 40 mg (dose level [DL]1) and 80 mg (DL2) were tested. Pts with a complete response (CR) or partial response after induction received ≤12 doses of Odro maintenance (320 mg once every 8 weeks). Part 1A primary endpoints were the incidence of dose-limiting toxicities (DLTs), and the incidence and severity of treatment-emergent adverse events (TEAEs). Objective response rate (ORR; assessed by local investigator per Lugano criteria) was a secondary endpoint. Biomarker analyses were exploratory endpoints. Results At the data cutoff (April 30, 2025), 21 pts with FL were enrolled in Part 1A and were evaluable for safety (DL1, n=9; DL2, n=12). Median age was 67 years (range 39–80), 6 pts were male, and 8 pts had bulky disease. In the DL1 and DL2 groups, 77.8% and 50.0% of pts completed 6 cycles of induction, with median durations of treatment exposure of 37.0 months (range 4.7–62.1) and 13.8 months (10.1–33.0), respectively. Treatment was ongoing in 16 pts (DL1, n=5; DL2, n=11). DLTs were evaluable in 15 pts (DL1, n=7; DL2, n=8). One pt in the DL1 group had a DLT during the observation period. All 21 pts experienced ≥1 TEAE, which led to treatment interruption in 11 pts (DL1, n=3; DL2, n=8). One pt discontinued treatment due to a TEAE (pneumonia; in the DL1 group). The most common TEAEs were neutropenia (DL1, 55.6%; DL2, 83.3%), anemia (44.4%; 41.7%), asthenia (22.2%; 58.3%), cytokine release syndrome (CRS) (22.2%; 58.3%), and pyrexia (44.4%; 41.7%). Gr ≥3 TEAEs occurred in 77.8% and 100% of pts at DL1 and DL2, respectively. Most common Gr ≥3 TEAEs were neutropenia (DL1, 55.6%; DL2, 83.3%) and anemia (22.2%; 16.7%). Infections occurred in 77.8% of pts in the DL1 group and 66.7% in the DL2 group, with Gr ≥3 infection rates of 44.4% and 16.7%, respectively. Seven pts required prolonged inpatient hospitalization due to infection (DL1, n=4; DL2, n=3). CRS events were all Gr 1 (DL1, 11.1%; DL2, 25.0%) or Gr 2 (11.1%; 33.3%). No tumor lysis syndrome or ICANS events were reported. No TEAE resulted in death. Among 16 evaluable pts, ORR was 88.9% (95% CI 51.8–99.7) for DL1 and 100% (95% CI 59.0–100) for DL2, with CR rates of 77.8% (95% CI 40.0–97.2) and 85.7% (95% CI 42.1–99.6), respectively. Serum cytokines IL6, IL8, IFN-γ, and TNFα were elevated with the first Odro-CHOP/CVP doses only, and T-cell margination was similar to that previously reported with Odro monotherapy. After the C2D8 first full dose, cytokine and T-cell counts were comparable between DL1 and DL2. B-cell counts decreased moderately during Week 1 of chemotherapy and cleared completely after the first dose of Odro. Baseline CD20 status and on-treatment ctDNA clearance will be presented. Conclusions In Part 1A of the Phase 3 OLYMPIA-2 study, the safety profile of Odro-CHOP/CVP induction was generally manageable, with no new safety signals. Preliminary efficacy was promising, with CR rates of 78% for DL1 and 86% for DL2. Updated Part 1A data, including biomarkers, will be presented.