Introduction

Odro, a CD20×CD3 bispecific antibody, demonstrated compelling efficacy and generally manageable safety as monotherapy in patients (pts) with heavily pretreated R/R FL and marginal zone lymphoma (MZL) in the Phase 2 ELM-2 study (NCT03888105; complete response [CR] rates 74% and 77%; Grade (Gr) ≥3 treatment-emergent adverse events [TEAEs] 87% and 83%; respectively). OLYMPIA-5 (NCT06149286) is a Phase 3, open-label, randomized, multicenter study evaluating the efficacy and safety of Odro+Len in pts with R/R FL or MZL after ≥1 prior line of therapy (LOT). OLYMPIA-5 consists of Part 1 (safety lead-in) and Part 2 (Odro+Len vs rituximab+Len). Here, we report the first results from the FL cohort of Part 1.

Methods

Part 1 included pts aged ≥18 years with histologically confirmed Gr 1–3a FL or MZL (nodal, splenic, or extranodal) that was R/R after ≥1 prior line of systemic therapy and an ECOG performance status of ≤2. Odro+Len was administered in 12 × 28-day cycles. Odro was administered intravenously with 0.7/4/20 mg step-up dosing on Cycle (C)1 (Day [D]1, 8, and 15; hospitalization not required), followed by full dose on C1D22 and C2–3 (D1, 8, 15, and 22), 2 × full dose on C4–6 (D1 and 15), and 4 × full dose on C7–12 (D1). Odro full doses of 40 mg (dose level [DL]40) and 80 mg (DL80) were tested. Oral Len 20 mg was given once daily on D1–21 of each cycle. Part 1 primary endpoints: incidence of dose-limiting toxicities (DLTs), and incidence and severity of TEAEs. Secondary endpoints: pharmacokinetics (PK), investigator-assessed objective response rate (ORR), CR rate, and duration of response (DOR) per Lugano criteria. Biomarker analyses were exploratory endpoints.

Results

At the data cutoff (April 17, 2025), 32 pts with FL were enrolled in Part 1 (DL40, n=6; DL80, n=26) and were evaluable for efficacy and safety. Median age was 59 years (range 35–80), 14 pts were male, 23 pts had Lugano stage III–IV disease, and median number of prior LOT was 1 (range 1–7). Median duration of Odro+Len treatment exposure was 47.9 weeks (range 5.7–49.3) for DL40 and 26.9 weeks (4.0–58.3) for DL80. At data cutoff, all pts had completed ≥1 cycle of treatment, and 14 pts (all in the DL80 group) were still receiving study treatment. DLTs were evaluable in 30 pts (DL40, n=6; DL80, n=24).

No evaluable pts experienced a DLT. All 32 pts experienced TEAEs, most commonly neutropenia (DL40, 66.7%; DL80, 76.9%; all Gr ≥3), cytokine release syndrome (CRS; 33.3%; 53.8%), and hypogammaglobulinemia (33.3%; 34.6%). Gr ≥3 TEAEs occurred in 66.7% of pts in the DL40 group and 92.3% of pts in the DL80 group. TEAEs led to treatment discontinuation in 5 pts in the DL80 group, and to death in 2 pts (influenza [n=1] at DL40 and hemorrhagic stroke [n=1] at DL80, which were not considered treatment related). Infections occurred in 66.7% (Gr ≥3, 33.3%) of pts at DL40 and 76.9% (Gr ≥3, 23.1%) at DL80. CRS events were all Gr 1 (DL40, 33.3%; DL80, 34.6%) or Gr 2 (0%; 19.2%). There was one Gr 3 ICANS event in the DL80 group. No tumor lysis syndrome was reported.

Among pts in the DL40 and DL80 groups, investigator-assessed ORRs (95% CI) were 83.3% (35.9–99.6) and 88.5% (69.8–97.6); CR rates (95% CI) were 66.7% (22.3–95.7) and 65.4% (44.3–82.8); respectively. Among evaluable pts, median DOR (95% CI) was not reached (5.0–not evaluable [NE]) in the DL40 group (n=5) and not reached (NE–NE) in the DL80 group (n=23); 9-month event-free probabilities (95% CI) were NE (NE–NE) and 92.3% (56.6–98.9), respectively.

PK analyses indicated that Odro exposure in the presence of Len was similar to that reported previously with Odro alone.

Serum IL6, IL8, and IFNγ levels were similar in the DL40 and DL80 groups after the first full dose (C1D22), with C2D1 IFNγ levels elevated versus previously reported Odro monotherapy data. T-cell margination during C1 was similar to previous reports with Odro monotherapy and Odro plus chemotherapy. CD4/8 T-cell counts were consistently higher from C7 to end of treatment versus baseline, with no long-term differences between the DL groups. B-cell counts depleted completely during step-up dosing in both DL groups, with no recovery after ≤90 days post last dose.

Conclusions

Odro+Len showed generally manageable safety and encouraging preliminary efficacy in pts with R/R FL after ≥1 prior LOT in OLYMPIA-5. Updated data will be presented.

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2025
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