Odronextamab Monotherapy in Previously Untreated Patients with High-Risk Follicular Lymphoma (FL): Results of the Safety Lead-in of the Phase 3 Olympia-1 Study

Introduction

Odronextamab, an investigational, off-the-shelf, CD20×CD3 bispecific antibody, has shown compelling efficacy and generally manageable safety in patients (pts) with heavily pretreated relapsed/refractory FL. In the primary analysis of the FL cohort of ELM-2 (NCT03888105), odronextamab treatment achieved an objective response rate (ORR) of 80%, complete response (CR) rate of 73%, and 24-month CR rate of 50%, with Grade ≥3 treatment-emergent adverse events (TEAEs) reported in 86% of pts (Taszner M et al. EHA 2024). These results support the investigation of a potential chemotherapy-sparing regimen in previously untreated pts with FL. OLYMPIA-1 (NCT06091254) is a Phase 3, open-label, multicenter study evaluating the efficacy and safety of odronextamab monotherapy in pts with previously untreated Grade 1–3a FL. The study consists of Part 1 (safety lead-in) followed by Part 2 (randomized investigation of odronextamab monotherapy vs standard chemo-immunotherapy). Here, we report safety and preliminary efficacy results for odronextamab monotherapy in pts with high-risk Grade 1–3a FL from the safety lead-in part of OLYMPIA-1.

Methods

In OLYMPIA-1, pts aged ≥18 years with CD20+ Grade 1–3a FL, ECOG PS 0–2, FLIPI 3–5 (Part 1), and an indication for treatment based on the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria, were enrolled. Odronextamab monotherapy was administered intravenously for 6 × 21-day cycles (C), with steroid prophylaxis during step-up dosing (0.7/4/20 mg) in C1 to help mitigate the risk of cytokine release syndrome (CRS). There was no mandated hospitalization period during step-up dosing. Pts then received odronextamab 80 mg in C2–4 and 160 mg in C5–6. Pts with a CR or partial response at the end of C6 subsequently received fixed-dose maintenance therapy, consisting of 12 doses of odronextamab monotherapy administered at 320 mg every 8 weeks. All patients received infection prophylaxis. The primary endpoint of Part 1 was the incidence of dose-limiting toxicities (DLT) during the DLT observation period, and the incidence and severity of TEAEs. ORR (as assessed by local investigator per Lugano criteria) and analysis of biomarkers were key secondary endpoints.

Results

Between February 2024 and May 2024, a total of 13 pts were enrolled in Part 1 of OLYMPIA-1 at 11 centers worldwide. Overall, the median age was 62 years, and 7 pts were male. All pts had FLIPI 3–5. At the time of data cutoff (July 2, 2024), 12 pts were DLT-evaluable (1 pt discontinued the study prematurely due to elevation of liver enzymes). Efficacy was evaluable in 5 pts at Week 12. The median duration of exposure was 3.05 weeks (range 1.7–8.7). All 12 DLT-evaluable pts completed >1 cycle of treatment and all 12 DLT-evaluable pts were receiving study treatment at the time of data cutoff.

No pts experienced a DLT. All 13 pts experienced TEAEs. The most common TEAEs of any grade were diarrhea (n=6), rash (n=5), and CRS (n=4). Grade ≥3 TEAEs occurred in 5 pts, the most common being alanine aminotransferase increased and aspartate aminotransferase increased (both occurred in 2 different pts). Among pts with CRS, the highest grade of CRS was Grade 1. Infusion-related reactions occurred in 2 pts; Grade 2 was the highest grade in 1 pt, and Grade 1 in the other. Grade ≥3 infections occurred in 1 pt. No events of tumor lysis syndrome or immune effector cell associated neurotoxicity syndrome (ICANS) were reported. No new safety signals were observed.

Among the 5 DLT-evaluable pts who had the opportunity to undergo response assessment at Week 12, odronextamab monotherapy demonstrated an ORR and CR rate of 100%.

Conclusions

The OLYMPIA-1 Phase 3 trial addresses the important question of whether odronextamab, administered as monotherapy, is superior to current standard of care in previously untreated pts with FL. Based on the prespecified criteria for assessment of safety of odronextamab monotherapy in Part 1, enrollment is proceeding for Part 2 of OLYMPIA-1, with a recommended Phase 3 dose of 80 mg. No DLTs were observed, and there were no Grade ≥2 CRS or ICANS events with odronextamab treatment in this outpatient-monitored setting. Preliminary efficacy data were promising, with 100% of response-evaluable pts achieving CR at the Week 12 assessment. Updated data, including efficacy and preliminary biomarker data in pts from Part 1, will be presented.