Follicular lymphoma is a slow-growing B-cell cancer primarily affecting lymph nodes and has a histological appearance similar to follicular lymphoid structures. The malignant cells in follicular lymphoma originate from germinal center B-cells within the lymphoid follicle, particularly centrocytes and centroblasts.

One of the EMA-approved drugs ORDSPONO (odronextamab) for DLBCL and follicular lymphoma. Odronextamab is a CD20xCD3 bispecific antibody designed to bridge CD20 on cancer cells with CD3-expressing T cells to facilitate local T-cell activation and cancer-cell killing. 

The company presented updated Phase II results for odronextamab in relapsed/refractory follicular lymphoma (Grade 1–3a) as of the August 15, 2024, data cutoff. A total of 157 patients were enrolled, with a median treatment duration of 42.0 weeks; 96.2% completed Cycle 1, and 82.8% completed Cycle 4. The efficacy analysis included 128 patients (excluding Chinese and Japanese cohorts), with a median follow-up of 28.3 months. The objective response rate (ORR) by independent review was 80.5%, and the complete response (CR) rate was 74.2%; 92.2% of responders achieved a CR. Responses were durable, with a median duration of response (DoR) of 26.0 months and a median duration of CR (DoCR) of 32.2 months. ORR remained high across high-risk subgroups: 78.4% in patients with FLIPI scores of 3–5 and 81.0% in those with early progression. Median progression-free survival (PFS) was 23.0 months, with 24- and 36-month PFS rates of 49.8% and 37.5%. Median overall survival (OS) was 54.2 months, with estimated 24- and 36-month OS rates of 70.9% and 62.6%. MRD-negative patients at Week 12 had longer PFS (42.4 months) compared to MRD-positive patients (21.6 months). Of 47 patients who switched to once-every-4-weeks dosing, 32 maintained CR.

The long-term safety profile was consistent with earlier findings. All patients experienced treatment-emergent adverse events (TEAEs), with 86.0% experiencing Grade ≥3 events, and 15.3% discontinuing treatment due to TEAEs, most commonly from COVID-19 infection (2.5%). Among 89 patients receiving the 0.7/4/20 mg step-up dosing, cytokine release syndrome (CRS) events were mostly low grade (Grade 1: 46.1%; Grade 2: 13.5%; Grade 3: 1 case; no Grade ≥4 events), resolving in a median of 8.4 hours. One case of Grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported. Serious infections occurred in 45.2% of patients, with COVID-19-related infections in 38.2%, including 5.7% Grade 5 events.

KOL insights

“With longer follow-up, odronextamab demonstrated durable responses in heavily pretreated patients with relapsed/refractory follicular lymphoma from ELM-2, with robust efficacy in those with high-risk features, and a generally manageable safety profile. Overall, these compelling results support odronextamab as a potential off-the-shelf treatment option for patients with relapsed/refractory follicular lymphoma.” – Expert Opinion.

Conclusion

The follicular lymphoma market across the 7MM is currently led by Rituximab ± chemotherapy, a dominance expected to continue through 2034. The follicular lymphoma treatment landscape also includes several other approved therapies—such as TAZVERIK, BRUKINSA, YESCARTA, and BREYANZI—each offering unique advantages. Among emerging therapies, ORDSPONO faces significant competition from other bispecific T-cell engagers (BiTEs) such as AbbVie and Genmab’s EPKINLY (epcoritamab), and Roche’s COLUMVI (glofitamab) and LUNSUMIO (mosunetuzumab). All these therapies leverage mechanisms like antibody-dependent cellular cytotoxicity (ADCC), positioning them as direct competitors.

While ORDSPONO shows promise, it lags behind LUNSUMIO in terms of regulatory reach—LUNSUMIO is approved in the US, EU, and Japan, whereas ORDSPONO currently holds approval only in the EU. Additionally, its intravenous administration over two days is less convenient compared to EPKINLY’s subcutaneous dosing and the more defined, less frequent IV schedules of COLUMVI and LUNSUMIO. Despite the competitive environment, Regeneron is actively advancing ORDSPONO’s regulatory pathway. On February 26, 2025, the US FDA accepted the resubmission of the Biologics License Application (BLA) for odronextamab in relapsed/refractory follicular lymphoma after two or more prior therapies. A final decision is expected by the target action date of July 30, 2025, potentially paving the way for broader market access. The large unmet need in relapsed/refractory non-Hodgkin lymphoma presents a strong market opportunity for odronextamab.