Does Odronextamab Show Hope in FL and DLBCL Despite Regulatory Hurdles?

Findings from the ELM-2 study (NCT03888105) offer promising results on odronextamab (Ordspono), an investigational bispecific antibody targeting CD20 on B cells and engaging T–cell-mediated cytotoxicity in relapsed/refractory (R/R) follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL).^1,2 With durable response rates and positive quality-of-life (QOL) outcomes, odronextamab could transform therapeutic approaches for these challenging lymphomas, especially for patients with limited options.

However, regulatory challenges from the FDA have created a roadblock for this agent’s approval in the US, despite it receiving European approval for the treatment of patients with R/R FL or DLBCL following 2 prior treatments.^3,4

Promising Clinical Efficacy and Quality of Life in ELM-2

The phase 2 ELM-2 trial assessed the efficacy and patient-reported QOL of odronextamab in 140 patients with R/R FL (grades 1-3a).1,2 Interim data, as of January 2023, highlighted high efficacy, including an objective response rate (ORR) of 80%, and a complete response (CR) rate of 73% in patients with FL. For those achieving CR, the median duration of response was 25 months (95% CI, 20-not evaluable [NE]).

Among the 127 patients with DLBCL evaluated, the ORR reached was 52% with a CR rate of 31%. Patients who achieved a CR had a median duration of response of 18 months (95% CI, 10-NE).

“This study yielded some very good overall response rates of 80%, and mostly complete response rates. Those responses were durable, with a median duration of response of 22 months,” Benoît Tessoulin, MD, Nantes University Hospital, Nantes, France, told Targeted Oncology^TM in an interview. “Patient-related health outcomes regarding quality of life…were good because patients had good baseline scores. When looking at the changes from baseline through week 50, they either maintained or improved their quality-of-life scores.”

Beyond efficacy, ELM-2 trial findings reveal that odronextamab has favorable impacts on patients' QOL. Health-related QOL metrics remained stable, with no significant determinants observed over time, even as patients continued therapy until disease progression. These findings were supported by high completion rates in HRQoL assessments using EORTC QLQ-C30, FACT-Lym, and EQ-5D-3L, indicating the feasibility of tracking patient-centered outcomes in this context.

Patients reported moderate to high baseline levels in physical and role functioning and lower-than-average fatigue levels. These levels were maintained over 50 weeks, underscoring odronextamab’s tolerability and its ability to sustain patient functioning.

Statistically significant improvements were seen in several QOL scales, with most patients showing meaningful improvement or stability in critical areas. For example, meaningful improvements in fatigue and lymphoma symptoms were reported between weeks 10 and 42.

Sabarish Ram Ayyappan, MD, medical director of hematologic malignancies, City of Hope Cancer Treatment Center in Atlanta, Georgia, explained that response data for odronextamab were consistent with results from the phase 1 ELM-1 trial (NCT02290951), which evaluated the safety and efficacy of odronextamab in patients with relapsed or refractory non-Hodgkin lymphoma.

“The responses were durable with a median duration of complete response up to 18 months. At 24 months, the CR rate was maintained in 47% of the patients. The safety of the drug also was evaluated and consistent with previous reports that odronextamab is safe in patients who received them with relapsed/refractory diffuse large B-cell lymphoma,” explained Ayyappan in an interview with Targeted Oncology^TM.

FDA Setbacks and European Approval

The path to regulatory approval has been complex. While odronextamab demonstrated efficacy and a safety profile that met clinical standards, in March, 2024, the FDA issued 2 complete response letters for the biologics license application of odronextamab in relapsed/refractory FL and relapsed/refractory DLBCL after 2 or more lines of systemic therapy.³ The complete response letters were related to the enrollment status of confirmatory trials that evaluating the agent.

Importantly, there were no issues regarding the efficacy or safety of odronextamab, as well as no issues regarding trial design, labeling, or manufacturing.

Shortly after in August 2024, the European Medicines Agency approved odronextamab in relapsed/refractory FL or DLBCL who have received at least 2 prior lines of systemic therapy.⁴ This regulatory decision was supported by findings from the phase 1 ELM-1 and phase 2 ELM-2 trials.

What’s Next for Odronextamab?

Odronextamab’s development pipeline remains active, with ongoing randomized trials exploring its use in various clinical settings, including both first-line and relapsed/refractory contexts. These studies will help clarify its role as either a monotherapy or in combination with other agents, further solidifying its therapeutic potential. Long-term follow-up in these trials will be vital to understanding how odronextamab stacks up against chimeric antigen receptor T-cell therapies and other emerging options.

“Odrenextumab is under development in randomized clinical trials, either in the first-line setting or in the relapsed/refractory setting, [studying the agent] either as monotherapy or in combinations,” added Tessoulin.

REFERENCES:

1. Tessoulin B, Choo SG, Taszner M, et al. Maintenance of moderate to high levels of functioning and quality of life with odronextamab monotherapy in patients with relapsed or refractory follicular lymphoma. Blood. 2023;142(1):669. doi:10.1182/blood-2023-181942.

2. Ayyappan S, Kim WS, Kim TM, et al. Final analysis of the phase 2 ELM-2 study: Odronextamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Blood. 2023;142(1):436. doi:10.1182/blood-2023-179818.

3. Regeneron provides update on biologics license application for odronextamab. News release. Regeneron. March 25, 2024. Accessed October 31, 2024. https://tinyurl.com/38dhaxh6

4. Ordspono (odronextamab) approved in the European Union for the treatment of relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma. News release. Regeneron Pharmaceuticals, Inc. August 26, 2024. Accessed October 31, 2024. https://tinyurl.com/ybffrkf3