ELM-2 Data Display Long-Term Efficacy and Safety of Odronextamab in R/R Follicular Lymphoma

Stefano Luminari, MD

Long-term efficacy and safety data with odronextamab (Ordspono) in heavily pretreated patients with relapsed/refractory follicular lymphoma demonstrate deep and durable responses with the bispecific antibody and support its continuous use in this population, according to Stefano Luminari, MD.

Updated data from the follicular lymphoma cohort of the single-arm phase 2 ELM-2 trial (NCT03888105), which were presented at the 2025 EHA Congress, showed that at a median follow-up of 28.3 months (95% CI, 25.5-32.8), 128 evaluable patients achieved an overall response rate (ORR) of 80.5% (95% CI, 72.5%-86.9%), including a complete response (CR) rate of 74.2% (95% CI, 65.7%-81.5%).1 The median duration of response (DOR) was 26.0 months (95% CI, 18.8-42.5), and the median duration of CR (DOCR) was 32.2 months (95% CI, 20.8-42.6).

This data readout followed the August 2024 European Commission approval of odronextamab for the treatment of adult patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma who have received 2 or more prior lines of systemic therapy.2 This regulatory decision was supported by data from the phase 1 ELM-1 (NCT02290951) trial, as well as earlier data from ELM-2. In the initial ELM-2 readout, among patients with follicular lymphoma (n = 128), the ORR per independent review committee was 80%, and the CR rate was 73%. The median DOCR was 25 months (95% CI, 20-not evaluable).

Notably, in the US, the FDA has accepted a resubmission of the biologics license application seeking the approval of odronextamab for the treatment of patients with relapsed/refractory follicular lymphoma who have received at least 2 prior lines of systemic therapy.3 The new Prescription Drug User Fee Act goal date is July 30, 2025.

"With the longer follow-up, the efficacy data are confirmed, with the suggestion of an additional slight improvement," Luminari said in an interview with OncLive®.

In the interview, Luminari discussed unmet needs for patients with follicular lymphoma that ELM-2 aimed to address, updated efficacy and safety data from the trial, and key advice for hematologists regarding infection risk management and prophylaxis.

Luminari is an associate professor of oncology at the University of Modena and Reggio Emilia in Italy.

OncLive: What was the rationale for conducting the ELM-2 trial?

Luminari: Follicular lymphoma is a curable disease; however, [there are] some exceptions. [There is a] patient population with unmet needs. Among these unmet needs, the treatment of multiple-relapsed follicular lymphoma [has been] associated with unsatisfactory results until recently.

[The paradigm] changed, hopefully in the right direction, thanks to the novel agents that are available. Among these novel agents, we have the bispecific [antibody] class of agents, which is associated with promising activity. Among the bispecific agents tested in follicular lymphoma, we have odronextamab, which is an off-the-shelf, CD20xCD3-directed bispecific antibody. Based on preliminary results observed in follicular lymphoma, [this agent] was approved in Europe [in August 2024] for use in patients with follicular lymphoma [who have] relapsed after 2 prior lines of therapy. The rationale behind this [most recent ELM-2] presentation was to provide updated results from the follicular lymphoma cohort of the study with odronextamab in relapsed non-Hodgkin lymphoma.

What was the design of the follicular lymphoma cohort of ELM-2?

The ELM-2 study is an open-label, multicohort, multicenter study of odronextamab as a single agent. In the follicular lymphoma cohort, the eligibility criteria [included] a histological diagnosis of grade 1 to 3a follicular lymphoma, good performance status, and most importantly, refractory or relapsed [disease] after at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. The study design was that of a single-arm study with a step-up dose [of odronextamab], which was initially designed [to be administered over] 2 weeks; [the trial protocol was] updated to [include] an improved step-up dosing [administered over] 3 weeks, which was followed by weekly dosing of odronextamab intravenously for up to 12 weeks. Then, odronextamab dosing was [switched to] every other week for up to 9 months. After 9 months, the drug had to be continued in monthly administrations.

The primary end point of this study was ORR by independent central review. Secondary end points were other activity signals like CR, DOR, progression-free survival [PFS], safety, and tolerability.

What baseline characteristics are important to highlight?

[Data from the] follicular lymphoma cohort were already presented and published; the data are available in Annals of Oncology. In total, 128 patients were registered. [Regarding] the patient characteristics, we saw characteristics of patients that are typical of a high-risk population.

A total of 57.8% of patients had a high-risk Follicular Lymphoma International Prognostic Index score. The median number of prior lines of therapy was 3, [with a maximum of] 13 prior lines of therapy. Additionally, 71.9% of the patients were refractory to their last line of therapy. Overall, 49.2% of the patients were classified as POD24, [meaning] they had relapsed on their first line of therapy within the first 2 years.

What were the key efficacy findings from this analysis?

The activity of the treatment was confirmed [in this analysis] with even better results compared with the original data. The complete CR rate was improved by 1 additional CR case converted from an initial partial response. The median PFS [in all patients], which was initially reported to be 20.7 months, has now been reported to be 23.0 months.

What safety data were observed in this analysis?

The safety signals were similar [to what we have seen previously], without any new findings compared with the initial publication. The treatment’s safety profile was dominated by cytokine release syndrome, which had a total rate of 56.3% but was mostly grade 1 and 2 and mostly [reported] during cycle 1. The other frequent adverse effects [AEs] were neutropenia, fever, and, unfortunately, due to the registration of patients during the bad time of the pandemic, COVID-19 was reported in 32.8% of the patients. AEs were considered significant when they led to treatment discontinuation; however, treatment discontinuation was mostly due to infection, [primarily] COVID-19 infection.

Among the treatment-emergent AEs, which are meaningful to evaluate, 5 patients were reported to have treatment-related AEs [leading to] death. This was mostly due to infections, including progressive multifocal leukoencephalopathy, pneumonia, pseudomonal pneumonia, 1 case of sepsis, and 1 case of COVID-19. However, there were no new safety signals in this update, which has a longer follow-up compared with the original report.

What is your advice for colleagues about how odronextamab may continue to be safely incorporated into clinical practice going forward?

Since most of the AEs that were considered clinically relevant were related to infections, the only rule we have to follow when a patient is considered for a treatment with a bispecific antibody in general—or odronextamab in particular—is to carefully assess the patient, consider the profile of the patient’s infections risk, and adopt all possible preventive measure that can be applied to the patient, including prophylactic antibiotics, prophylactic antivirals, and, if needed, prophylactic supplementation of immunoglobulin, which can be delivered in patients with low immunoglobulin levels observed during treatment with their bispecific antibody to keep the rate and risk of infection as low as possible.

Disclosures: Luminari reported advisory board participation with and receipt of consultancy fees from AbbVie, Bristol Myers Squibb, Incyte, Kite, Regeneron Pharmaceuticals, Inc., and Roche; as well as advisory board participation with BeOne.

References

1. Luminari S, Taszner M, Chong G, et al. Long-term efficacy and survival outcomes with odronextamab for patients (pts) with relapsed/refractory follicular lymphoma (R/R FL): 2-year follow-up from the phase 2 ELM-2 study. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract S235.
2. 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 July 14, 2025. https://investor.regeneron.com/news-releases/news-release-details/ordsponotm-odronextamab-approved-european-union-treatment
3. Odrenextamab BLA accepted for FDA review for the treatment of relapsed/refractory follicular lymphoma. News Release. Regeneron. February 26, 2025. Accessed July 14, 2025. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-bla-accepted-fda-review-treatment