Ordspono (odronextamab)

P2/3, N=210, Recruiting, University of Birmingham | Active, not recruiting --> Recruiting

CD3 × CD20 BsAbs have shown the most promise in clinical development for B-NHL patients, with structural variations affecting their target affinity and potency. This review summarizes the current clinical trials of BsAbs for relapsed/refractory FL, highlighting the approval of some agents, their role in first-line treatment or combination therapies, their toxicity profiles, and the future of this therapeutic approach compared to other immune cell therapies.

P3, N=470, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Oct 2029 --> Jan 2029 | Trial primary completion date: Oct 2029 --> Jan 2029

P2, N=576, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Feb 2028 --> Dec 2029 | Trial primary completion date: Dec 2025 --> Aug 2028

Odronextamab achieved high complete response rates with generally manageable safety in patients with heavily pretreated R/R FL.

P2/3, N=210, Active, not recruiting, University of Birmingham | Not yet recruiting --> Active, not recruiting

Rituximab was the first one approved...Polatuzumab, a CD79b-targeting ADC, is approved as first-line treatment in high-risk patients in combination with chemo-immunotherapy...To date, two BsAbs (glofitamab and epcoritamab) are approved as monotherapy in third-line treatment in DLBCL. Combination strategies with chemotherapy, immunotherapy, and ADCs are currently under investigation with encouraging results in first-line or subsequent lines of treatment. In the following review, we focus on the structure of BsAbs, the mechanism of action, clinical efficacy, and the mechanisms of resistance to BsAbs.

P3, N=733, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Jan 2030 --> Jul 2029 | Trial primary completion date: Jan 2030 --> Jul 2029

P2/3, N=210, Not yet recruiting, University of Birmingham | Trial completion date: Oct 2032 --> May 2033 | Initiation date: Oct 2023 --> May 2024 | Trial primary completion date: Oct 2030 --> May 2031

This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.

P1, N=62, Recruiting, Regeneron Pharmaceuticals | Active, not recruiting --> Recruiting

P3, N=216, Recruiting, Regeneron Pharmaceuticals

P3, N=470, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Jun 2029 --> Oct 2029 | Trial primary completion date: Jun 2029 --> Oct 2029

Eligible treatments included CAR T cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), T cell engagers (mosunetuzumab, glofitamab, epcoritamab, odronextamab), phosphatidylinositol 3-kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib), HSCT, yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, and conventional therapies (immunochemotherapies, single- or multiagent chemo- or immunotherapies, and alkylating agents). This SLR demonstrated an evolving FL treatment landscape, with new agents such as CAR T cell therapies and T cell engagers exhibiting potential for improving effectiveness of treatment for patients in 3L+, 4L+, and 2L+ POD24 populations.

P3, N=470, Recruiting, Regeneron Pharmaceuticals

These data support the potential role of odronextamab in the treatment paradigm for R/R DLBCL. Further studies to evaluate the optimal sequencing and combinations of odronextamab with CAR-T therapy are warranted.

Molecular characterization in tumor biopsies, including CD20, will be presented. Ongoing monitoring of ctDNA may serve as an important early progression marker in R/R FL and DLBCL.

The studied regimens showed clinically meaningful activity and acceptable tolerability, and the risk of any Gr or Gr ≥3 TEAEs is not increased from low to high odronextamab exposures. Comprehensive PK, PD, exposure-efficacy, and exposure-safety analyses demonstrated that the selected odronextamab dose regimens have favorable efficacy and generally manageable safety profiles for the treatment of R/R FL and DLBCL.

P3, N=733, Recruiting, Regeneron Pharmaceuticals

P3, N=478, Recruiting, Regeneron Pharmaceuticals

P3, N=904, Recruiting, Regeneron Pharmaceuticals

P1, N=62, Active, not recruiting, Regeneron Pharmaceuticals | N=172 --> 62 | Trial completion date: Aug 2026 --> Dec 2026 | Trial primary completion date: Aug 2026 --> Dec 2026

P1, N=200, Active, not recruiting, Regeneron Pharmaceuticals | Recruiting --> Active, not recruiting | N=298 --> 200

Examples include the Phoenix study in which ibrutinib combined with R-CHOP was compared with R-CHOP in non-germinal centre derived DLBCL (defined by immunohistochemistry). The GOYA study investigated a more potent anti-CD20 antibody, obinutuzumab, combined with CHOP but again no benefit was seen compared with R-CHOP...The REMARC study was a phase 3 randomised, placebo-controlled trial in patients aged 60-80y who had achieved a PR or CR to 6-8 cycles of R-CHOP for DLBCL assessing 2 years of maintenance lenalidomide (Thieblemont et al, 2017)...Patients then received 5 cycles of R-CHOP or R-CHOP combined with bortezomib...This has led investigators to reason that if a better tolerated BTK were used and if primary prophylaxis with, for example, GCSF and co-trimoxazole were instituted for all patients, the benefit seen in younger patients could be seen for all...Furthermore there is a randomised phase III study (the Escalade trial) comparing R-CHOP with R-CHOP combined with acalabrutinib in patients 70y or younger. A very interesting novel group of molecules are the bispecific antibodies with a number in development in diffuse large B-cell lymphoma: glofitamab, epcoritamab and odronextamab...Whilst outcomes with R-miniCHOP are encouraging, more work clearly needs to be done in this patient group. One ongoing study to highlight is the POLAR BEAR trial which is a randomised studies comparing R-miniCHOP with R-miniCHP combined with polatuzumab vedotin in patients 80y or older or frail patients 75y or older.

This Ph 1 trial is determining the tolerability and preliminary clinical efficacy of odronextamab plus cemiplimab to treat pts with R/R aggressive B-NHL.

OLYMPIA-4 will determine the utility of odronextamab monotherapy as a novel alternative treatment option for pts with aggressive R/R B-NHL who have relapsed early (within 1 year) and/or were refractory to first-line therapy.

OLYMPIA-1 is a Phase 3, open-label, randomized, multicenter trial of odronextamab versus CIT (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]; rituximab, cyclophosphamide, vincristine, prednisone [R-CVP]; or rituximab-bendamustine) in previously untreated FL. This Phase 3 trial will determine the utility of odronextamab monotherapy compared with CIT as a first-line treatment for patients with previously untreated FL. Non-Hodgkin's lymphoma, Follicular lymphoma, Bispecific, Phase III

The study population will be selected based on similar eligibility criteria as the FL Grade 1–3a arm of the odronextamab ELM-2 trial (NCT03888105; Figure)...When complete, FLORA will provide important current information on the RW outcomes of patients with FL and provide a valuable source of control data for comparative studies in R/R FL. Follicular lymphoma, Non-Hodgkin's lymphoma, Relapsed lymphoma, Real world data

Options after progression on rituximab-based regimens include the Bruton's tyrosine kinase inhibitor ibrutinib, which demonstrated an ORR of 46%, but a complete response (CR) rate of only 3%, in its pivotal trial in R/R MZL. The ELM-2 study will assess the activity of odronextamab monotherapy across different subtypes of R/R B-NHL, including in patients with R/R MZL who are in need of new, effective therapies. Relapsed lymphoma, Bispecific, Non-Hodgkin's lymphoma, Marginal zone

This Phase 3 trial will determine the efficacy and safety of odronextamab plus lenalidomide compared with R2 in patients with R/R FL and MZL. Phase III, Bispecific, Non-Hodgkin's lymphoma, Follicular lymphoma

This Phase 3 trial will determine the utility of odronextamab plus chemotherapy (Odro-CHOP/Odro-CVP) compared with R-CHOP/R-CVP as a first-line treatment for patients with previously untreated FL. Follicular lymphoma, Non-Hodgkin's lymphoma, Phase III, Bispecific

This Phase 1, open-label, first-in-human study will assess the safety and tolerability of REGN5837 in combinationwith odronextamab in patients with R/R aggressive B-NHL.

Background: While the first-line combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R- CHOP) has improved outcomes for diffuse large B-cell lymphoma (DLBCL), up to 40% of patients will experience relapsed/refractory (R/R) disease (Sehn & Salles. OLYMPIA-3 will determine the tolerability and clinical efficacy of O-CHOP versus R-CHOP as first-line treatment inpatients that have IPI intermediate- to high-risk DLBCL. Monoclonal antibody, Diffuse large B cell lymphoma, Bispecific, Non-Hodgkin's lymphoma

The study population will be selected based on similar eligibility criteria as the R/R DLBCL arm of the odronextamab ELM-2 trial (NCT03888105; Figure)...When complete, ORCHID will provide important current information on the RW outcomes of patients with DLBCL and provide a valuable source of control data for comparative studies in R/R DLBCL. Non-Hodgkin's lymphoma, Relapsed lymphoma, Diffuse large B cell lymphoma, Real world data

With the 0.7/4/20 step-up regimen (n=63), Gr 3 CRS was observed in 1 (2%) pt (no Gr 4 or 5 CRS), and all CRS events resolved; 19% of pts received tocilizumab for CRS management. In the ELM-2 study, odronextamab demonstrated compelling efficacy in pts with R/R FL, with 75% of pts achievingCR. Responses were durable, and survival outcomes favorable, in the context of heavily pretreated R/R FL. Odronextamab showed an acceptable safety profile; results with the 0.7/4/20 step-up regimen compared favorably to other CD20×CD3 bispecific antibodies, with only 1 case of Gr ≥3 CRS.

In the trials, mosunetuzumab, glofitamab, epcoritamab, odronextamab, IGM-2323, and plamotamab were identified as antiCD20-CD3 bsAbs, which are evaluated against RRDLBCL as monotherapy and in combination regimens (Table). Based on our analysis , antiCD20-CD3 bsAbs are safe and efficacious. Among these drugs, glofitamab, epcoritamab and odronextamab as monotherapy and/or in combination regimens are the most effective therapies against RRDLBCL. Drug (s) **Author Efficac y ORR, CR per Lugano/RR C for ML criteria **CRS Overall/G 3 per ASTCT/ Lee et al criteria Overall Toxicity G≥3 per CTCAE CNS Toxicity G≥3 Per CTCAE aNHL 35%Mosun IV Budde et al.

In the ELM-2 trial, odronextamab showed clinically meaningful efficacy, durable CRs, and a manageable safety profile. These data confirm odronextamab efficacy in hard-to-treat, highly aggressive R/R DLBCL. The 0.7/4/20 odronextamab step-up regimen mitigates the risk of high-grade CRS, which is consistently observed with other bispecifics and CAR T therapies, and may present an important future option for the management of R/R DLBCL.

Patients who progressed were treated with Bendamustine-containing regimen (6 out of 10) and one patient received Odronextamab and anti-CD22xCD3 bispecific antibodies...Two patients prematurely discontinued the treatment, one patient had a PD at C4 and has subsequently been treated with R-CHOP, one patient relapsed after treatment completion and has been treated with Glofitamab... The Ibrutinib-Venetoclax-Obinutuzumab triplet is associated with a sustained disease control, in both R/R (4-y PFS of 50%) and newly diagnosed (4y-PFS of 80%) patients presenting with high risk-profiles (no low-MIPI patients were included in the Oasis Trial). The anti-CD20+Ibrutinib vs anti-CD20+Ibrutinib+Venetoclax combinations are currently under investigation in OASIS-II trial (NCT04802590) for untreated patients with MCL. Venetoclax, ibrutinib, Targeted therapy, Mantle cell lymphoma

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity, independent of T-cell receptor-mediated recognition. The model was also able to predict the CD8+ T-cell and B-cell profiles over time following IV odronextamab split-dosing regimen.Conclusion This QSP model was developed to address the safety concern related to CRS following treatment with odronextamab. The work demonstrated that the QSP modeling is a powerful tool that enabled optimization of odronextamab step-up dosing to minimize the risk of higher grade (i.e. Grade 2 and 3) CRS in lymphoma patients treated with odronextamab.