odronextamab (REGN1979)

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.

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

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.

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.

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 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

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

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

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

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

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.

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.

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. This indicates that the same therapeutic levels are achieved with both regimens, which is beneficial for the treatment of disease.Conclusion This optimized odronextamab dosing regimen was associated with lower risk of CRS and lower levels of baseline cytokine levels compared with the original regimen. The drug exposure was lower in the first cycle when the risk of CRS is greater, but it was comparable to that of the original regimen after the full dose of treatment was received, ensuring that odronextamab dose levels required for efficacy are maintained.

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, eliciting T-cell-mediated cytotoxicity independent of T-cell receptor-mediated recognition. Simulated IL-6 profiles, obtained using the SC QSP model, showed the peak IL-6 values during Cycle 1 with the proposed SC step-up dosing regimen (2/26/100 mg) would not exceed those of 0.7/4/20 mg IV.Conclusion SC administration of odronextamab may be simpler and more convenient than IV dosing. PK and IL-6 modeling and simulation analyses enabled the identification of SC regimens for clinical evaluation, which may improve the tolerability while preserving the efficacy for the treatment of patients with B-cell NHL.

Odronextamab, a CD20xCD3 bispecific antibody that provides "signal 1" through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. In addition, analysis of non-Hodgkin lymphoma clinical samples reveals an increase in CD28CD8 T cells after odronextamab treatment, demonstrating the presence of a population that could potentially be targeted by REGN5837. Collectively, our data demonstrate that REGN5837 can markedly enhance the antitumor activity of odronextamab in preclinical NHL models, and the combination of these two bispecific antibodies may provide a chemotherapy-free approach for the treatment of DLBCL.

Both achieved complete responses that remain ongoing for ≥2 years following odronextamab. Neither patient experienced Grade ≥3 cytokine release syndrome or Grade ≥3 neurological adverse events during treatment.

Odronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials.

The development of CD19 × CD3 BsAbs such as blinatumomab was met with significant challenges due to dose-limiting neurologic side effects. However, several CD20 × CD3 BsAbs including odronextamab, mosunetuzumab, glofitamab, and epcoritamab emerged recently...In addition, how do BsAbs compare to CAR T-cell therapy and how to choose and sequence between BsAbs and CAR T-cell therapy need to be addressed. While many of these critical questions remain to be answered in clinical studies, we believe the future of BsAbs in the NHL is very bright.

Thereafter, we reviewed the currently available therapeutic strategies: conventional chemotherapy, antibody-drug conjugate ADC (mainly polatuzumab and loncastuxumab), bispecific antibodies (CD19/CD3 and focus on novel CD20/CD3 Abs), immunomodulatory drugs (covering tafasitamab and lenalidomide, checkpoint inhibitors mainly in PMBL), small molecules (selinexor, BTK, and PI3K inhibitors), and the role of radiotherapy. Navigating this scenario, will uncover new challenges, including identifying an ideal sequence for these therapies, the most effective combinations, and search for consistent predictive factors to help selecting the appropriate population of LBCL patients. At present, supporting clinical research for CAR-T ineligible patients, a new and challenging group, must remain a major focus that is complementary to advances in CAR T-cell therapy.