Bispecific Antibody Precision Immunotherapy in Non-Hodgkin Lymphoma

Epkinly, Glofitamab and Lunsumio (mosunetuzumab), bi-specific antibody immunotherapies-the next great advance in the treatment of non-Hodgkin lymphoma

Charles H. Weaver, MD
8–12 minutes
Home » Non Hodgkins Lymphoma » Bispecific Antibody Precision Immunotherapy in Non-Hodgkin Lymphoma

Bispecific antibodies represent an innovative immunotherapy approach that helps the body’s immune system target lymphoma cells is very promising. Bispecific antibodies have two arms. One arm of the drug attaches to a specific protein on the lymphoma cell. The other arm activates immune cells in the patient to kill the lymphoma cells. Several bispecific antibodies are in development for the treatment of non-Hodgkin lymphoma (NHL) and may represent a paradigm shift in lymphoma treatment. 

Bispecifics appear capable of inducing complete remissions in patients with refractory or resistant NHL including patients that have failed multiple therapies, stem cell transplantation or CAR T cell therapy. Bispecific antibodies are an “off the shelf” treatment that could potentially replace more toxic and expensive therapies including stem cell transplant and CAR T cell therapy .7,8,11,12

Epkinly (epcoritamab-bysp) 

Epkinly is the first T-cell–engaging bispecific antibody approved by the FDA for the treatment of adult lymphomas.13,14 Epkinly is a IgG1-bispecific antibody designed to direct cytotoxic T cells selectively to the lymphoma to elicit an immune response toward the malignant cells. Epkinly is designed to simultaneously bind to CD3 on T cells and CD20 on B-cells and induces T cell mediated killing of lymphoma B cells.6

Results from the the EPCORE™ NHL-1 phase 1/2 clinical trial evaluating Epkinly in 157 patients with relapsed/refractory large B-cell lymphoma (LBCL) who received at least two prior lines of systemic therapy, including 38.9 percent who received prior treatment with chimeric antigen receptor (CAR) T-cell therapy were the basis for the FDA approval. 

  • Overall response rate of 63%
  • Median duration of response was 12 months.

At a median follow-up of 9.8 months in responders, the median duration of response was estimated to be 15.6 months.  The most common reported side effects were fever and injection site reactions.7,8 

Epkinly has also been reported to have an 82% response rate in patients with relapsed or refractory follicular lymphoma who received 2 or more prior systemic treatments.15  This led to an FDA approval in June of 2024.

Subcutaneous administration distinguishes Epkinly from competing therapies in the class. Besides being more convenient and less time consuming, subcutaneous administration leads to more gradual increases in plasma cytokine levels and lower peak levels.  Epkinly has a Boxed Warning for serious or life-threatening cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Of the 157 patients with relapsed or refractory LBCL treated 51% experienced CRS and 6% had ICAN.

Epkinly Plus Salvage Chemotherapy for Relapsed/Refractory DLBCL

Subcutaneous Epkinly is being combined with rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C) salvage chemotherapy and demonstrated manageable safety in patients with relapsed/refractory DLBCL eligible for autologous stem cell transplant (ASCT), according to preliminary results from a phase 1/2 trial presented at the 2022 ASCO Annual Meeting. Initial results reported an overall response rate prior to transplant of 100% (82% complete metabolic response; 18% partial metabolic response). A total of 12 patients had postponed or canceled high-dose therapy and ASCT and continued Epkinly monotherapy. Of these patients, 5 (42%) had complete metabolic response and 3 (25%) had partial metabolic response.9  A Phase 3 study in diffuse DLBCL is ongoing to evaluate Epkinly versus investigators’ choice of chemotherapy regimen (either bendamustine and rituximab or gemcitabine, oxaliplatin, and rituximab) in patients with relapsed or refractory DLBCL. Epkinly is being co-developed by Genmab and AbbVie.5

Glofitamab

A novel bispecific anti CD20xCD3 T-cell engaging antibody, Glofitamab shows promise in the treatment of individuals with relapsed or refractory large B-cell lymphoma (LBCL) and has the potential to be the first, off-the-shelf CD20xCD3 T-cell engaging bispecific antibody for use in aggressive lymphomas. 

Glofitamab is an investigational CD20xCD3 T-cell-engaging bispecific antibody engineered to have one region that binds to CD3, a protein on T-cells, a type of immune cell, and two regions that bind to CD20, a protein on B-cells, which can be healthy or malignant. This dual-targeting brings the T-cell in close proximity to the B-cell, activating the release of cancer cell-killing proteins from the T-cell. 

The results of a phase 1/2 study (ClinicalTrials.gov Identifier: NCT03075696) that included 291 adults with relapsed/refractory LBCL have been released. Patients were pretreated with obinutuzumab to mitigate the risk of cytokine release syndrome followed by glofitamab every 3 weeks for a maximum of 13 infusions. The overall response rate was 53%, and the complete response rate was 35% with a median time to first remission of only 43 days. 

The the estimated 12-month survival rate with lymphoma progression was 93%. The 61 patients who remained in complete remission at the end of treatment had previously received a median of 3 lines of therapy (range, 2-9), 43% had primary refractory disease, and 74% had disease that was refractory to their last therapy. 

Lunsumio (mosunetuzumab)

Lunsumio is a novel CD20-CD3 T-cell engaging bispecific antibody that was designed to target the CD20 antigen on the surface of B-cells and the CD3 antigen on the surface of T-cells. This dual targeting activates and redirects a lymphoma patient’s existing T-cells to engage and eliminate lymphoma targeted B-cells by releasing cytotoxic proteins into the B-cells.1-3

New data on mosunetuzumab were presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in Dec. 2022 leading to US FDA Approval.1,10

About the GO29781 Clinical Trial

The GO29781 clinical trial [NCT02500407] is a Phase I/Ib, multi-center, open-label, dose-escalation study designed to evaluate the safety of Lunsumio and determine optimal dosing in people with relapsed or refractory B-cell NHL. The clinical trial has evaluated over 270 patients with refractory or resistant NHL, including patients who had relapsed following, or are resistant to CAR T-cell therapy.

Lunsumio Initial Summary Results

  • Lunsumio induces durable complete responses lasting at least 18 months in heavily pretreated patients with relapsed or refractory follicular lymphoma who have received two or more prior therapies, with a 60% complete response rate and a median progression-free survival of 18 months.1
  • Objective response rate of 37% in aggressive NHL including a 19% complete response rate with 71% of patients remaining in remission up to 16 months off initial treatment.
  • Objective response rate of 39% in CAR T cell therapy failures including a 22% complete response rate. In some patients molecular testing showed that the CAR T cells increased in number following treatment suggesting that Lunsumio may boost the effect of CAR treatment.
  • Notable side effects include cytokine release syndrome (CRS) in 29% and neurological adverse events occurred in 4% percent of patients. Only 3% required treatment of CRS with Actemra (tocilizumab).
  • Data from the phase Ib/II GO40516 study evaluating Lunsumio in combination with Polivy® (polatuzumab vedotin) showed promising efficacy and favorable safety in heavily pretreated patients with aggressive refractory NHL with an objective response rate of 65% and a CR rate of 48%.3

Lunsumio in the Elderly

Single-agent Lunsumio was effective and well tolerated as first-line treatment for elderly and unfit patients with diffuse large B-cell lymphoma, according to findings presented at the 2020 annual meeting of the American Society of Hematology.3

Researchers assessed Lunsumio among patients with untreated DLBCL or high-grade B-cell lymphomas who were not eligible to receive standard chemo-immunotherapy because they were at least 80 years old or had a comorbidity that made them unable to tolerate a full dose of chemo-immunotherapy.

Overall almost two-thirds of patients responded to treatment and about 45% of patients achieved a complete response after four cycles of therapy and all have maintained their response through the end of eight cycles.

Treatment-related side effects were minimal and were mostly related to cytokine release syndrome and infusion reactions, with rare fatigue and gastrointestinal adverse events. No fatal side effects were reported. In total, 7% of patients developed neutropenia and 7% of patients experienced infections. Six patients experienced cytokine release syndrome, all which resolved within 1-2 days.

Lunsumio is available in ongoing clinical trials and received approval by the FDA in December 2022.. Patients with resistant or refractory NHL may want to follow its development as it appears to represent a significant treatment advance.

Odronextamab

Findings for 136 patients with previously treated NHL were presented the December 2020 American Society of Hematology Annual Meeting. All patients had received at least one prior line of therapy and 80% were refractory to their most recent therapy.

All follicular lymphoma patients had some response to treatment and objective responses were reported in six of 11 patients with DLBCL and no prior CAR T-cell therapy and eight of 24 patients with prior CAR T-cell therapy. For individuals achieving a complete response, responses were durable and persisted for as long as 21 months at the time of the report.

Cytokine release syndrome (CRS) occurred in 64% of patients and reached a “severe” level in 7.5% of patients.

In November Regeneron paused new enrollment of patients with B-cell non-Hodgkin lymphomas in compliance with a U.S. Food and Drug Administration (FDA) partial clinical hold. The FDA requested that the company amend the trial protocols in order to further reduce the incidence of ≥Grade 3 CRS during step-up dosing.4

References:

  1. Budde LE, et al. Mosunetuzumab Monotherapy is an Effective and Well-Tolerated Treatment Option for Patients with Relapsed/ Refractory (R/R) Follicular Lymphoma (FL) who have Received ≥2 Prior Lines of Therapy: Pivotal Results from a Phase I/II Study. Presented at: ASH Annual Meeting and Exposition; 2021 Dec 11-14. Abstract #127.
  2. Morschhauser F, et al. Mosunetuzumab in Combination With Lenalidomide has a Manageable Safety Profile and Encouraging Activity in Patients With Relapsed/Refractory Follicular Lymphoma: Initial Results From a Phase Ib Study. Presented at: ASH Annual Meeting and Exposition; 2021 Dec 11-14. Abstract #129.
  3. Budde LE, et al. Mosunetuzumab Plus Polatuzumab Vedotin has Promising Efficacy and a Favorable Safety Profile in Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma: Updated Results from a Phase Ib/II Study. Presented at: ASH Annual Meeting and Exposition; 2021 Dec 11-14. Abstract #533. [8] Trudel S, et al. Cevostamab monotherapy continues to show clinically meaningful activity and manageable safety in patients with heavily pre-treated relapsed/refractory multiple myeloma (RRMM): updated results from an ongoing Phase I study. Presented at: ASH Annual Meeting and Exposition; 2021 Dec 11-14. Abstract #157.
  4. Bannerji R, et al “Odronextamab (REGN1979), a Human CD20 x CD3 Bispecific Antibody, Induces Durable, Complete Responses in Patients with Highly Refractory B-Cell Non-Hodgkin Lymphoma, Including Patients Refractory to CAR T Therapy” ASH 2020; Abstract 400.
  5. Hutchings M, et al “Subcutaneous epcoritamab induces complete responses with a favorable safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: Updated dose-escalation data” ASH 2020; Abstract 402.
  6. Engelbert et al. “DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing.” EBioMedicine. 2020 Feb;52: 102625. doi: 10.1016/j.ebiom.2019.102625. Epub 2020 Jan 23. PMID: 31981978; PMCID: PMC6992935.

  7. Genmab announces US Food and Drug Administration granted orphan drug designation to epcoritamab (DuoBody®-CD3xCD20) in follicular lymphoma. News release. Genmab A/S; March 8, 2022. Accessed March 8, 2022. https://bit.ly/3Ku3O7u

  8. Hutchings M, Mous R, Clausen MR, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021;398(10306):1157-1169. doi:10.1016/S0140-6736(21)00889-8

  9. Abrisqueta P, Falchi L, Phillips TJ, et al. Subcutaneous epcoritamab + R-DHAX/C in patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) eligible for autologous stem cell transplant (ASCT): Preliminary phase 1/2 results. Presented at: ASCO Annual Meeting; June 3-7, 2022. Chicago, IL, and virtual. Abstract 7528.

  10. FDA approves Genentech’s Lunsumio, a first-in-class bispecific antibody, to treat people with relapsed or refractory follicular lymphoma. News release. Genentech. December 22, 2022. Accessed December 22, 2022. https://bit.ly/3hHrIUh

  11. Hutchings M, et al. Relapse Is Uncommon in Patients with Large B-Cell Lymphoma Who Are in Complete Remission at the End of Fixed-Course Glofitamab Treatment. Presented at: ASH Annual Meeting and Exposition; 2022 Dec 10-13. Abstract #441.

  12. Dickinson MJ et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. The New England Journal of Medicine. 2022. doi: 10.1056/NEJMoa2206913

  13. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. FDA. May 19, 2023. Accessed May 19, 2023.https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b-cell

  14. EPKINLY™ (epcoritamab-bysp) approved by US FDA as the first and only bispecific antibody to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). News release. AbbVie. May 19, 2023. Accessed May 19, 2023. https://news.abbvie.com/article_display.cfm?article_id=12584

  15. Genmab and AbbVie announce positive topline results from phase 1/2 EPCORE NHL-1 trial evaluating epcoritamab (DuoBody CD3xCD20) in patients with relapsed/refractory follicular lymphoma (FL). News release. Genmab A/S. June 28, 2023. Accessed June 28, 2023. https://ir.genmab.com/news-releases/news-release-details/genmab-and-abbvie-announce-positive-topline-results-phase-12

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