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by Dr. C.H. Weaver M.D. 8/2022

Bispecific antibodies represent an innovative immunotherapy approach that helps the body’s immune system target lymphoma cells and appears 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)

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. Despite recent advances in the treatment of NHL some patients still succumb to NHL and new treatments are needed. Epcoritimab recently received FDA Fast Track Designation for development.7,8

CancerConnect Lymphoma 490

Mosunetuzumab

Mosunetuzumab is an investigational 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 63rd American Society of Hematology (ASH) Annual Meeting and Exposition in Dec. 2021.1

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 mosunetuzumab 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.

Mosunetuzumab Initial Summary Results

  • Mosunetuzumab 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 mosunetuzumab 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 mosunetuzumab 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

Mosunetuzumab in the Elderly

Single-agent mosunetuzumab 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 mosunetuzumab 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.

Mosunetuzumab is currently only available in ongoing clinical trials and must still undergo approval by the FDA. 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.

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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

Lymphoma Newsletter 490

Epcoritamab

Epcoritamab is an investigational IgG1-bispecific antibody designed to direct cytotoxic T cells selectively to the lymphoma to elicit an immune response toward the malignant cells. Epcoritamab 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 first cohort of the EPCORE™ NHL-1 phase 1/2 clinical trial evaluating epcoritamab 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 shared at the 2022 American Society of Clinical Oncology Annual Meeting. 

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

The most common reported side effects were fever and injection site reactions. Cytokine release syndrome was common but mild without severe toxicity.7,8

Subcutaneous administration distinguishes epcoritamab 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.

Findings from a phase I/II trial involving adults with relapsed/refractory CD20-positive B-cell NHL and prior treatment with an anti-CD20 antibody were reported at ASH 2020. Investigators enrolled a total of 68 patients, including 48 with DLBCL and 12 with FL. Almost all the patients had received anthracyclines and alkylating agents, about 10% had undergone autologous stem-cell transplants, and 10% had received prior CAR T-cell therapy.

The investigators evaluated epcoritamab at varying doses and 15 of 22 (68%) of evaluable patients with DLBCL responded to the bispecific antibody, including CRs in 10 patients.

In Follicular lymphoma nine of 10 evaluable patients responded, including five CRs and two of four patients with mantle cell lymphoma responded to epcoritamab.

Subcutaneous Epcoritamab Plus Salvage Chemotherapy for Relapsed/Refractory DLBCL

Subcutaneous epcoritamab combined with salvage chemtherapy with rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C) demonstrated manageable safety in patients with relapsed/refractory diffuse large B-cell lymphoma (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 from arm 4 of the EPCORE NHL-2 phase 1/2 trial exploring epcoritamab plus R-DHAX/C in adult patients with relapsed/refractory CD20-positive DLBCL who were eligible for high-dose therapy and ASCT 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 epcoritamab monotherapy. Of these patients, 5 (42%) had complete metabolic response and 3 (25%) had partial metabolic response.9

A Phase 3 study of epcoritamab in diffuse large B-cell lymphoma (DLBCL) is ongoing to evaluate subcutaneous epcoritamab, a fully-human IgG1-bispecific antibody designed to recognize and bind to both CD3 and CD20, versus investigators’ choice of chemotherapy regimen (either bendamustine and rituximab or gemcitabine, oxaliplatin, and rituximab) in patients with relapsed or refractory DLBCL. Epcoritamab is being co-developed by Genmab and AbbVie.5

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.