Bispecific antibodies bind to two antigens or two parts of the same antigen at the same time. The U.S. Food and Drug Administration (FDA) recently approved two CD20xCD3 bispecific antibodies —mosunetuzumab (mosun) for patients with relapsed or refractory follicular lymphoma and glofitamab (glofit) for patients with relapsed or refractory diffuse B cell lymphoma (DLBCL) or large B cell lymphoma (LBCL) treated with two or more prior lines of therapy. (1)
In recent studies, these drugs demonstrated high response rates with a manageable safety profile in previously untreated patients. Memorial Sloan Kettering Cancer Center (MSK) hematologist-oncologist Lorenzo Falchi, MD, presented the latest results of two phase 2 trials at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, held in San Diego, December 9 to 12, 2023.
MSK is the largest of only a few centers investigating bispecific antibodies as promising treatments for patients with lymphoma. “These drugs represent the next milestone in lymphoma therapy as they are achieving high response rates with manageable safety profiles and may improve results in treatment-naive patients,” said Dr. Falchi. “The novel step-up dosing protocols allow us to mitigate cytokine release syndrome (CRS) and treat it as soon as it emerges.”
High Response Rates for Mosunetuzumab in Patients with Follicular Lymphoma
The current standard of care for patients with newly diagnosed, high-burden follicular lymphoma is chemotherapy plus anti-CD20 antibodies. While effective, this approach is associated with toxicities, including infections, and second cancers, and up to 20% of patients progress within two years and experience poor outcomes.
In December 2022, the FDA approved intravenous (IV) mosunetuzumab for treating patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy based on remarkable efficacy and manageable safety data in the phase 2 trial (NCT02500407). Specifically, the objective response rate was 80%, with 60% of patients achieving a complete response. The estimated duration of response was 23 months, and the estimated response rates at 12 months and 18 months were 62% and 57%, respectively. (2)
The FDA approval included a boxed warning for serious or life-threatening CRS.2 In the trial, CRS occurred in 39% of 218 patients with various hematologic malignancies who received mosunetuzumab at the recommended phase 2 dose, and most CRS cases were grade 1 or 2. (3)
Notably, the more convenient subcutaneous format of mosunetuzumab proved as effective as the IV format and was possibly better tolerated, implying the drug may be an excellent treatment option for chemotherapy-naive patients. (2)
Today, Dr. Falchi and colleagues at MSK, the Hackensack Meridian School of Medicine, and the Lombardi Comprehensive Cancer Center are conducting an investigator-initiated phase 2 trial (NCT05389293) of subcutaneous mosunetuzumab in adult patients with untreated, high-burden follicular lymphoma. The trial protocol uses a step-up dose approach where patients receive 5 mg of mosun on day 1 and 45 mg on day 8 and day 15 of cycle 1, followed by 45 mg on day 1 of each subsequent 21-day cycle. In addition, patients are premedicated with dexamethasone, diphenhydramine, and acetaminophen during cycle 1, when the risk of CRS is highest. Notably, no hospitalization is required for premedication.
Preliminary results for the first 45 evaluable patients were highly encouraging, with an overall response rate (ORR) of 96%, and CR rate of 76%. The investigators observed similarly high response rates in high-risk subgroups, including patients with grade 3A disease (ORR 91%, CR 73%), bulky disease greater than 7 cm (ORR 100%, CR 80%), and those with a standardized uptake value max of 13 or higher (ORR 92%, CR 67%). At a median follow-up of six months, only three patients experienced progression. Most CRS events were predictable, mild, and managed in the outpatient setting. (4)
“We have been waiting for drugs that can compete with traditional chemotherapy for treatment-naive patients with follicular lymphoma, and I’m excited to see bispecific antibodies being developed in this space,” said Dr. Falchi.
The trial (NCT02500407), which is sponsored by Genentech, continues to recruit participants at all three centers, seeking to enroll an estimated 76 patients.
High Response Rates for Glofitamab in Combination with R-CHOP in Patients with Large B Cell Lymphoma
Up to one-third of newly diagnosed patients with LBCL who are treated with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) do not achieve long-term remission or cure. Circulating tumor DNA (ctDNA) is a promising sensitive biomarker for identifying optimal responses to R-CHOP in newly diagnosed patients. A reduction in ctDNA levels after one to two therapy cycles is associated with improved survival. (5)
Glofitamab has a novel 2:1 design that enables high-avidity bivalent binding to CD20 on B cells. Glofitamab is currently approved by the FDA (6) and the European Medicines Agency7 as monotherapy for relapsed or refractory DLBCL or LBCL arising from follicular lymphoma after two or more prior lines of therapy based on results from the phase 1/2 NP30179 trial (NCT03075696), which is still in progress. In particular, the ORR was 56%, with 43% of patients achieving complete responses. The estimated median duration of response was 18.4 months, with an estimated response rate of 68% of patients at 9 months. The median time to response was 42 days. (6)
Further, glofitamab plus R-CHOP showed favorable safety and efficacy in the first line setting in phase 1b results reported at ASH 2022. (8)
As with mosunetuzumab, the FDA approval of glofitamab included a boxed warning for serious or fatal CRS, given that CRS occurred in 70% of 145 patients evaluated for safety, including grades 3 or higher events in 4.1%, immune effector cell-associated neurotoxicity syndrome (ICANS) in 4.8%, serious infections in 16%, and tumor flare in 12% of patients. (6)
Now, Dr. Falchi and colleagues from multiple institutions worldwide are conducting a phase 2 study (NCT04980222) of IV glofitamab combined with R-CHOP as a first-line treatment in adults with ctDNA-high-risk DLBCL. All patients receive baseline ctDNA testing and are tested again after the first R-CHOP treatment. Patients who do not show a sufficient drop in ctDNA receive glofitamab in addition to R-CHOP. During cycle 3 glofitamab is given with step-up dosing: 2.5 mg on day 8, 10 mg on day 15, then at the dose of 30 mg every three weeks, on day 8 of cycles 4 to 6 and on day 1 of cycles 7 to 10.
Dr. Falchi presented interim study results at ASH 2023. Among 144 patients screened with ctDNA, 29 or 20% had high-risk disease. The interim ORR after cycle 2 and end-of-treatment ORR were the same at 95%. The interim CR was 60%, and the end of treatment CR was 85%. Among the 29 high-risk patients who received one or more doses of glofitamab, 22 (76%) experienced glofitamab-related adverse events, including 9 (31%) who experienced grade 3 or grade 4 events. CRS occurred in only six patients (21%), including five grade 1 and one grade 2 events. All CRS events occurred early and resolved with management. No glofit-related ICANS events were reported.9
“Since glofitamab is only active when cancer cells are present, the combination with R-CHOP minimized the risk of CRS and allowed us to give treatment-naive DLBCL patients everything they need and nothing they don’t,” said Dr. Falchi.
The trial is sponsored by Hoffman-La Roche.
Advancing the Promise of Bispecific Antibodies at MSK
The review article “Bispecific antibodies for the treatment of B cell lymphoma: promises, unknowns, and opportunities” by MSK lymphoma specialists Dr. Falchi, Santosha Vardhana, MD, PhD, and Gilles Salles, MD, PhD, published recently in Blood, provides an in depth overview of the comparative characteristics of CD20xCD2 bispecific antibodies currently in development, and offers greater context for current clinical research results. (10)
Check out MSK clinical trials testing bispecific antibodies and MSK clinical trials for LBCL and DLBCL.
Consensus Recommendations: Managing Distinct Toxicities Associated with CD3xCD20 Bispecific Antibody Therapy
In clinical trials to date, the guidance for anticipating, mitigating, and managing adverse events such as CRS have been based on guidance for toxicities associated with chimeric antigen T cell (CAR T) cell therapy. However, there are notable differences in the timing, quality, and severity of toxicities between these two therapies. For example, CRS is often milder with bispecific antibody treatment, but may still be life-threatening.
Dr. Falchi is a member of an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3xCD20 bispecific antibodies in clinical trials and other settings. The panel recently developed consensus recommendations on managing specific toxicities associated with CD3xCD20 bispecific antibody therapies. Their paper, published in Blood, outlines recommendations for anticipating and managing CRS, neurological toxicity, and other toxicities experienced by this patient population.
The panel and Dr. Falchi, corresponding author on the paper, plan to update the recommendations as additional information or agents become available.
Access disclosures for Dr. Falchi.
Originally published in 2023, this article has been updated to include the consensus recommendations for managing toxicities associated with CD3xCD20 bispecific antibodies.