In relapsed or refractory B-cell lymphomas, bispecific T-cell engager antibodies are finding a place in the treatment algorithm, said Christopher Flowers, MD, MS, FASCO, Professor and Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, Houston.
At the 2021 Pan Pacific Lymphoma Conference, Dr. Flowers described the bispecific antibodies targeting CD20, a relevant target in B-cell lymphoma.1 As single agents, CD3/CD20 bispecific antibodies can produce complete responses in patients with relapsed or refractory lymphoma, including those with disease progression after CAR T-cell therapy and stem cell transplant and those with poor-risk indolent non-Hodgkin lymphoma. Some patients have been shown to maintain remission after they complete treatment.
Mechanisms of Action
In general, bispecific antibodies can exert efficacy via three different mechanisms of action: (1) by engaging the tumor cells and the immune cells (T cells or natural killer cells); (2) by binding to both payload and tumor cells and offering targeted delivery of the payload; and (3) by using both arms of the compound to block key signaling areas of the tumor. Most of the bispecific antibodies that have been explored in clinical trials employ the first mechanism.
One bispecific antibody, blinatumomab, has been approved, and there are 23 others in clinical trials in hematologic cancers and 34 in solid tumor trials. For both types of malignancies, these constructs workpredominantly by engaging immune cells.
“It appears that by using subcutaneous dosing [of epcoritamab], you can get a more gradual increase in … peak plasma cytokine level as well as a longer plasma half-life.”— Christopher Flowers, MD, MS, FASCO
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Dr. Flowers described five CD3/CD20 bispecific antibodies in phase I trials for B-cell non-Hodgkin lymphoma. These drugs bind to malignant B cells (CD20) as well as to T cells (CD3): mosunetuzumab, glofitamab, plamotamab, odronextamab, and epcoritamab. As with CAR T cells, bispecific antibodies also pose a risk for cytokine-release syndrome, but attempts are being made to mitigate this through step-up dosing, subcutaneous delivery, and pretreatment with obinutuzumab. This toxicity is almost always mild and occurs primarily during the first treatment cycle. “The important question is how these bispecific antibodies compare with CAR T-cell therapy,” Dr. Flowers said. “Ultimately, if bispecific antibodies move into the marketplace, we will need to know the best way to select between these approaches in terms of benefits, duration of effects, and also risk for cytokine-release syndrome.”
Response rates with these agents range from 40% to 70% in diffuse large B-cell lymphoma (DLBCL) cohorts and from 70% to 90% in follicular lymphoma. Dr. Flowers commented that “currently, these drugs look more similar than they do different … with meaningful complete responses seen across all agents in this class.” He also noted there may be variations in the study populations, which could lead to slight differences in the outcomes observed, but perhaps there are also differences in the drugs themselves. They also are similar in terms of safety: the most common adverse event is cytokine-release syndrome, which occurs in about 50% to 60% of patients, is almost always grade 1 or 2, and is generally limited to cycle 1 of treatment.
He broadly compared these outcomes for CD20/CD3 bispecific antibodies. For DLBCL, objective response rates have ranged from 50% to 73% and complete response rates, from 32% to 54%; cytokine-release syndrome has been observed in 46% to 94% and has been grade ≥ 3 in 13% to 23%.
In the clinical trials arena, the preference for choosing a bispecific antibody over CAR T-cell therapy may be driven by the nature of the lymphoma. A more aggressive disease such as DLBCL may warrant one approach, whereas the indolent nature of other subtypes, such as follicular lymphoma, may pose “a different trade-off,” he said.
Mosunetuzumab
Mosunetuzumab is afull-length humanized IgG1 antibody that brings the T cell into close proximity to the target tumor cells. This leads to T-cell activation, formation of immune synapses, and killing of the tumor cell through T-cell engagement and B-cell elimination. In a large phase I dose-escalation trial, whose results were presented at the 2019 American Society of Hematology (ASH) Plenary Session, mosunetuzumab elicited promising responses in relapsed patients, including a subset previously treated with CAR T-cell therapy.2
The population included 270 patients, 117 with DLBCL. In the DLBCL cohort, the median number of prior treatment lines was five, including prior CAR T-cell therapy in 30 patients; 22 patients were refractory to prior CAR T-cell therapies.
“Of interest, and why this study was presented at an ASH Plenary Session, is that it reflects one of the first approaches for therapy in patients whose disease failed to respond to prior CAR T-cell therapy,” Dr. Flowers commented.
The drug was given intravenously on days 1, 8, and 15 of cycle 1, then on day 1 of each 21-day cycle thereafter. Patients received 8 cycles, then discontinued treatment upon a complete response; with partial response or stable disease, patients continued treatment for a total of 17 cycles.
The objective response rate was 37%, with complete responses observed in 19% of patients. In the aggressive types of lymphoma—DLBCL and transformed follicular lymphoma—these rates were “impressive for a single-agent bispecific antibody” at 38% and 20%, respectively, he noted.
Many responses were durable. Among patients with aggressive disease, 71% of complete responders remained in remission up to 16 months off treatment, whereas 83% of complete responders in the indolent disease cohort remained progression-free up to 26 months, he reported.
Among patients with prior CAR T-cell therapy, a 40% response rate was observed, with 22% being complete responses. For patients with DLBCL who had received prior CAR T-cell therapy, 39% of these patients responded and 22% had complete responses. A description for one responder revealed a rise in copy number of persistent CAR T cells.
A phase II trial of relapsed or refractory follicular lymphoma is evaluating a subcutaneous formulation of mosunetuzumab, and a phase III trial will study mosunetuzumab plus lenalidomide vs lenalidomide plus rituximab as a chemotherapy-free regimen. Another phase III study is enrolling patients with untreated DLBCL, giving mosunetuzumab upfront in combination with CHP (cyclophosphamide, doxorubicin, prednisone) and polatuzumab vedotin-piiq, vs rituximab, CHP, and polatuzumab.
Glofitamab
Glofitamab has a unique 2:1 molecular configuration that allows two binding sites to CD20 (B cells) and a single binding site for CD3 (T cells). Under experimental conditions, this design is associated with higher potency than the 1:1 binding bispecific antibodies and allows for concomitant treatment with anti-CD20 antibodies.
An ongoing phase I dose-escalation study in patients with relapsed or refractory non-Hodgkin lymphoma is investigating the use of obinutuzumab at 1,000 mg given 7 days prior to cycle 1, day 1 of glofitamab, to debulk B cells and mitigate cytokine-release syndrome.3,4 Patients then receive escalating doses of glofitamab in either a fixed-dose schema (10, 16, and 26 mg) or a step-up dosing schema (2.5, 10, and 16 mg or 2.5, 10, and 30 mg).
“With glofitamab step-up dosing, antitumor activity was seen across non-Hodgkin lymphoma subtypes, including patients with both aggressive and indolent non-Hodgkin lymphomas,” Dr. Flowers reported. In aggressive subtypes, the objective response rate to step-up dosing was 61%, with 54% of patients achieving complete responses. In indolent subtypes, these rates were 67% and 54%, respectively.
Response rates were even higher in patients receiving 10 mg or higher doses. In these patients, the projected median progression-free survival was 3 months and 14.5 months, respectively, and although follow-up is short, the curves are plateauing, as many responses are being maintained with patients remaining on treatment. The median duration of response was not reached for either cohort, he said.
Plamotamab
Plamotamab involves an approach similar to that with glofitamab, displaying a “tunable” binding affinity that allows for optimization of potency and safety. In a study of 45 patients with non-Hodgkin lymphoma and 8 patients with chronic lymphocytic leukemia who underwent weekly dosing, encouraging dose-dependent clinical activity was seen in the initial cohorts of 18 patients with DLBCL treated with at least 80 μg/kg.5 In this subtype, objective responses were achieved by 39% of patients and complete responses, by 28%, with rates rising to 50% and 25%, respectively, at the highest dose of 170 μg/kg.
Odronextamab
Odronextamab is a bispecific IgG4 antibody modified to reduce Fc binding. In a phase I dose-escalation trial of 96 patients who were heavily pretreated (mostly with aggressive subtypes), including 12 patients with prior CAR T-cell therapy, response rates were dose-related, as seen with other agents.6
In the DLBCL cohort, responses were seen in 54% among patients receiving 18 to 40 mg, with complete responses achieved by 18%. Patients without prior CAR T-cell therapy who received at least 80 mg had a response rate of 71%, all complete responses; among patients who had received prior CAR T cells, 50% of patients with DLBCL responded, and 25% of them had complete responses. Response rates were higher in patients with indolent types of lymphoma.
Epcoritamab
The relatively unique feature of epcoritamab is its 1-mL subcutaneous administration. “It appears that by using subcutaneous dosing, you can get a more gradual increase in, and perhaps a lower, peak plasma cytokine level as well as a longer plasma half-life. The hope is that this will reduce toxicity, especially cytokine-release syndrome,” Dr. Flowers said.
In a study of 69 patients, 11 with follicular lymphoma received doses less than 1 mg to 48 mg, and 90% achieved responses, 50% of which were complete responses.7 Responses were present in patients remaining on treatment and in remission beyond 12 months, “suggesting that with ongoing treatment, responses can be quite durable,” he said.
A subcutaneous dosing approach is now being evaluated for mosunetuzumab as well. Compared with intravenous administration, side effects of subcutaneous delivery are similar, including cytokine-release syndrome, which is mostly mild.8
Safety of CD3/CD20 Bispecific Antibodies
The safety profiles of these five bispecific antibodies have not differed appreciably in clinical trials. Adverse events of grade ≥ 3 have been seen in 39% to 63% of patients. Neutropenia and fever are common but reported to be manageable. Anemia, hypophosphatemia, and lymphopenia are also observed across trials. Cytokine-release syndrome develops in about half the patients but is almost invariably mild and limited to the first cycle of treatment; there is some evidence that higher doses may pose a greater risk for this toxicity. Neurologic toxicities also occur but are transient. Injection-site reactions have also been -observed.
Dr. Flowers emphasized that although his talk focused on CD3/CD20 antibodies, there are “a host” of other constructs and targets for bispecific agents, both for solid and blood cancers. The future for the development of bispecific antibodies is bright. This new class of agents is likely to bring new therapies and many additional clinical trials to patients with lymphomas and other cancers in the near term.
DISCLOSURE: Dr. Flowers has served as a consultant or advisor to AbbVie, AstraZeneca, Bayer, BeiGene, Celgene/Bristol Myers Squibb, Denovo Biopharma, Genentech/Roche, Gilead, OptumRx, Karyopharm, Pharmacyclics/Janssen, and Spectrum; and has received research funding from AbbVie, Acerta, BeiGene, Celgene/Bristol Myers Squibb, Gilead, Genentech/Roche, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, and the V Foundation.
REFERENCES
1. Flowers C: What’s next for bispecific T-cell engager antibodies in lymphoid malignancies. 2021 Pan Pacific Lymphoma Conference. Presented August 10, 2021.
2. Schuster SJ, Bartlett NL, Assouline S, et al: Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell therapies, and is active in treatment through multiple lines. Blood 134(suppl 1):6, 2019.
3. Patel K, Michot JM, Chanan-Khan AA, et al: Preliminary safety and anti-tumor activity of XmAb13676, an anti-CD20 x anti-CD3 bispecific antibody, in patients with relapsed/refractory non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Blood 134(suppl 1):4079, 2019.
4. Hutchings M, Morschhauser F, Iacoboni G, et al: Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: A phase I trial. J Clin Oncol 39:1959-1970, 2021.
5. Patel K, Michot J, Chanan-Khan A, et al: Preliminary safety and anti-tumor activity of XmAb13676, an anti-CD20 x anti-CD3 bispecific antibody, in patients with relapsed/refractory non-hodgkin’s lymphoma and chronic lymphocytic leukemia. 2019 ASH Annual Meeting & Exposition. Abstract 4079.
6. Bannerji R, Allan JN, Arnason JE, et al: Clinical activity of REGN1979, a bispecific human, anti-CD20 x anti-CD3 antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Blood 134(suppl 1):762, 2019.
7. Hutchings M, Mous R, Clausen MR, et al: Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: Updated dose escalation data. Blood 136(suppl 1):45-46, 2020.
8. Matasar MJ, Cheah CY, Yoon DH, et al: Subcutaneous mosunetuzumab in relapsed or refractory B-cell lymphoma: Promising safety and encouraging efficacy in dose escalation cohorts. Blood 136(suppl 1):45-46, 2020.
