By Chase Doyle
Although CAR-T cell therapies have shown promising results in relapsed/refractory non-Hodgkin lymphoma (NHL), widespread applicability is limited due to manufacturing time and toxicities. Bispecific antibodies and antibody-drug conjugates (ADCs) offer convenient, off-the-shelf availability with high response rates and low toxicity.
During the ASCO20 Virtual Education Program, Nilanjan Ghosh, MD, PhD, a hematologist-oncologist at the Levine Cancer Institute, in North Carolina, presented the latest clinical data for these highly targeted antibodies.1
As Dr. Ghosh explained, bispecific antibodies can simultaneously bind to two separate and unique antigens (or different epitopes of the same antigen). Bispecific antibodies with CD20 and CD3 specificity, for example, bind to targets on B cells and T cells, respectively. This leads to immune synapse formation, followed by T cell activation and elimination of malignant B cells.
CD20/CD3 bispecific antibodies in development for B cell NHL have either a one-to-one format (one CD20-binding site and one CD3-binding site) or two-to-one configuration (two CD20-binding sites and one CD3-binding site). The majority of these antibodies are administered intravenously.
Odronextamab, mosuntuzumab, plamotamab, and epcoritamab are one-to-one configuration antibodies that have been tested in early-phase studies of follicular lymphoma, diffuse large B cell lymphoma (DLBCL), and B cell NHL.
Due to significant differences in dosing intensity as well as patient and disease characteristics, comparisons should not be made between agents, said Dr. Ghosh. However, these data provide an early glimpse into the efficacy of this technology.
According to Dr. Ghosh, overall responses and complete responses are slightly higher in B cell NHL and follicular lymphoma compared to relapsed/refractory DLBCL. Importantly, these agents have also shown activity in patients who have failed CAR-T cell therapy.
“Patients who fail CAR-T therapies often have very poor prognosis, and this is an area of unmet need,” said Dr. Ghosh. “We can see that bispecific antibodies have complete responses even in this subgroup of patients.”
Although cytokine release syndrome is a common side effect of these agents, said Dr. Ghosh, it is primarily low grade, and the safety profile is generally manageable.
In the case of glofitamab
Glofitamab is a bispecific antibody with a two-to-one configuration, which has been shown to be more beneficial in experimental conditions. According to Dr. Ghosh, this configuration also enables concomitant treatment with CD20-directed antibodies, such as rituximab or obinutuzumab.
A recent study of single-agent glofitamab in B cell NHL showed very good overall response rates across all histologies. Dr. Ghosh noted that approximately half of patients with aggressive disease responded and over a third of patients had a complete response.2 Moreover, in patients with indolent NHL, two thirds of patients responded, and half of patients had a complete response.
“These are very encouraging data with a single agent in relapsed/refractory disease,” said Dr. Ghosh.
For patients who obtained a complete response, the duration of response was also durable. With a median follow-up of 10.2 months, the median duration of response has not been reached for either aggressive B cell lymphoma or indolent NHL.
With respect to adverse events, cytokine release syndrome occurred in over 50% of patients but was primarily low grade. Only 3.2% of patients experienced grade 3 or higher cytokine release syndrome. Neurological events occurred in approximately 30% of patients but were also generally mild.
Future studies exploring combinations of bispecific antibodies with chemotherapy and antibody-drug conjugates are ongoing.
Antibody-Drug Conjugates (ADCs)
As Dr. Ghosh explained, ADCs are a new class of biological drugs built by attaching a small molecule anticancer drug or another therapeutic agent to an antibody, with either a permanent or a labile linker. The antibody targets a specific antigen only found on target cells.
There are currently two ADCs in relapsed/refractory NHL: brentuximab vedotin and polatuzumab vedotin.
Brentuximab vedotin is a CD30 ADC and is approved in combination with CHP chemotherapy (cyclophosphamide, doxorubicin, prednisone) in previously untreated CD30-positive T cell lymphomas and in relapsed/refractory anaplastic large cell lymphoma and mycosis fungoides.
Approval was based on ECHELON-2, a multicenter, phase 3, randomized, double-blind and double-dummy trial, comparing brentuximab-CHP to a standard chemotherapy arm of CHOP chemotherapy in newly diagnosed CD30-positive T cell lymphomas.3
The most common histology included in the study was anaplastic large cell lymphoma, followed by peripheral T cell lymphoma not otherwise specified and angioimmunoblastic T cell lymphoma.
The median progression-free survival (PFS) of patients randomized to brentuximab-CHP was 48.2 months versus 20.8 months with CHOP chemotherapy. Although median overall survival (OS) has not been reached in either arm, OS was also improved with brentuximab-CHP compared to CHOP (HR = 0.66).
Adverse were also comparable between study arms. Dr. Ghosh noted that more than 50% of patients experienced peripheral neuropathy with both treatment regimens.
A separate study of single-agent brentuximab in relapsed/refractory anaplastic large cell lymphoma showed “excellent activity,” said Dr. Ghosh, with an overall response rate of 86% and a complete response rate of 57%. The median PFS is 13.3 months in this disease.4
Polatuzumab vedotin is a CD75b ADC and is approved in combination with bendamustine and rituximab to treat patients with relapsed/refractory DLBCL who have received at least two prior therapies. Polatuzumab vedotin combined with bendamustine and rituximab was compared with bendamustine and rituximab in a randomly assigned cohort of patients with transplantation-ineligible, relapsed/refractory DLBCL.5
The overall response rate with the polatuzumab combination was 45%, with a complete response rate of 40%. The median PFS was 9.5 months with the ADC combination compared to 3.7 months for bendamustine and rituximab alone. The main toxicity with polatuzumab was also a neuropathy.
“Based on these results, ADCs offer improved target specificity and potency with low toxicity,” said Dr. Ghosh. ADCs are now being combined with bispecific antibodies in several ongoing phase 2 studies.
- Ghosh, N. Antibody-Drug Conjugate Therapies and BiTEs: Here to Stay in Lymphomas? Presented at: 2020 ASCO Virtual Education Program; August 8, 2020.
- Dickinson MJ, Morschhauser F, Iacoboni G, et al. CD20-TCB in relapsed or refractory non-Hodgkin lymphoma: Durable complete responses and manageable safety observed at clinically relevant doses in phase I dose escalation. Presented at: EHA25 on June 12, 2020. Abstract S241.
- Horwitz S, O’Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2019 Jan 19;393(10168):228]. Lancet. 2019;393(10168):229-240.
- Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190-2196.
- Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020;38(2):155-165.