Bispecific Antibodies: How They Work and When to Use Them

Ashley Ames

Hi, Diane. It's so nice to be back talking with you. One of the most exciting things in oncology is the development of novel agents that advance our ability to treat patients with relapsed/refractory disease. One of the newer drug classes that we've been using in relapsed/refractory DLBCL is a group called bispecific antibodies. Are you very familiar with bispecific antibodies and how they work? 

Diane Lee

Yes, I am. Bispecific antibodies are a novel class of immunotherapy that have two distinct binding domains that can be thought of as the next generation of monoclonal antibodies. So, with respect to DLBCL, these agents work by binding onto the CD3 receptor on the T cell and the CD20 receptor on B cells, and then redirects and activates the T cell to kill the CD20-expressing malignant lymphoma cells. 

Ashley Ames

The EPCORE NHL trial evaluated the use of epcoritamab, a subcutaneously administered bispecific antibody targeting CD3 and CD20. The clinical trial was a phase I/II study that evaluated subcutaneous epcoritamab and those with CD20-positive relapsed/refractory large B-cell lymphoma. Epcoritamab targets CD3 and CD20 and induces cell-mediated cytotoxic activity against the CD20-positive malignant B cells.¹ Similar to CAR T-cell therapy, there's a risk of cytokine release syndrome, or CRS, with epcoritamab. 

For cycle one, epcoritamab was administered with a step-up dosing approach. Patients on the EPCORE NHL trial received dosing that consisted of a 0.16-mg priming dose on cycle one, day 1, followed by a 0.8-mg intermediate dose on cycle one, day 8. Subsequently, on cycle one, day 15 and on, patients received 48-mg dosing. For the initial cycle one, day 15, 48-mg dosing, patients were admitted to the hospital for close monitoring of CRS. Patients continued to receive the 48-mg dosing once every 2 weeks, cycles four through nine, and then once every 4 weeks from cycle 10 on.¹ 

Diane Lee

As of January 31, 2022, there were 157 patients treated and they had an average of three prior lines of therapy. And of those patients, almost 39% had prior treatment with CAR T. At a median follow-up of almost 10.5 months, the overall response rate was about 63% and the complete response rate was almost 39%. The median duration of response was 12 months.¹ 

As you mentioned about CRS, the most common treatment-emergent adverse event was CRS with grade 1/2 being the most common, followed by pyrexia, and then fatigue. Immune effector cell-associated neurotoxicity syndrome, or ICANS, occurred in about 6%, and there was one fatal event.¹

Ashley Ames

The clinical trial showed that single agent epcoritamab demonstrated a high overall response rate, as you stated, as well as deep and durable complete responses in a really challenging-to-treat highly refractory patient population. Epcoritamab was mostly well tolerated with few discontinuations because of adverse events. The CRS that occurred was manageable and predictable with timing, and as you mentioned, mostly grade 1 to 2.¹ 

As long-term treatment, epcoritamab is administered on a once-monthly basis and it's a subcutaneous injection. This makes it an attractive and convenient off-the-shelf alternative to other anti-lymphoma immunotherapies. The subcutaneous mode of administration also makes it an ideal agent, as it decreases chair time in chemotherapy infusion suites. 

Diane Lee

That's a lot of great information, Ashley. Another important factor to note is that treatment with epcoritamab is indefinite until progression of disease or unacceptable levels or toxicity. That being said, it's important to discuss treatment goals patients. There is another bispecific antibody that is time-limited. Glofitamab is a bispecific monoclonal antibody that, again, targets CD3 and CD20. This one is unique as it has a 2:1 tumor T-cell binding configuration that confers bivalency for CD20 B cells and valency for CD3 T cells, leading to the engagement and redirection of the patient's existing T cells to target and attack the malignant B cells. 

In clinical trials, glofitamab was administered to patients with relapsed/refractory DLBCL with two prior lines of therapy and they received pre-treatment with obinutuzumab. That was used to help mitigate CRS. It should be noted that glofitamab was administered as a monotherapy with a fixed duration of 12 cycles, or 1 year only.² 

On clinical trial, patients received obinutuzumab pre-treatment, and this had to be given within a 7-day period before starting. Similar to epcoritamab, glofitamab was administered by IV with a step-up dosing schedule. So, for cycle one, on day 1 they received obinutuzumab, on day 8 they received 2.5 mg, and on day 15 they received 10 mg. This was followed by a dose of 30 mg on day 1 of cycles two through 12, with each cycle lasting 21 days. On the study, patients were hospitalized for the first full dose of glofitamab, and the hospitalization requirements evolved during the study so that subsequent doses were administered in the outpatient setting unless a patient experienced CRS of grade 2 or higher after the first dose. Patients were treated for 12 cycles or until disease progression or unacceptable levels of toxicity.² 

Ashley Ames

Of the 155 patients who were enrolled, 154 patients received at least one dose of the study drug, either obinutuzumab or glofitamab. At a median follow-up of about 12.5 months, 39% of the patients had a complete response. Results were consistent among the 52 patients who previously received CAR T-cell therapy. The median time to a complete response was 42 days. Of the participants, 78% had ongoing responses at 12 months. The 12-month progression-free survival was 37%. Discontinuation of glofitamab due to adverse events was relatively uncommon and only occurred in 9% of patients. The most common adverse event was CRS. Most of the CRS was grade 1/2. Only 4% of patients experienced grade 3/4 CRS, and 3% of patients experienced neurologic toxicity.² 

Diane Lee

We can think of these bispecific antibodies almost as an off-the-shelf CAR T product. I think that brings up an important topic for our patients. Do we use CAR T-cell therapy or bispecifics if they're both available? 

Ashley Ames

I think that's a really good question and that's definitely something that we take into consideration when we collaborate with our attending physician colleagues. 

Unfortunately, we know with CAR T-cell therapy, there are sometimes barriers to care. These include barriers to access of CAR T-cell therapy. Oncology centers administering cellular therapy must have certain credentials. Patients receiving care in rural sites may not have easy access to those institutions that administer cellular therapy. 

Diane Lee

One of the other barriers to CAR T-cell therapy is that the production of the actual CAR T-cell product can take several weeks. As we use bridging therapy while we wait, many of these patients with DLBCL have aggressive disease and many are often, at this point, chemo-refractory. So, if there is a race to treat, bispecifics seem to be an appealing treatment option. 

Ashley Ames

This is a really exciting new class of medication and I'm excited for the benefits that this novel drug class can offer to our patients with relapsed/refractory disease.  

Diane Lee

I am too, Ashley. I look forward to seeing how we can improve patient treatments and outcomes with bispecifics.