Optimizing Bispecific Therapy Selection and Monitoring Across Oncology Practice Settings

In this interview with Pharmacy Times at Oncology Pharmacists Connect in Austin, TX, Brooke Peters, PharmD, BCOP, Clinical Pharmacist, American Oncology Network (AON), discusses the evolving landscape of bispecific therapies and the importance of understanding their distinct mechanisms of action. She explains how T-cell–engaging bispecific antibodies, non–T-cell–engaging bispecific antibodies, and T-cell receptor–based therapies each have unique toxicity profiles, monitoring requirements, and clinical considerations. Peters highlights the critical role of pharmacists in assessing risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), developing monitoring strategies, and supporting safe outpatient administration in community oncology settings.

Pharmacy Times: The title of your session emphasizes that not all bispecific antibodies are equal. What are some of the most important mechanistic differences among currently available bispecifics that oncology pharmacists should understand when selecting and managing these therapies?

Brooke Peters, PharmD, BCOP: When we hear the word “bispecifics,” what first comes to mind are bispecific T-cell-engaging antibodies. However, bispecifics can also include bispecific antibodies that do not engage T cells and bispecific T-cell-engaging therapies that are not antibodies. Therefore, each of those 3 categories is considered a bispecific therapy.

Our bispecific T-cell-engaging antibodies bring the T cell into proximity with the tumor cell and essentially create a synapse, causing the release of cytokines. This results in cytokine release syndrome (CRS) and generally a low incidence of immune effector cell-associated neurotoxicity syndrome (ICANS). In contrast, with bispecific antibodies that do not engage the T cell, we do not have that release of cytokines. These therapies generally rely on inhibition of signaling pathways associated with those antigens on the tumor cell or antibody-dependent cellular cytotoxicity. Because we do not have that rapid release of cytokines from T cells, we generally are not seeing CRS or ICANS. Therefore, there are bispecifics that are not T-cell engaging and have a completely different toxicity profile. The toxicities associated with those therapies are dependent on the antigens they bind.

We also have bispecific T-cell engagers that use a T-cell receptor (TCR) mechanism for T-cell redirection, so they are not antibodies. Tebentafusp is our currently FDA-approved example of that. In this case, we do have T-cell recruitment and release of cytokines, but it is more specific to the tumor region. We have less systemic T-cell activation, so we still see CRS, but it occurs for a shorter period of time. Generally, it happens early after infusion and lasts for up to 12 hours after the infusion. However, we do not see the potential for CRS that can last for several days, and we also do not see ICANS. With TCR-based T-cell redirection, we see some CRS for a shorter duration and no ICANS.

Pharmacy Times: As more bispecific antibodies enter clinical practice, how can pharmacists anticipate and proactively manage differences in toxicity profiles, particularly when it comes to adverse events such as cytokine release syndrome, neurotoxicity, or infection risk?

Peters: When new bispecifics come to market, the first consideration for pharmacists should be the mechanism of the bispecific. Is it a T-cell-engaging antibody, or is it an antibody that binds to 2 antigens on the tumor cell and does not engage the T cell?

If it is a T-cell-engaging antibody, pharmacists need to consider cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). They should review the clinical data to determine when CRS occurred, assess its incidence and severity, and evaluate the recommended monitoring period according to the FDA-approved labeling.

If it is a bispecific antibody that does not bind to the T cell, pharmacists should consider which receptors the antibody targets and what toxicities are known to be associated with those receptors. Whether the targets are HER2, EGFR, MET, or others, the toxicities are often similar to those observed with monospecific antibodies directed against the same targets. Pharmacists should consider which adverse effects may occur and what monitoring strategies, premedications, or prophylactic interventions, such as skin care measures, may be recommended to prevent or mitigate those toxicities.

Another consideration is the structure of the drug itself. Pharmacists should evaluate whether the agent is likely to cause cytopenias, whether it has an extended half-life, and how its structure and binding characteristics may influence its safety and pharmacologic profile.

Pharmacy Times: Implementing bispecific antibodies often requires coordination across multiple disciplines and care settings. What workflow strategies have you found most effective for safely integrating these therapies into both community and academic oncology practices?

Peters: Pharmacists play a vital role in this setting. In academic institutions, it is fairly easy to operationalize these therapies because there is typically the ability to monitor patients overnight, during weekend hours, and in the late evening. More resources are available, and staffing is generally already in place for this type of monitoring, particularly for bispecific T-cell-engaging antibodies, where there is a risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

In the community setting, however, patients can still be safely treated in the outpatient setting. Although this approach is not always directly consistent with labeling, institutions are finding that patients can be observed safely in the outpatient setting while receiving these therapies. Pharmacists can play a critical role in determining the monitoring required while the patient is in the clinic. How long should the patient remain in the clinic? How frequently should symptoms be assessed, blood pressure measured, and temperature monitored? What type of monitoring will be required once the patient returns home?

Another important consideration is caregiver involvement. What requirements should be in place to ensure that the caregiver can effectively monitor the patient at home and help maintain safety during treatment?

Lastly, pharmacists can help determine whether modifications to the treatment schedule are needed. Should the step-up dosing schedule be adjusted to accommodate regular business hours? Should the patient return for intravenous fluids or dexamethasone? Should prophylactic tocilizumab be incorporated to reduce the incidence of CRS? These are all considerations that pharmacists can bring to the multidisciplinary team and discuss with nursing staff and providers to determine the best approach for implementing these therapies in the community setting.

Pharmacy Times: When evaluating a patient for bispecific antibody therapy, what clinical or patient-specific factors are most important in determining which agent may be the best fit, and how can pharmacists help guide those decisions?

Peters: Clinically, there are really only a few considerations to make. There are some settings where we have multiple options available. For example, in multiple myeloma, we have several drugs that target BCMA and 1 that targets GPRC5D. These therapies can have slightly different toxicity profiles. GPRC5D-targeted therapies, for example, can be associated with skin toxicities. Therefore, there may be patients for whom those therapies are less desirable, such as individuals at higher risk for skin toxicities or those receiving other therapies that can cause photosensitivity or rash.

Another factor to consider when differentiating among these therapies is prior treatment exposure. For example, a patient may have recently received BCMA-targeted CAR T-cell therapy or a BCMA-targeted antibody-drug conjugate. In that situation, you might be more inclined to select a GPRC5D-targeted therapy. This remains a relatively data-free zone, and we do not yet know the optimal sequencing strategy for these agents. However, considering the tumor target of the therapy may be relevant when making treatment decisions.

In both lymphoma and multiple myeloma, differences in step-up dosing schedules may also influence drug selection. Some therapies can be administered with step-up dosing without hospital observation, whereas others may require inpatient monitoring. In some cases, observation may be needed for 24 hours, while in others it may extend to 48 hours. Depending on the patient, the availability of a caregiver, and institutional resources for monitoring and support, one option may be more appropriate than another.

These are the types of patient-specific factors we consider when selecting one therapy over another.