Dr Sweis on the Expected Safety Profile of XmAb819 in RCC

"The body seems to adjust to the drug, and [we see] less of the cytokine release syndrome that [a patient would [typically experience] if we were to give all of the intended dose on day 1."

Randy F. Sweis, MD, an assistant professor of medicine at the University of Chicago Medicine, outlined potential safety concerns associated with the XmAb 2+1 bispecific antibody XmAb819 in renal cell carcinoma (RCC), as well as common mitigation strategies for these toxicities.

Previous clinical experience with bispecific T-cell engagers in other tumor types aids in the development of XmAb819 by helping researchers anticipate potential common adverse effects (AEs). Cytokine release syndrome (CRS) is the most common and concerning AE related to this class of therapies, Sweis stated. CRS is recognized as a known class effect resulting from the global activation of T cells. Symptoms typically include fevers and flu-like symptoms, although severe cases can involve a decrease in blood pressure or hypoxia, he detailed.

As several FDA-approved drugs already utilize this therapeutic approach, effective mitigation strategies are already available to prevent CRS, Sweis stated. One such option is step-up dosing as one of the most common methods employed. This strategy involves initiating treatment at a dose that is significantly lower than the intended target dose. The dose is then incrementally increased with each subsequent administration until the therapeutic target is reached. This method leverages tachyphylaxis, which effectively reduces the risk of CRS. Sweis noted that the patient's body appears to adapt to the drug, leading to less cytokine release than if the full dose were administered immediately. This step-up dosing technique is used for other agents, such as tarlatamab, a bispecific T-cell engager approved for small cell lung cancer, Sweis added.

In addition to CRS, skin rash is another [adverse effect] risk commonly observed with bispecific T-cell engagers. However, since the target of XmAb819, ENPP3, is not expressed on virtually any normal human cells, no other specific AEs are anticipated beyond the general class-related effects, Sweis concluded.