Prophylactically administering tocilizumab before bispecific antibody treatment can slash the incidence of cytokine release syndrome (CRS) from ~75% down to 20%. This simple intervention, analogous to using G-CSF for neutropenia, mitigates side effects and makes outpatient administration a much safer and more feasible option for patients.

Unlike immunotherapy, where re-challenge after progression is dubious, there is an emerging clinical practice of re-challenging patients with the same antibody-drug conjugate (ADC), such as enfortumab vedotin (EV), after a treatment break forced by toxicity. Anecdotally, patients are showing great responses, highlighting a key area for prospective data generation.

In the EV+pembrolizumab combination, if a patient achieves an excellent response but develops prohibitive EV-related toxicities like neuropathy, a viable strategy is to discontinue EV and maintain the patient on pembrolizumab monotherapy. This can sustain the response while improving quality of life.

When managing drug-induced rash, recurrence is often caused by restarting therapy before the initial rash has completely resolved. Patients may be eager to resume treatment and minimize lingering symptoms, so clinicians must explicitly educate them on the need for full resolution to prevent a cycle of recurrence.

Although enfortumab vedotin (EV) targets nectin-4, its expression level is a poor predictive biomarker. Even patients with no detectable nectin-4 have achieved complete responses. This makes expression testing clinically unhelpful for patient selection, a counterintuitive finding for a targeted therapy.

While avoiding severe toxicities of older IL-2 drugs, Synthakyne's therapy causes a manageable rash. The company views this as a favorable, on-target effect, indicating the drug is successfully activating the immune system as intended, rather than as a problematic side effect.

When a toxicity like rash occurs with EV+pembrolizumab—which could be caused by either drug—the recommended strategy is to stop both. After the rash improves, reintroduce the drug least suspected of causing it first. If the rash does not recur, it helps confirm the other agent was the culprit.

While guidelines recommend any second-generation antihistamine for rash prophylaxis, clinical data indicate cetirizine is more effective than others for histamine-mediated cutaneous events caused by drugs. Clinicians should preferentially recommend cetirizine unless a patient has a known preference or intolerance.

Unlike neuropathy from vincristine which peaks during therapy, polatuzumab vedotin exhibits a "late cresting phenomenon." Patients can experience worsening neuropathy even after completing their sixth and final cycle, a crucial detail for patient counseling and proactive management.