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.

Advances in drug design mean newer PI3K inhibitors are more targeted, resulting in significantly less off-target toxicity. For example, some investigational agents have a hyperglycemia risk under 15%, a substantial improvement over earlier drugs, making them easier to manage clinically.

Extrapolating from the metastatic setting, clinicians should anticipate that most patients on the 9-cycle perioperative EV-pembrolizumab regimen will require dose reductions or holds. Cumulative peripheral neuropathy is the primary driver, suggesting a need for proactive, individualized dose management rather than strict adherence to the trial's protocol.

On-body glucose monitors give oncologists a richer understanding of a patient's glucose control, including 24-hour trends, time-in-range, and an A1c equivalent (GMI). This real-time data is critical for managing hyperglycemia from targeted therapies, offering more insight than periodic fasting tests.

The practice-changing Keynote B15 trial showed strong efficacy for neoadjuvant EV-Pembro. However, about half of patients discontinued treatment due to side effects. This creates a clinical paradox: patients who complete the full regimen may be over-treated, while those who stop early due to toxicity may be under-treated, complicating patient management and counseling.

A key eligibility criterion for the landmark EV-302 trial was glycemic control. Patients with an A1C above 8 were excluded due to hyperglycemia and diabetic ketoacidosis (DKA) risk from the enfortumab vedotin component. This has critical implications for patient selection and monitoring.

While severe (Grade 3+) neuropathy from enfortumab vedotin is rare, oncologists emphasize that Grade 2 toxicity is common and significantly impairs patients' quality of life. This 'moderate' side effect is often painful and interferes with daily activities, warranting an immediate hold on treatment, not just waiting for Grade 3.

Oncologists typically initiate metformin for drug-induced hyperglycemia but are hesitant to manage more complex regimens. They prefer collaborating with endocrinologists who can navigate different drugs, dosages, and interactions, especially for complex oncology patients where frequent follow-up is needed.

The demonstrated superiority of the enfortumab vedotin (EV) and pembrolizumab combination over platinum chemotherapy has effectively made the Galski criteria, used for determining cisplatin eligibility, irrelevant. This marks a major paradigm shift in how frontline bladder cancer is approached, moving beyond platinum-based decisions.