Unlike traditional chemotherapy, the EV+pembrolizumab combination is producing a "tail on the curve" in survival data. This indicates a significant minority of patients with metastatic bladder cancer are achieving durable, long-term responses—a phenomenon previously unseen and a paradigm shift for the disease.

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.

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.

For rashes caused by enfortumab vedotin (EV), dupilumab is an emerging steroid-sparing treatment. It can decrease the risk and severity of EV-related rashes, offering an alternative to corticosteroids, which some clinicians worry may blunt the efficacy of concurrent immunotherapy.

Data from the Checkmate 743 trial shows that patients who stopped dual immunotherapy (Nivo/Ipi) due to toxicity can still achieve long-term benefits. A third of these patients had an ongoing response at three years, despite stopping treatment after only four months on average, providing confidence in the regimen.

Data on Enfortumab Vedotin suggests that for modern therapies, maintaining patients on treatment longer via a lower, more tolerable starting dose is more important than administering the maximum labeled dose upfront, a concept inherited from the cytotoxic chemotherapy era.

Perioperative enfortumab vedotin-pembrolizumab (EV-Pembro) is surprisingly well-tolerated on a per-cycle basis compared to the traditional GEMSYS chemotherapy regimen. This challenges preconceived notions about the toxicity of this powerful combination, though cumulative toxicity over longer durations remains a key factor.

While KEYNOTE-905 showed dramatic survival benefits with neoadjuvant plus adjuvant EV-pembrolizumab, its design makes it impossible to isolate the benefit of each phase. The high (57%) pathologic complete response after neoadjuvant therapy alone suggests many patients may be overtreated with adjuvant cycles, risking unnecessary long-term toxicity like neuropathy.

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.