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.

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.

The neuropathy caused by polatuzumab vedotin can be severe and is not always reversible. Clinicians must be vigilant in assessing for symptoms like numbness or difficulty with fine motor skills and be prepared to reduce the dose promptly to prevent long-term, debilitating side effects.

To improve long-term tolerability of amivantamab, some experts advocate for a "marathon, not a sprint" approach. This involves aggressive dose holds or reductions at the earliest signs of toxicity, even low-grade, to prevent side effects from escalating and ensure patients can remain on effective therapy longer.

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.

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.

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.

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.

Unlike chemotherapy, immune-related adverse events have a delayed onset. Nurses must educate patients that toxicities can appear long after treatment initiation and even after its conclusion, requiring long-term vigilance.