This is a crucial concept for predicting ADC toxicities. ADCs with a topoisomerase payload (like TDXD) cause nausea and myelosuppression, while those with a tubulin inhibitor payload (like MERV) cause neuropathy and ocular issues.

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.

A critical reason patients stop ADC treatments is the burden of side effects like skin toxicity or GI issues, not just disease progression. This underscores the urgent need to develop ADCs with better safety profiles, enabling patients to stay on effective therapy longer.

GPRC5D-targeting bispecifics like talquetamab require a specific learning curve due to their unique 'on-target, off-tumor' side effects. Because the GPRC5D target is also present on skin and taste bud tissues, patients can experience significant dysgeusia, skin changes, and nail toxicities that require active management.

Though ADCs like Sacituzumab Govitekan cause notable side effects like diarrhea and neutropenia, patient-reported outcome data shows they provide a meaningful and sustained improvement in quality of life compared to standard chemotherapy. This was observed even with longer treatment durations and lower discontinuation rates.

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.

A key principle for clinicians is that an antibody-drug conjugate's adverse events are primarily dictated by its linker-payload (e.g., deruxtecan, vedotin), not its specific antibody target. This allows for anticipating toxicities like neuropathy or GI issues based on the payload class, creating a predictable framework for management across different ADCs.

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.