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.

A common clinical observation is that patients who develop significant immune-related toxicities, like colitis or pneumonitis, are frequently the same ones who experience the most profound and durable responses to checkpoint inhibitor therapy.

When a patient on enfortumab vedotin (EV) develops a severe rash, clinicians must consider delayed toxicity from a prior checkpoint inhibitor (ICI). Immune effects like pemphigoid can manifest months after stopping an ICI, requiring different management and potentially precluding EV re-challenge.

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.

A challenging side effect of Mogamulizumab is a rash that mimics the lymphoma itself. However, emerging data suggests patients who develop this rash may have better treatment outcomes. This encourages clinicians to manage the rash with steroids or methotrexate rather than discontinuing the effective therapy.

When educating staff and patients about immunotherapies, it is helpful to distinguish between the desired effect (cytokine release killing cancer cells) and the dangerous toxicity (CRS). This reframing clarifies that CRS is an over-expression of the drug's intended mechanism, not a separate, unrelated side effect.

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.

To prevent irreversible toxicities like neuropathy from enfortumab vedotin, clinicians should proactively set expectations. Emphasize that dose adjustments are normal and part of a long-term strategy. Framing it as a "marathon, not a sprint" encourages patients to report side effects early, rather than hiding them for fear of stopping treatment.