As neoadjuvant enfortumab vedotin plus pembrolizumab (EVP) achieves high pathologic complete response rates in MIBC, a critical question emerges: is adjuvant EVP necessary for everyone? Continuing treatment in patients who are already cancer-free post-surgery may offer no extra benefit while increasing toxicity.

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.

The rationale for combining ADCs with checkpoint inhibitors extends beyond additive effects. Preclinical data shows ADCs can increase T-cell infiltration into the tumor, potentially turning immunologically 'cold' tumors 'hot.' This offers a promising synergistic strategy, especially for PD-L1 negative patients who typically don't respond to immunotherapy alone.

For elderly or frail patients with metastatic bladder cancer, treatment choice hinges on goals. Enfortumab vedotin (EV) monotherapy is preferred for a rapid response in symptomatic or bulky disease. In contrast, pembrolizumab monotherapy is better for a lower-intensity approach in patients with low-volume disease where durable benefit and quality of life are prioritized.

The combination of enfortumab vedotin and pembrolizumab is not just improving median survival in metastatic bladder cancer; it's creating a "tail on the curve," suggesting a subset of patients may achieve long-term durable responses, a rarity in this advanced setting.

In an ongoing confirmatory trial, investigators rarely re-challenge PD-1 refractory patients with another PD-1 inhibitor alone. This real-world clinical consensus, viewing the practice as futile, provides strong practical evidence that the nivolumab in the combination isn't the sole driver of efficacy, supporting RP1's significant contribution.

For endometrial or cervical cancer patients who progress after receiving a checkpoint inhibitor, re-challenging with a single-agent immunotherapy is a less desirable approach. Emerging data suggests that a combination therapy—such as an ICI paired with a TKI like lenvatinib or a bispecific antibody—offers a more promising chance of response.

While adjuvant immunotherapy benefits ctDNA-positive patients, it may not be the optimal strategy. Given their near-certainty of relapse (95%), using a single-agent immunotherapy when a more potent combination like EV-Pembro exists for metastatic disease raises the critical question of whether these high-risk patients are being undertreated.