Contrary to concerns about tolerating Enfortumab Vedotin (EV) after major surgery, 80% of muscle-invasive bladder cancer patients who began the adjuvant phase in the KEYNOTE B15 trial successfully completed it. This suggests the regimen is more manageable post-cystectomy than anticipated.

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 transformative efficacy of EV-Pembro has ushered in a new, aggressive treatment philosophy for both muscle-invasive and metastatic bladder cancer. The approach is to administer the combination upfront to gain rapid disease control, and only then make subsequent decisions about surgery, radiation, or further therapy.

Achieving a pathologic complete response (path CR) in the bladder after neoadjuvant therapy is a marker of drug efficacy, not a signal to stop treatment. Because patients die from metastatic, not local, disease, a path CR should be seen as a reason to "double down" on the effective systemic therapy to eradicate micrometastases.

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.

Despite the perception that cisplatin-ineligible patients have worse disease biology, the pathologic complete response rates to neoadjuvant EV Pembro were nearly identical (56-57%) in both cis-ineligible (KEYNOTE-905) and cis-eligible (KEYNOTE-B15) trials. This suggests the regimen's high efficacy may overcome underlying biological differences.

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.

In cisplatin-ineligible muscle-invasive bladder cancer, neoadjuvant enfortumab vedotin plus pembrolizumab demonstrated a 57% pathologic complete response rate in the KEYNOTE-905 trial. This is an unprecedented result, significantly higher than any previously studied regimen and signals a major shift in perioperative treatment.

Giving EV Pembro perioperatively for muscle-invasive bladder cancer provides the best chance for a cure. Waiting to use it in the first-line metastatic setting is a major gamble, as many patients relapse and may not get a second chance at effective therapy. The consensus is to use the best treatment upfront.