Unlike traditional chemotherapy, the EV+pembrolizumab combination is producing a "tail on the curve" in survival data. This indicates a significant minority of patients with metastatic bladder cancer are achieving durable, long-term responses—a phenomenon previously unseen and a paradigm shift for the disease.

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 B15 trial shows EV-Pembro is superior to chemotherapy in muscle-invasive bladder cancer. However, the true benchmark is now the Niagara study (chemo + durvalumab), which already beat chemo alone. The debate will focus on whether EV-Pembro offers a significant enough improvement to become the definitive standard over this new chemo-IO combination.

The 6% two-year landmark OS benefit for EV Pembro in the B15 trial appears modest compared to other EV Pembro studies. However, this is due to comparing it against an active, effective control (GEM-CIS chemotherapy), unlike trials that used surgery alone, reinforcing the value of neoadjuvant therapy overall.

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 both the B15 (EV Pembro) and Niagara (Gem-Cis-Durvalumab) trials were positive, B15 demonstrated a significantly higher pathologic complete response rate (56% vs 37%) and more favorable hazard ratios for survival endpoints. This suggests EV Pembro is the "more positive" regimen and likely the preferred standard of care.

Perioperative enfortumab vedotin-pembrolizumab (EV-Pembro) is surprisingly well-tolerated on a per-cycle basis compared to the traditional GEMSYS chemotherapy regimen. This challenges preconceived notions about the toxicity of this powerful combination, though cumulative toxicity over longer durations remains a key factor.

Expert consensus shows a major paradigm shift: perioperative systemic therapy (like EV-Pembro, scoring 2.9) is the undisputed standard for muscle-invasive bladder cancer. Approaches starting with cystectomy alone now score below 1.8, formally branding them as inferior options.

With pathologic complete response rates approaching 67% in patients completing neoadjuvant EV-Pembro, a majority of cystectomies are now removing cancer-free bladders. This creates an ethical and clinical imperative to rapidly launch prospective trials to validate bladder preservation strategies and avoid overtreatment.