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.

In muscle-invasive bladder cancer, cisplatin ineligibility is frequently due to renal insufficiency caused by large, aggressive tumors obstructing the ureter. This redefines this patient group as having more advanced local disease, rather than simply being unfit for chemotherapy, explaining their poor outcomes with surgery alone.

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.

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.

Historically, aggressive variants like micropapillary went directly to surgery. However, recent data suggests these patients do poorly due to micrometastatic disease. The trend is now to give neoadjuvant EV-Pembro to treat systemic disease, even with limited specific evidence.

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.

A key lesson in bladder cancer is that patient attrition is rapid between lines of therapy; many who relapse from localized disease never receive effective later-line treatments. This reality provides a strong rationale for moving the most effective therapies, like EV-pembrolizumab, to earlier settings to maximize the number of patients who can benefit.

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.