An advisory panel split 50/50 on a two-year immunotherapy regimen but voted 7-to-1 for a one-year drug with similar efficacy. This reveals that for adjuvant therapies in non-metastatic cancer, halving the treatment duration and toxicity exposure can decisively shift the risk/benefit calculation in favor of approval.

The anticipated approval of the highly effective EV-Pembro combination in the perioperative setting will create a new clinical challenge. When these patients eventually relapse years later, clinicians will face a dilemma: re-challenge with the same potent regimen that worked before or switch to older, likely less effective chemotherapies.

The next frontier in CSCC isn't just about new drugs, but about optimizing existing ones. A key research area is determining the minimum number of immunotherapy doses required for an optimal response—potentially just one or two—to limit toxicity, reduce treatment burden, and personalize care for high-risk patients.

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.

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.

As survival times for metastatic gastric cancer patients extend, managing long-term toxicity is paramount. Clinicians typically administer only 6-8 cycles of oxaliplatin to prevent severe, cumulative peripheral neuropathy, allowing for longer, better-tolerated maintenance therapy with biologics.

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.