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.

Even in healthcare systems with universal free access, like the UK's NHS, the actual uptake of immunotherapy for metastatic kidney cancer is only about 60%. This real-world gap strengthens the argument for adjuvant therapy, as it ensures high-risk patients receive potentially life-saving treatment they might otherwise miss upon relapse.

The Rampart study's main contribution wasn't its specific drug data, but that it became the second positive trial in the adjuvant kidney cancer space. This balanced the 'scorecard' against multiple negative trials, reinforcing the general principle that early immune therapy is beneficial.

Despite exciting early efficacy data for in vivo CAR-T therapies, the modality's future hinges on the critical unanswered question of durability. How long the therapeutic effects last, for which there is little data, will ultimately determine its clinical viability and applications in cancer versus autoimmune diseases.

In adjuvant bladder cancer trials, ctDNA status is both prognostic and predictive. Patients with positive ctDNA after surgery are at high risk of relapse but benefit from immune checkpoint inhibitors. Conversely, ctDNA-negative patients have a lower risk and derive no benefit, making ctDNA a critical tool to avoid unnecessary, toxic therapy.

Treating 'non-clear cell' kidney cancer as a single entity is a major research limitation. Experts argue that distinct histologies like papillary and chromophobe are different diseases. Future progress requires dedicated, international trials for each subtype rather than grouping them due to rarity.

An overall survival (OS) benefit in an adjuvant trial may not be meaningful for patients in systems (e.g., the U.S.) with guaranteed access to the same effective immunotherapy upon recurrence. The crucial, unanswered question is whether treating micrometastatic disease is inherently superior to treating macroscopic disease later, a distinction current trial data doesn't clarify.

A significant criticism of the pivotal KEYNOTE-564 trial is that only half the patients in the control arm received standard-of-care immunotherapy upon relapse. This lack of subsequent optimal treatment complicates the interpretation of the overall survival benefit, raising questions about its true magnitude.

A sophisticated concern regarding the HIF-2 inhibitor belzutifan is its potential to diminish kidney cancer's antigenicity by reducing human endogenous retrovirus expression. While providing an early benefit, this could theoretically make tumors less responsive to subsequent immunotherapies, negatively impacting long-term outcomes—a critical consideration for sequencing.