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.

Kaplan-Meier curves from the VICTORIA-1 trial show a steep, immediate drop-off for patients on fulvestrant monotherapy, with ~60% progressing quickly. In contrast, the giredestrant combination arms show a much flatter initial curve, visually demonstrating that a primary benefit is protecting the large subset of patients who would otherwise fail therapy very early.

Developers often test novel agents in late-line settings because the control arm is weaker, increasing the statistical chance of success. However, this strategy may doom effective immunotherapies by testing them in biologically hostile, resistant tumors, masking their true potential.

Current bladder cancer trials often fail to differentiate between patients with primary resistance (never responded) versus acquired resistance (responded, then progressed). Adopting this distinction, common in lung cancer research, could help identify patient subgroups more likely to benefit from immunotherapy re-challenge and refine trial eligibility criteria.

The failure of the Checkmate 914 adjuvant trial, which used a six-month duration of nivolumab plus ipilimumab, suggests this shorter treatment window may be inadequate. In contrast to positive trials with one year of therapy, this outcome indicates that treatment duration is a critical variable for achieving a disease-free survival benefit in the adjuvant RCC setting.

A pooled FDA analysis of four major kidney cancer trials found no "magic number" or threshold for tumor shrinkage that guarantees a favorable outcome. Instead, the relationship is linear: any incremental increase in tumor reduction correlates with better 36-month overall survival.

Unlike immunotherapy, neoadjuvant osimertinib yields poor pathologic complete response (pCR) rates. However, it significantly improves major pathologic response (MPR) and survival, suggesting pCR may be the wrong efficacy endpoint for cytostatic EGFR TKIs, which have a different mechanism of action than immunotherapy.

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.

While depth of response strongly predicts survival for an individual patient, the FDA analysis concludes it cannot yet be used as a surrogate endpoint to replace overall survival in pivotal clinical trials. It serves as a measure of drug activity, similar to response rate, but is not sufficient for drug approval on its own.