Traditional non-inferiority trials for reducing treatment are difficult to fund and execute. A proposed paradigm shift is to use superiority trial designs, where the burden of proof is on demonstrating that a higher dose or longer duration of therapy is actually better than a de-escalated approach.
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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.
Medical progress isn't just about new therapies; it's also about de-escalation, such as reducing the number of radiotherapy sessions. This type of innovation significantly improves a patient's quality of life by minimizing the exhaustive and disruptive time spent in treatment, a benefit patients value highly.
After years of successfully intensifying hormonal therapy, the focus in prostate cancer is shifting toward de-intensification. Researchers are exploring intermittent therapy for top responders and developing non-hormonal approaches like radioligands to spare patients the chronic, life-altering side effects of permanent castration.
The traditional drug-centric trial model is failing. The next evolution is trials designed to validate the *decision-making process* itself, using platforms to assign the best therapy to heterogeneous patient groups, rather than testing one drug on a narrow population.
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.
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.
Data on Enfortumab Vedotin suggests that for modern therapies, maintaining patients on treatment longer via a lower, more tolerable starting dose is more important than administering the maximum labeled dose upfront, a concept inherited from the cytotoxic chemotherapy era.
Recent non-inferiority trials affirm that fixed-duration combination therapies are viable alternatives to continuous BTK inhibitors. However, clinicians must look beyond the headline conclusion, as numerical data can show slightly worse progression-free survival for high-risk subgroups within the acceptable non-inferiority margin, complicating treatment decisions.
The speakers highlight that negative trials in kidney cancer, which showed no benefit to immunotherapy re-challenge, were "super helpful." This is because they provided definitive evidence to stop a common clinical practice that was not helping patients and potentially causing harm, underscoring the constructive role of well-designed "failed" studies.
The PSMA edition trial's fixed six-cycle Lutetium regimen, designed nearly a decade ago, is now seen as suboptimal. This illustrates how the long duration of clinical trials means their design may not reflect the latest scientific understanding (e.g., adaptive dosing) by the time results are published and debated.