Despite the ASCENT-07 trial failing its primary progression-free survival (PFS) endpoint, an early overall survival (OS) signal emerged. This divergence suggests the drug may confer a survival advantage not captured by the initial endpoint, complicating the definition of a "negative" trial and warranting further follow-up.

The confirmatory Code Break 200 study for sotorasib demonstrated a statistically significant improvement in progression-free survival (PFS) over docetaxel. However, it failed to show a similar benefit in overall survival (OS), a critical distinction for oncologists weighing long-term patient outcomes.

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.

In trials like ASCENT-4, where over 80% of the control arm received sacituzumab govitecan upon progression, the true overall survival (OS) benefit is obscured. This makes progression-free survival (PFS) a more reliable endpoint for evaluating the drug's first-line efficacy.

Traditional endpoints like progression-free survival (PFS) incentivize continuous treatment. The NCI group proposes "treatment-free survival," a novel metric that quantifies time spent *off* therapy. This endpoint better captures the patient experience and rewards treatments that provide durable responses after a finite course.

In the ASCENT-07 trial, investigators may have prematurely switched patients from the standard chemotherapy arm to superior, commercially available ADCs at the first hint of progression. This real-world practice can mask an experimental drug's true benefit on progression-free survival.

In the CREST trial, the FDA's critique heavily emphasized an overall survival hazard ratio above one. Though statistically insignificant and based on immature data, this single figure created a powerful suggestion of potential harm that overshadowed the positive primary endpoint and likely contributed to the panel's divided vote.

In solid tumor immunotherapy, significant efficacy gains almost always correlate with increased toxicity. This study's claim of nearly doubled progression-free survival with identical toxicity rates is biologically implausible and was a primary reason for skepticism, even before analyzing the trial's methodology.

The study reported that no patients in the "before 3 PM" group ever received a dose after 3 PM over four cycles. In a busy, real-world cancer center, such perfect adherence is practically impossible due to logistical issues. This flawless data suggests the study might be a retrospective analysis of curated data rather than a truly prospective trial.