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.
Immunotherapy antibodies bind to immune cells for weeks or months, a pharmacodynamic (PD) effect far longer than their pharmacokinetic (PK) half-life. This long-lasting binding suggests that minor variations in infusion timing for subsequent doses are unlikely to impact overall outcomes, casting doubt on the study's core hypothesis.
When a study is presented at a major conference like ASCO, it gains visibility and a perception of having been vetted. This can create a "tailwind," leading subsequent journal reviewers to be less critical, as they may assume the work has already undergone rigorous scrutiny, which is often not the case for conference abstracts.
The study presented three different datasets over a short period. While efficacy endpoints like PFS and OS changed, the toxicity data remained identical. This is highly unusual, as resolving censored patient data for efficacy should also lead to updated toxicity information, suggesting a rushed or incomplete analysis process.
A key red flag was the study's ClinicalTrials.gov entry using past-tense language for its inclusion criteria (e.g., "patients received immunotherapy"). This, along with an exclusion criterion for "loss to follow up," strongly suggests the study was a retrospective analysis of existing patient data, not a prospective trial as presented.
The study's progression-free survival (PFS) curve was unusually smooth, lacking the stepwise drops expected from scheduled scans in oncology trials. More alarmingly, the "numbers at risk" table showed more patients remaining than were represented on the graph at certain time points—a statistical impossibility suggesting a significant reporting or programming error.
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.