The negative ANSA-RAD trial, when contrasted with the positive STAMPEDE trial, demonstrates that patient selection is paramount in adjuvant therapy. The difference in outcomes was driven by risk definition, not the drug. This reinforces that "negative" trials are clinically vital for defining which patient populations do not benefit, preventing widespread overtreatment.

After observing deep, MRD-negative responses at their starting dose, Colonia Therapeutics unconventionally tested a lower dose level. This counter-intuitive strategy aims to identify the minimum effective dose, which is crucial for maximizing the safety profile (the therapeutic window) and improving commercial viability through lower manufacturing costs.

The failure of an adjuvant trial for the TKI pazopanib was likely caused by a protocol change that reduced the dose to manage transaminitis. While well-intentioned to improve tolerability and adherence, the lower dose was sub-therapeutic. This serves as a critical lesson that managing side effects by compromising dose can nullify a drug's potential efficacy.

The panel reviews advanced, second-line ADC trials in China using novel targets and payloads. An expert remarks that these are the drugs and questions the US and Europe may only begin to study in two to three years, signaling a significant shift in the global oncology R&D landscape.

Experts question if HER2 status truly predicts ADC efficacy in urothelial cancer. The benefit seen across low-expression levels suggests HER2's main role may be simply to target the chemo payload to cancer cells, rather than indicating a specific biological dependency.

Sepsis is not a monolithic condition. The failure of more than 100 immunomodulatory drug trials is likely because they treated all patients the same. The future of sepsis treatment mirrors oncology: subtyping patients based on their specific inflammatory profile to match them with a targeted therapy.

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.

The differing efficacy and toxicity profiles of TROP2 ADCs like sacituzumab govitecan and Dato-DXD suggest that the drug's linker and payload metabolism are crucial determinants of clinical outcome. This indicates that focusing solely on the target antigen is an oversimplification of ADC design and performance.

Experts believe the stark difference in complete response rates (5% vs 30%) between two major ADC trials is likely due to "noise"—variations in patient populations (e.g., more upper tract disease) and stricter central review criteria, rather than a fundamental difference in the therapies' effectiveness.