While platinum chemotherapy is considered the standard treatment after a patient progresses on a first-line ADC-IO combination, experts admit this is a standard "based on nothing." There is no clinical trial data to prove its efficacy in this specific setting; it serves only as a placeholder for new clinical trials.
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.
An expert argues the path to curing metastatic cancer may mirror pediatric ALL's history: combining all highly active drugs upfront. Instead of sequencing treatments after failure, the focus should be on powerful initial regimens that eradicate cancer, even if it means higher initial toxicity.
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.
The failure of the TROPiCS-04 trial for sacituzumab govitecan may not indicate the TROP2 ADC class is ineffective. Experts suggest problems with dosing and toxicity management (e.g., neutropenia) during the trial could be the real culprit, arguing that the drug class still holds promise.
Rather than moving through distinct lines of therapy, a future strategy could involve an "ADC switch." When a patient progresses on an ADC-IO combination, the IO backbone would remain while the ADC is swapped for one with a different, non-cross-resistant mechanism, adapting the treatment in real-time.
Experts question the efficacy of sequencing ADCs like EV (Nectin-4 target) and DV (HER2 target) because they share the same MMAE chemo payload. Since resistance is often tied to the payload, not the target antibody, switching targets may not overcome resistance, though anecdotal responses have been observed.
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.