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.

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.

With highly active agents yielding 30% complete response rates, the immediate goal should be to cure more patients by exploring potent combinations upfront. While sequencing minimizes toxicity, an ambitious combination strategy, such as ADC doublets, offers the best chance to eradicate disease and should be prioritized in clinical trials.

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.

The common practice of switching from one ARPI to another upon disease progression is now considered ineffective for most patients. With the advent of proven alternatives like chemotherapy and lutetium, using an "ARPI switch" as the sole control arm in clinical trials is no longer ethically or scientifically sound.

Even when an ARPI is no longer effective as a standalone therapy, continuing it may be beneficial. By maintaining pressure on the androgen receptor pathway, the drug can upregulate downstream targets like PSMA, potentially enhancing the efficacy of subsequent PSMA-targeted therapies like radioligands or ADCs.

To demonstrate its drug could overcome resistance, Actuate designed a trial where patients who had already failed a specific chemotherapy were given the exact same regimen again, but this time with Actuate's drug added. The resulting increased efficacy across eight different cancers provided powerful, direct proof of the drug's mechanism.

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.