Modern antibody-drug conjugates (ADCs) like trastuzumab deruxtecan can kill nearby cancer cells that don't express the target protein. This 'bystander effect' is a game-changer, allowing ADCs to be effective even in tumors with varied (heterogeneous) protein expression, which has historically been a major clinical challenge.

Although enfortumab vedotin (EV) targets nectin-4, its expression level is a poor predictive biomarker. Even patients with no detectable nectin-4 have achieved complete responses. This makes expression testing clinically unhelpful for patient selection, a counterintuitive finding for a targeted therapy.

Unlike early ADCs requiring high biomarker expression (e.g., mirvetuximab), next-generation agents show efficacy even in low-expressing tumors. This allows for broader, "all-comer" clinical trial inclusion criteria instead of biomarker-gated entry, potentially expanding patient access to these novel therapies.

The TROPION-PanTumor01 study showed that patients who progressed on the TROP2-ADC sacituzumab govitecan still achieved responses to a second TROP2-ADC, Dato-DXD. This suggests that targeting the same antigen with a different payload can overcome initial resistance, informing future treatment sequencing.

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.

A significant clinical challenge is the sequencing of antibody-drug conjugates (ADCs). Retrospective data from large databases indicates that using a second TROP2-targeted ADC after a first one provides very limited efficacy, highlighting an urgent need for prospective trials to define optimal sequencing strategies and overcome resistance.

The difficulty in finding a single predictive biomarker for antibody-drug conjugate (ADC) efficacy suggests that complex, multi-marker classifiers, like those in the ISPY 2.2 trial, represent the future for guiding ADC therapy selection over simple IHC cutoffs.

The ASCENT-07 trial, while failing its primary endpoint, revealed a promising efficacy signal for its Trop-2 ADC in IHC0 tumors. This finding from a "negative" study directly spurred a new trial, Tropion-Brest-O6, to investigate another ADC specifically in this refined patient population, demonstrating the iterative nature of clinical research.

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.