Emerging data shows that a second ADC, particularly one with the same payload, often has limited efficacy. This suggests clinicians must be highly strategic in selecting the first ADC, as it may be their most impactful opportunity for this class of drugs.
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Trastuzumab deruxtecan (TDXD) and datopotamab deruxtecan (Dato-DXd) share the same cytotoxic payload, yet Dato-DXd has a much lower rate of interstitial lung disease (ILD). This indicates the toxicity is driven by the antibody-antigen interaction, not the payload itself.
Real-world data suggests that using one antibody-drug conjugate (ADC) immediately after another is often ineffective. A potential strategy to overcome this resistance is to administer a different class of chemotherapy before starting the second ADC.
For antibody-drug conjugates (ADCs) to make a meaningful impact in prostate cancer, the clinical development bar is exceptionally high. Merely showing activity in late-line settings is insufficient; the true measure of success is demonstrating superiority over the established chemotherapy standard, docetaxel.
The future of medicine isn't about finding a single 'best' modality like CAR-T or gene therapy. Instead, it's about strategic convergence, choosing the right tool—be it a bispecific, ADC, or another biologic—based on the patient's specific disease stage and urgency of treatment.
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.
In metastatic breast cancer, approximately one-third of patients are unable to proceed to a second line of therapy due to disease progression or declining performance status. This high attrition rate argues for using the most effective agents, such as ADCs, in the first-line setting.
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.
Unlike older antibody-drug conjugates (ADCs), newer agents are designed so their chemotherapy payload can diffuse out of the target cell and kill nearby tumor cells that may not even express the target antigen. This "bystander effect" significantly enhances their anti-tumor activity.
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.
An antibody-drug conjugate's (ADC) effectiveness is capped by its chemotherapy payload. In prostate cancer, topoisomerase inhibitors have a poor track record. Therefore, ADCs using this payload face an uphill battle compared to those with proven payloads like microtubule inhibitors (taxanes).