A decade ago, metastatic triple-negative breast cancer (mTNBC) had a median survival of about one year. Today, the duration of response to modern antibody-drug conjugates (ADCs) in the first-line setting can be longer than what the entire overall survival used to be, highlighting a massive therapeutic advancement.
New-generation antibody-drug conjugates (ADCs) are highly effective because their chemotherapy payload can diffuse out of the targeted cancer cell. This "bystander effect" allows the drug to kill adjacent, target-negative cancer cells, enhancing overall tumor destruction in heterogeneous tumors.
When patients progress on an antibody-drug conjugate (ADC), the resistance is frequently due to the tumor becoming resistant to the chemotherapy payload (e.g., a topoisomerase inhibitor). This is more common than the tumor losing the surface target, which critically impacts the sequencing of subsequent ADCs.
In the TROPION-Breast02 trial, a survival benefit for Dato-DXD was seen mainly in regions without later-line access to TROP2 ADCs. Western patients often received an ADC second-line, muting the first-line survival difference and showing how post-progression therapy access can confound trial results.
ADCs more frequently cause "oligoprogression," where most metastatic sites respond while only one or two progress. This allows for treating the progressing lesion with local therapy (e.g., radiotherapy) while continuing the systemic ADC, rather than abandoning an otherwise effective treatment.
Antibody-drug conjugates can disrupt the tumor microenvironment, leading to an influx of immune cells. This may turn an immunologically "cold" tumor "hot," creating a rationale for re-challenging with an immune checkpoint inhibitor, even if the patient's tumor previously did not respond to one.
Initial concerns about severe diarrhea with sacituzumab govitecan are now less relevant due to improved management. Prophylactic use of strong antiemetic regimens often causes constipation, effectively preventing diarrhea and dramatically improving the drug's tolerability based on clinical experience.
It is crucial to re-biopsy metastatic breast cancer upon progression because the tumor's fundamental biology can change. A patient initially diagnosed with ER-positive disease can develop triple-negative, PD-L1 positive disease, which opens up entirely new treatment options like immunotherapy and different ADCs.