ADC–Immunotherapy Combinations in PD-L1–Positive and Future Directions

This segment focuses on the evolving first-line treatment approach for metastatic TNBC in the PD-L1–positive population, highlighted by results from the ASCENT-04 trial. The study demonstrated improved progression-free survival with SG combined with pembrolizumab compared with standard chemotherapy plus pembrolizumab. Importantly, the combination did not result in increased overall toxicity, which was particularly reassuring given the overlapping risk of diarrhea associated with both immunotherapy and SG. These findings have led many clinicians to adopt SG plus pembrolizumab as a preferred first-line regimen for most PD-L1–positive patients, with chemotherapy-based approaches reserved for select lower-risk or oligometastatic cases.

The discussion also highlights the increasingly competitive ADC landscape, with ongoing studies evaluating alternative ADC–immunotherapy combinations, including Dato-DXd plus immune checkpoint inhibitors. Differences in trial design, such as eligibility based on disease-free interval, may influence future patient selection and interpretation of results.

Beyond the PD-L1–positive setting, several trials are investigating whether ADCs may enhance immunotherapy benefit in PD-L1–negative disease, where current options are limited. Studies such as Saci-IO TNBC and TROPION-Breast11 are evaluating ADC plus checkpoint inhibition compared with ADC alone or chemotherapy.

A key theme is the recognition that PD-L1 is an imperfect biomarker in TNBC, with inconsistent correlation to immunotherapy response. As a result, there is strong interest in identifying better predictive markers and expanding the role of immunotherapy to a broader patient population.

Overall, ADC–immunotherapy combinations are reshaping first-line TNBC management, with ongoing trials expected to further refine patient selection and treatment strategies.