PD-L1-Negative Triple-Negative Breast Cancer and Future Directions

Dr. Kruse reviews ASCENT-03 and TROPION-Breast02 data for PD-L1-negative or checkpoint inhibitor-ineligible metastatic TNBC, noting unsurprising ADC superiority in first-line treatment. ASCENT-03 importantly included patients previously treated with checkpoint inhibition, providing data for those with contraindications due to prior toxicity. The ethical crossover design allowing control arm patients to receive SG upon progression may impact OS endpoints but provides valuable sequencing information.

Both studies enrolled higher-risk patients with aggressive disease biology, including those with approximately 6-month disease-free intervals after prior therapy. ASCENT-03 utilized doublet carboplatin-gemcitabine comparators, creating more similar response rates between ADC and conventional therapy arms while potentially maintaining different disease control patterns. TROPION-Breast02 demonstrated expected toxicity and efficacy profiles based on prior Dato-DXd experience, with slightly lower-risk patient populations given comparator arm treatment options.

Dr. Kang anticipates practical factors influencing uptake, with potential preference for SG due to longer clinical experience and comfort levels. The "sandwich" approach using conventional chemotherapy between ADCs lacks definitive supporting data from retrospective analyses but feels appropriate for theoretical re-sensitization during intervals between overlapping mechanisms. Future priorities include developing ADCs with alternative payloads to address resistance mechanisms, investigating ADC-checkpoint inhibitor combinations building on ASCENT-04 success, and incorporating DESTINY-Breast05 and DESTINY-Breast11 data into clinical practice pending regulatory approvals.