Sara M. Tolaney, MD, MPH, FASCO, on PD-L1–Positive Advanced TNBC: First-Line Doublet Comparison

At ASCO this year, we presented results from the ASCENT-04 trial. This is a randomized phase three study of sacituzumab govitecan plus pembrolizumab compared to chemotherapy plus pembrolizumab in patients who have previously untreated PD-L1–positive metastatic triple-negative breast cancer. We know that about 15% of all breast cancers are triple-negative, and about 40% of triple-negative breast cancers are PD-L1–positive. Currently, these patients are treated with chemotherapy and checkpoint inhibition, where we've seen median progression-free survival that ranges between 7 to 9 months. We also have antibody-drug conjugates to treat pretreated metastatic triple-negative disease, and sacituzumab govitecan is a Trop-2–directed antibody-drug conjugate that has previously been found to improve both progression-free and overall survival in pretreated metastatic triple-negative breast cancer and is currently a second-line standard-of-care option. There has been a lot of interest in combining antibody-drug conjugates with checkpoint inhibitors given some robust preclinical and clinical data. And so ASCENT-04 was really designed to test the efficacy of sacituzumab plus pembrolizumab. This trial was designed in patients who had no prior systemic therapy in the metastatic triple-negative setting. They had to either have de novo metastatic disease or be at least six months out from completion of any systemic therapy in the early disease setting. Prior use of checkpoint inhibition for early-stage breast cancer was allowed, and patients were randomized 1:1 to receive sacituzumab govitecan plus pembrolizumab or chemotherapy. A physician’s choice plus pembrolizumab or choice of chemotherapy could either be paclitaxel, nab-paclitaxel, or carboplatin and gemcitabine. For those patients on the chemotherapy plus pembrolizumab arm, if they progressed, they were allowed to get crossover treatment with sacituzumab govitecan monotherapy if they had centrally confirmed disease progression during the crossover phase of the study. The primary endpoint was progression-free survival by blinded independent central review, and the primary endpoint progression-free survival data demonstrated that sacituzumab plus pembrolizumab led to significant improvement in progression-free survival when compared to chemotherapy plus pembrolizumab, with an improvement in PFS going from 7.8 to 11.2 months with a hazard ratio of 0.65 and an absolute difference of about 3.4 months. Seeing these data with an improvement in PFS suggests that the combination of sacituzumab and pembrolizumab could represent a new standard-of-care option for patients who have previously untreated PD-L1–positive metastatic triple-negative breast cancer.