ASTRAEA: ReinvigorAting ReSponse To ImmunotheRApy in MEtAstatic TNBC With Combination Myeloid Inhibition and Radiation

Checkpoint blockade-mediated immunotherapy (IO) is an emerging cornerstone in the treatment of triple negative breast cancer (TNBC) in both the metastatic and curative intent settings. Initial studies of IO monotherapy in heavily pretreated metastatic TNBC were disappointing with low objective response rate (ORR) (5.3%: KEYNOTE-086, KEYNOTE-119) and no effect in OS (1-3). However, recent studies in patients with previously untreated metastatic TNBC, showed IO combinations with chemotherapy were associated with improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone in patients with "PD-L1 positive" disease (IMpassion130 and KEYNOTE-355) (4-7). Nonetheless, nearly half of patients on IMpassion130 had grade 3 or higher toxicity, leading to a discontinuation rate of 16.9%, and over 70% of all patients on first-line IO containing regimens will experience disease progression within one year. Based on these data, IO-containing regimens have become the standard-of-care treatment option for metastatic TNBC, albeit with a high failure rate and a non-trivial toxicity profile. Second line antibody-drug conjugate Sacituzumab govitecan while also improving response in metastatic TNBC still has 85% of patients fail at 1 year (ASCENT, Bardia NEJM 2021). Therefore, novel strategies that augment IO-enhanced tumor-specific responses and limit treatment-associated toxicities are critically important in TNBC. Lastly, radiotherapy (RT), commonly used in palliation of metastatic TNBC, is a potent modulator of the immune response, and can produce responses in unirradiated tumors in combination with IO (8-11).