BackgroundChemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. MethodsWe report nal outcomes from a phase Ib trial evaluating pembrolizumab (200mg IV every 3 weeks) with either weekly paclitaxel (80mg/m 2 weekly) or at-dose capecitabine (2000mg orally twice daily for 7 days of every 14-day cycle) in the 1st /2nd line setting. The primary endpoint was safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥ 21-day delays). The secondary endpoint was e cacy (week 12 objective response rate). Exploratory aims were to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. ResultsBoth regimens met the pre-speci ed safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate was 29% for pembrolizumab/paclitaxel and 43% for pembrolizumab/capecitabine. Partial responses were observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens were associated with signi cant peripheral leukocyte contraction over time. Response was associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor in ltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). ConclusionsPembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens were lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted.