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Simple Summary  Advanced triple-negative breast cancer (TNBC) remains an extremely challenging situation in oncology, where new therapeutical strategies are desperately needed. Immunotherapy has opened a window of opportunity in this setting, with some promising results with chemo-immunotherapeutic schedules based on anti-PD1/PD-L1 agents, especially in the PD-L1-positive cohort. However, there is certainly room for improvement; thus, new schemes that could potentially boost synergism against cancer cells must be explored. This work analyzes the effects of combination therapy with anti-PD1 (pembrolizumab) and gemcitabine, specifically in the TNBC cohort of the PANGEA-Breast trial. Patients included in this study were not selected by PD-L1 status, and most of them were also heavily pretreated, which could explain the modest objective response rate of 15% achieved. Complementary translational subanalyses, focused on T infiltrating lymphocytes, myeloid-derived suppressor cells, and PD-L1 were accomplished.    Abstract  The PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon’s design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years; 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2–37.9). Four patients were on treatment >6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment >6 months.

Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study