Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015-04 (PANGEA-Breast) study

Abstract Background: We evaluated a combination of two immunomodulatory agents considering a synergism that may induce long-term clinical benefit in advanced breast cancer (ABC). Methods: HER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6+6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed. Results: Fourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon’s design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5–32). Eight patients were treated ≥6 months before progression. Fourteen patients reported grade ≥3 treatment-related adverse events. No association was found between TILs density and treatment efficacy. Patients with negative PD-L1 expression showed significantly prolonged progression-free survival. MDSCs levels were associated with treatment response.Conclusion: Pembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥6 months. Tumor PD-L1 expression and MDSCs levels suggested a potential predictive role in this population.Trial registration number: ClinicalTrials.gov and EudraCT (NCT03025880 and 2016-001779-54, respectively).