Abstract OT1-01-02: A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab and gemcitabine in patients with HER2-negative advanced breast cancer: GEICAM/2015-04 PANGEA-Breast

Abstract

Abstract Background: Treatment options for advanced breast cancer (ABC) are multiple but unable to properly respond to current clinical needs. In particular, improved therapies are needed for triple negative and hormone receptor (HR)-positive but heavily pretreated patients. Pembrolizumab (P) is a human monoclonal antibody that blocks the PD-1/PD-L1 interaction hence potentiates anticancer T cell responses. Gemcitabine (G) is a cytotoxic drug with well-known immunostimulatory properties. Here, we report an ongoing phase II clinical trial to identify the Recommended Phase II Dose (RP2D) and the efficacy of the combination of these two agents in ABC patients. We hypothesize that these agents may synergize to induce responses with long term clinical benefit (ClinicalTrials.gov Identifier: NCT03025880). Trial Design: Eligible patients are HER2-negative ABC patients who received prior treatment with anthracyclines and taxanes and two or more prior lines of hormone therapy, if HR-positive disease. Patients with CNS involvement are also eligible if clinically stable. Treatment consists of 21-day cycles with 200 mg P on day 1 and G on days 1 and 8. In the safety dose testing, we use a standard 6+6 design with 2 dose levels (DL) of G: 1250 mg/m2 (DL0) and 1000 mg/m2 (DL1). Patients are treated until radiologic or symptomatic progression, or unacceptable toxicity. The primary objectives are RP2D and objective response rate (ORR) of the combination; secondary objectives include evaluation of safety and tolerability and other efficacy variables (progression-free survival [PFS], clinical benefit rate [CBR], response duration [RD] and overall survival [OS]). Efficacy is measured by RECIST 1.1. and irRECIST. Safety is measured using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 4.0. As exploratory objectives, immunological biomarkers are analyzed in tumor biopsies and blood samples and correlated with (1) clinical efficacy and (2) disease outcomes.Sequential tumor samples are collected at baseline, cycle 3 and at progression. Blood samples are drawn at baseline, cycle 3, and cycle 6, or at post-treatment visit (whatever occurs first). Tumor samples are characterized for intratumoral and stromal tumor-infiltrating lymphocytes, tumor-associated macrophages and myeloid-derived suppressor cells, PD-L1 expression in tumor cells and stroma. Moreover, molecular and genetic profiling will be performed. Blood samples are characterized for peripheral blood mononuclear cell (PBMC) phenotype (including expression of co-activatory and co-inhibitory receptors), cytokine profile, and activity of other immunosuppressive pathways (e.g., IDO1-dependent tryptophan catabolism). These results will be compared with data from a cohort of healthy volunteers. A maximum of 65 patients will be included. The study is approved by the ethical committee and Competent Authority of Spain and already open for patient recruitment in 2 of the 10 participating sites. Keywords: Breast HER2 negative Pembrolizumab Immunotherapy Citation Format: de la Cruz L, Sánchez-Margalet V, Berraondo P, Benito S, Escudero MJ, Caballero R, Carrasco E, Galluzzi L, Rojo F. A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab and gemcitabine in patients with HER2-negative advanced breast cancer: GEICAM/2015-04 PANGEA-Breast [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-01-02.