Abstract OT3-01-01: A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer

Abstract Background A hallmark of cancer is its ability to evade the immune system, however, it can be harnessed to detect and destroy cancer cells through inhibition of immune checkpoints such as CTLA-4 and PD-L1. This strategy has complementary and non-redundant mechanisms resulting in immune activation and antitumor synergy; progression free survival benefit has already been demonstrated in melanoma. A critical barrier in developing immunotherapies, however, is the identification of predictive biomarkers of response to therapy. Immunopharmacogenomic biomarkers, such as mutational burden, neoantigen profiles, and T cell receptor sequencing will elucidate the molecular interface between cancer and immune system, and may predict those most likely to benefit. Methods A single arm Phase II study was designed to determine the efficacy of PD-L1 and CTLA-4 inhibition and effects on immunopharmacogenomic dynamics in patients with metastatic breast cancer. The primary endpoint of this proposal is to investigate the response rate of the PD-L1 inhibitor, durvalumab, and the CTLA-4 inhibitor, tremelimumab, in metastatic breast cancer; secondary endpoints will examine the T cell receptor repertoire clonality, tumor mutational burden and neoantigen profiles. A total of 30 patients will be enrolled and treated with durvalumab 1500mg IV and tremelimumab 75mg IV monthly for 4 doses, then durvalumab 750mg every 2 weeks for 18 doses to complete 1 year of therapy with the option to renew therapy for an additional year; biopsies and blood at baseline and 2 months will be collected to assess immunopharmacogenomic biomarkers. Patients are eligible if they have triple negative or ER-positive breast cancer and have progressed on at least one line of chemotherapy and standard endocrine therapy if applicable. This is the first study to investigate immunopharmacogenomic biomarkers of response to dual checkpoint blockade in patients with metastatic breast cancer. Citation Format: Santa-Maria CA, Jain S, Flaum L, Park J-H, Kato T, Gross L, Uthe R, Tellez C, Stein R, Rademaker A, Gradishar WJ, Nakamura Y, Giles FJ, Cristofanilli M. A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-01-01.