Abstract OT2-08-03: Immunogenicity of pembrolizumab and doxorubicin in a phase I trial for patients with metastatic triple negative breast cancer
Authors: Egelston Colt A. , Guo Weihua , Yost Susan E. , Ge Xuan , Lee Jin Sun , Frankel Paul H. , Cui Yujie , Ruel Christopher , Schmolze Daniel , Murga Mireya , Tang Aileen , Martinez Norma , Karimi Misagh , Somlo George , Lee Peter , Waisman James , Yuan Yuan 
Published: March 2023

Abstract
Background: Combination of immune checkpoint inhibitor pembrolizumab and chemotherapy are standard of care therapy for patients with programmed death-ligand 1 positive (PD-L1+) metastatic triple negative breast cancer (mTNBC). However, a greater understanding of how immune checkpoint inhibitors and chemotherapies synergize to yield anti-tumor T cell responses is needed. The current phase I study evaluated the immunogenicity of doxorubicin plus pembrolizumab in patients with mTNBC. Patients and Methods: Patients with mTNBC, no prior anthracycline use, and 0-2 lines of prior systemic chemotherapies received pembrolizumab 200 mg IV and doxorubicin 50-60 mg/m2 IV every 3 weeks for 6 cycles followed by pembrolizumab maintenance until disease progression or intolerance. Patients were not selected based on PD-L1 expression. The primary objectives were safety and objective response rate per RECIST 1.1. Peripheral blood samples were collected at baseline, Cycle 2 Day 1 (C2D1), and post Cycle 3 for analysis by high parameter flow cytometry. Results: Ten patients were enrolled between March 2016 and November 2019. Best responses included one patient with complete response (CR), five with partial responses (PR), two with stable disease (SD), and one with progression of disease (PD). Flow cytometry showed increased CD3+ T cells (p=0.03) from pre-treatment to C2D1 with substantial inter-patient variation in CD3+ T cells. The expansion of proliferative exhausted-like PD-1+ CD8+ T cell population was identified in 8/9 patients, and exhausted CD8+ T cells were significantly expanded from pre-treatment to C2D1 in the patient with CR (p=0.01). Notably, frequencies of PD-1 high proliferative CD8+ T cells contracted significantly from C2D1 to post Cycle 3 (p=0.005), with a return to near baseline frequencies in the majority of the patients. In the context of all identified T cell subsets, PD-1hi proliferative CD8+ T cells demonstrated the greatest increase in fold change from pre-treatment to C2D1. In contrast, PD-1lo proliferative CD8+ T cells demonstrated the greatest decrease in fold change from pre-treatment to C3D1. Conclusion: Anthracycline-naïve patients with mTNBC treated with the combination of pembrolizumab and doxorubicin yielded robust peripheral blood T cell responses. Further studies dissecting the dynamics and durability of anti-tumor T cell responses and concurrent tumor immune microenvironment changes are needed to optimize combined immune checkpoint inhibitor and chemotherapy treatment for patients with mTNBC.
Citation Format: Colt A. Egelston, Weihua Guo, Susan E. Yost, Xuan Ge, Jin Sun Lee, Paul H. Frankel, Yujie Cui, Christopher Ruel, Daniel Schmolze, Mireya Murga, Aileen Tang, Norma Martinez, Misagh Karimi, George Somlo, Peter Lee, James Waisman, Yuan Yuan. Immunogenicity of pembrolizumab and doxorubicin in a phase I trial for patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-08-03.