Park, BH

Abstract Background: Thirty percent of patients with breast cancer may experience chest wall recurrence, which is associated with a higher risk of developing distant metastases and a poor prognosis. Cancer cells may evade immune rejection through the programmed cell death 1 (PD-1) pathway. Pembrolizumab, an anti-PD-1 antibody, binds PD-1 and inhibits its interaction with the programmed death ligand 1 (PD-L1) to facilitate tumor immune rejection. We hypothesize that pembrolizumab may be an effective therapy in chest wall recurrence, given the inflammatory nature, and the high expression of PD-1 in tumors with lymphovascular invasion. Platinum agents may enhance anti-tumor immunity in a synergistic manner, and the combination of pembrolizumab and carboplatin has demonstrated efficacy in advanced lung cancer. In this study, the combination of pembrolizumab and carboplatin is being evaluated in breast cancer patients with chest wall disease. Methods: This is a randomized phase II study of breast cancer patients with advanced, unresectable breast cancer involving the chest wall, being conducted through the Translational Breast Cancer Research Consortium (TBCRC). Patients may have hormone resistant disease (at least 2 prior lines of hormone therapy), triple negative breast cancer, or refractory HER2+ disease for enrollment. They may have other sites of distant metastases, have received any number of prior lines of therapy, have had prior surgery, but prior chest wall radiation is not necessary. Eighty-four patients at 7 TBCRC sites will be randomized 2:1 to treatment with pembrolizumab 200 mg IV and carboplatin AUC 5 IV every 3 weeks followed by pembrolizumab 200 mg IV alone every 3 weeks (Arm A, n=56) or carboplatin AUC 5 IV every 3 weeks (Arm B, n=28), with an option for patients in Arm B to cross-over to single agent pembrolizumab 200 mg IV every 3 weeks (arm Bx) on progression. Patients will undergo imaging with CT chest, abdomen, and pelvis at baseline and every 2 cycles of treatment for response evaluation. The primary endpoint is the disease control rate in the chest wall and distant sites at 18 weeks of treatment, and this study is powered to determine a 20% difference in disease control rates between arms A and B (hazard ratio of 0.52, α= 0.10, β= 0.20). After 18 patients are enrolled into Arm B, an interim analysis for futility will be conducted to enable early closure of that arm for lack of efficacy. Secondary endpoints in the study are toxicity, progression free survival, and response based on PD-L1 expression and irRECIST. Exploratory endpoints, which will be studied using peripheral blood testing and chest wall tumor biopsies at baseline and after 2 cycles of treatment, include determining associations of response with changes in tumor and peripheral blood immune composition, soluble PD-L1 expression, circulating tumor cells, cell free DNA, and tumor PD-L1 and MYC genomic expression. Ultimately this study promises to improve our understanding of checkpoint inhibition and chemotherapy for chest wall disease, and the underlying mechanism of action. This study is open for enrollment and 2 patients are currently enrolled. (NCT03095352). Citation Format: Vidula N, Goga A, Hwang J, Liu MC, Park BH, Nanda R, Pohlmann PR, Storniolo AM, Brufsky A, Abramson V, Rugo HS. A randomized phase II study of pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease, with immunologic and genomic correlative studies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-04.

Abstract Background: Patients with breast cancer (BC) and chest wall disease have limited treatment options. We hypothesize that checkpoint inhibition may be an effective treatment approach due to the inflammatory nature of chest wall infiltration, and the association of PD-1 expression with lymphocytic infiltration. Platinum chemotherapy may facilitate anti-tumor immunity in a synergistic manner, and clinical studies of the PD-1 inhibitor pembrolizumab with platinum combinations have been effective in the treatment of advanced lung cancer. In this study, we will evaluate the combination of carboplatin and pembrolizumab in BC patients with chest wall disease. Methods: This is a randomized phase II multicenter study in the TBCRC including patients with advanced, unresectable BC with hormone resistant or triple negative chest wall disease. Patients may have had prior surgery, prior chest wall radiation is not required, and other sites of distant metastases are allowed. Eighty-four patients at TBCRC sites will be randomized 2:1 to receive pembrolizumab and carboplatin (n=56, Arm A) or carboplatin alone (n=28, Arm B) until disease progression. Patients randomized to Arm B may cross-over following progression to pembrolizumab alone (Arm Bx). Patients in Arm A will be treated with pembrolizumab 200 mg IV and carboplatin AUC 5 IV every 3 weeks for at least 6 cycles followed by maintenance pembrolizumab 200 mg IV every 3 weeks if stable or responding disease. Patients in Arm B will be treated with carboplatin AUC 5 IV every 3 weeks until progression, then may cross-over to pembrolizumab 200 mg IV every 3 weeks alone (Arm Bx). An interim analysis for futility will be performed after 18 patients are enrolled into Arm B to allow early closure of that arm for lack of efficacy. The primary endpoint is disease control rate at 18 weeks of treatment; the study is powered to detect a 20% difference in disease control rates between arms (hazard ratio 0.52, α= 0.10, β= 0.20). Secondary endpoints include progression free survival, toxicity, and response based on PD-L1 expression and irRECIST. Exploratory endpoints include association of response with a number of biomarkers including tumor PD-L1 gene expression, tumor and peripheral blood immune composition and cytokine expression, peripheral T-cell PD-1 expression, circulating tumor DNA, circulating tumor cells, and tumor MYC genomic expression using tumor biopsy and peripheral blood testing before and after treatment. This study should be open to accrual by August of 2017. (NCT03095352) Citation Format: Vidula N, Goga A, Krummel M, Hwang J, Liu M, Park BH, Nanda R, Pohlmann P, Storniolo AM, Van Poznak C, Brufsky A, Abramson V, Wolff A, Rugo HS. TBCRC 044: A randomized phase II study of pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease [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 OT1-02-03.