Abstract CT120: Phase II study of radiotherapy in combination with chemotherapy and immunotherapy in patients with PD-L1-positive metastatic triple-negative breast cancer

Background: Metastatic triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking hormone receptor expression and HER2 over-expression. Metastatic TNBC has been difficult to treat due to a general lack of targeted therapies, however, immunotherapy has shown substantial activity in a subset of patients. In metastatic TNBC patients with PD-L1-positive (combined positive score (CPS) ≥ 10) disease, KEYNOTE-355 demonstrated that addition of pembrolizumab (PD-1 inhibitor) to chemotherapy (nab-paclitaxel, paclitaxel, or carboplatin/gemcitabine) prolonged median progression free survival (PFS) compared to chemotherapy alone (9.7 months vs 5.6 months). Median 1-year PFS was also increased from 12.0% to 39.1% in these patients treated with pembrolizumab. These data led to the FDA approval of pembrolizumab with chemotherapy in PD-L1-positive metastatic TNBC patients. Despite these encouraging results, the majority of patients do not have long-term disease control. Radiotherapy (RT) in combination with immunotherapy and chemotherapy represents a promising avenue to prolong long-term response. RT can stimulate cellular damage and cause the release of tumor antigens, promoting a local T cell response. In addition, localized RT can result in the shrinkage of distant sites of metastasis via the abscopal effect when used with immunotherapy. The purpose of this study is to investigate the benefit of combining RT with pembrolizumab and chemotherapy in patients with metastatic PD-L1-positive TNBC. Methods: This two-stage, single-arm phase II study will assess the efficacy of RT in combination with nab-paclitaxel/paclitaxel plus pembrolizumab in PD-L1-positive unresectable or metastatic TNBC patients aged ≥18 years. To be included, patients must have only received < 1 prior line of systemic therapy in the metastatic setting or adjuvant/neoadjuvant setting if metastatic recurrence was within 12 months of treatment. The primary endpoint of the study is the 1-year PFS rate and a total of 29 subjects will be enrolled. Patients will be treated first with RT followed by the initiation of systemic therapy within seven days. Ablative RT will be directed at 1-4 sites of metastatic disease in 3 fractions of 8 Gy each. Nab-paclitaxel or paclitaxel will be given weekly day 1, day 8 every 3 weeks and pembrolizumab will be given every 3 weeks. Imaging will be repeated every 9 weeks to assess response based on RECIST 1.1. Systemic treatment will be continued until disease progression or intolerable toxicity. Treatment beyond progression will be allowed in certain patients who had initial response followed by progression. In these patients, repeat RT to new sites of disease can be administered with continuation of pembrolizumab to investigate the potential of re-sensitizing patients to immunotherapy. Blood will be collected before and after treatment for immune profiling. The sample size was determined using a null hypothesis for the 1-year PFS rate of 39% and an alternate hypothesis of 60%. The sample size of 29 yields a power of 80% to detect this difference with an alpha of 0.1 (1-sided). An interim analysis will be performed after enrollment of seventeen subjects in stage one. Citation Format: Anna R. Schreiber, Jodi Kagihara, Andrew Nicklawsky, Dexiang Gao, Anosheh Afghahi, Anthony Elias, Peter Kabos, Elena Shagisultanova, Todd Pitts, Julie Lang, Sana Karam, Virginia Borges, Christine Fisher, Jennifer R. Diamond. Phase II study of radiotherapy in combination with chemotherapy and immunotherapy in patients with PD-L1-positive metastatic triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT120.