Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer. Issue 2 (4th February 2022)

• Record Type: Journal Article
• Authors: Anders, Carey K; Woodcock, Mark G; Van Swearingen, Amanda E D; Moore, Dominic T; Sambade, Maria J; Laurie, Sonia; Robeson, Alexander; Kolupaev, Oleg; Cuaboy, Luz A; Garrett, Amy L; McKinnon, Karen; Cowens, Kristen; Bortone, Dante; Calhoun, Benjamin C; Wilkinson, Alec D; Carey, Lisa; Jolly, Trevor; Muss, Hyman; Reeder-Hayes, Katherine; Kaltman, Rebecca; Jankowitz, Rachel; Gudena, Vinay; Olajide, Oludamilola; Perou, Charles; Dees, E Claire; Vincent, Benjamin G; Serody, Jonathan S
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 2(2022)
• Publication Date: 2022-02-04
• Subjects: breast neoplasms -- clinical trials -- phase II as topic -- immunotherapy -- programmed cell death 1 receptor; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2021-003427
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Purpose: Triple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have demonstrated that intratumoral regulatory T cells (Tregs ) dampen the antitumor response to ICI. We performed a single-arm phase II trial to evaluate the efficacy of a single low dose of cyclophosphamide (Cy) to deplete Tregs administered before initiating pembrolizumab. Patients and methods: 40 patients with pretreated metastatic TNBC were enrolled. The primary endpoints were progression-free survival (PFS) and change in peripheral blood Tregs after Cy. Secondary endpoints included overall response rate (ORR), duration of response, overall survival, treatment-related adverse events (AEs), and correlative evaluations. Results: Median PFS was 1.8 months, and the ORR was 21%. Tregs were not significantly decreased after Cy prior to ICI (−3.3%, p=0.19), and increased significantly after the first cycle of therapy (+21% between cycles 1 and 2, p=0.005). Immune-related AEs were similar to historical pembrolizumab monotherapy, and were associated with response to therapy (p=0.02). Patients with pretreatment tumors harboring increased expression of B cell metagene signatures and increased circulating B cell receptor repertoire diversity were associated with clinical response and immune-related toxicity (IRT). Conclusions: Among patients with heavily pretreated TNBC, Cy prior to pembrolizumab did not significantly deplete Tregs, and in those with decreased numbers there was rapid recovery following therapy. Increased B cell gene expression in baseline samples was associated with clinical response and IRT.