A phase II study of dual immune checkpoint blockade (ICB) plus androgen receptor (AR) blockade to enhance thymic T-cell production and immunotherapy response in metastatic breast cancer (MBC).

Abstract

TPS1106 Background: ICB (atezolizumab, anti-PD-L1) is known to improve survival when added to chemo, however only in PD-L1-positive, triple-negative MBC. ICB is less effective in hormone receptor positive (HR+) MBC, or when administered following palliative chemo. Novel approaches are required to broaden clinical benefit of ICB, particularly in PD-L1-negative, HR+, or chemo-experienced MBC. Dual ICB with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) is associated with enhanced activity in melanoma other malignancies, but has not been explored extensively in MBC. Androgen receptor (AR) blockade, in addition to known direct cytostatic effects in AR-expressing MBCs (50% of TNBC, > 75% of HR+ MBC), may also modulate immune response. AR blockade has been shown experimentally to stimulate thymic production of naïve T-cell clones, which in turn can facilitate de novo anti-tumor immune responses. Concurrent ICB can enhance the activity of these T-cell clones by interfering with PD-1-mediated peripheral tolerance. This combination approach is promising in MBC in light of known AR positivity, and the routine use of lymphodepleting chemo regimens in the curative-intent setting. Methods: This is a phase II trial of dual immune checkpoint blockade (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) plus AR blockade (bicalutamide, 150mg PO daily, dose reduction allowed) in triple-negative MBC (cohort A: AR-positive [ > 1% by IHC]; cohort B: AR-negative) or HR+ MBC (cohort C) in subjects who received 0/1 prior chemotherapies in the non-curative setting. Objectives include 24-week clinical benefit rate by iRECIST (primary), safety (CTCAE v4.0), and other response measures (RECIST1.1, PFS, OS). Efficacy for each cohort is defined as > 20% improvement in response over historical control (30% per EMBRACE clinical trial) employing a Simon 2-stage design to minimize futility (n = 46/cohort, stage I n = 15). Thymic generation of T-cells will be measured via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay) and TcR excision circles (TRECs), as well as real-time flow cytometry using surrogate cell surface markers of recent thymic emigration. Enrollment has commenced, sites: Earle A. Chiles Research Institute (Portland, OR), Memorial Sloan Kettering Cancer Center (New York, NY). Clinical trial information: NCT03650894.

A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer

“…Preclinical evidence has suggested a potential therapeutic synergy by combining AR modulation and PD-1 blockade. Androgens are immunosuppressive and target both innate and adaptive immune systems to dampen the immune response [28][29][30][31][32][33][34]. Inhibition of AR sensitizes cancer cells to immunemediated killing.…”

“…AR suppresses PD-L1 expression by binding to the PD-L1 promotor and directly attenuating PD-L1 gene transcription [29,30]. In addition, AR signaling inhibits thymocyte production [31], whereas AR blockade has been shown to increase naive T cell generation resulting in a larger diversity of T cell repertoire that could potentially respond to PD-1 blockade [32,33]. Moreover, AR blockade yielded increased survival benefits to vaccination in a murine prostate cancer model [34].…”

“…In addition, preclinical studies demonstrated that blockade of AR stimulates thymic volume and maturation of naive T cell clones, which can facilitate antitumor immune responses and induce synergic effect with ICI [32, 37]. Currently, a phase II trial studying dual immune checkpoint blockade (nivolumab plus ipilimumab) plus bicalutamide is ongoing in patients with metastatic AR+ HER2− breast cancer (BC) and TNBC [33]. Our modest result could also reflect modest efficacy of enobosarm as an AR‐targeted agent.…”

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

“…In a pilot study of anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab), the estimated ORR for TNBC was 43% (n = 4/7) [40]. A study of dual immune checkpoint blockade using nivolumab and ipilimumab with androgen receptor blockade in metastatic HR-positive and TNBC is currently enrolling [41]. Furthermore, a number of early phase studies are ongoing to evaluate the safety and efficacy of anti-PD-1/ L1 with other immune checkpoint agents, including modulators of macrophage or natural killer cell activity.…”

“…Additionally, a phase II study combining bicalutamide with dual immune checkpoint blockade with nivolumab plus ipilimumab is currently underway (NCT03650894) [41].…”