A phase II study of nivolumab plus ipilimumab and androgen receptor antagonist bicalutamide to stimulate thymic T cell generation in HER2-negative metastatic breast cancer

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oregon; chiles


Background: Systemic chemotherapy is used commonly in breast cancer and is associated with lymphopenia, potentially limiting efficacy of immune checkpoint blockade. The androgen receptor (AR) serves as a negative regulator of thymic function. AR antagonists, such as bicalutamide, may stimulate thymic production of naïve T-cells, which may help to restore lymphocyte diversity and augment immunotherapy response. The AR is expressed in 50% of hormone receptor negative (HR-) metastatic breast cancer (MBC) and >75% of HR+ MBC, and bicalutamide is clinically active with stable disease as best response. We hypothesize that bicalutamide could be combined with dual immune checkpoint blockade (anti-programmed death 1, nivolumab; plus anti-cytotoxic T-lymphocyte antigen 4, ipilimumab), stimulating T-cell production and resulting in durable clinical response. Methods: This is a phase II Simon 2-stage trial of nivolumab (240 mg IV q2w), ipilimumab (1 mg/kg IV q6w), and bicalutamide (150mg oral daily) for first- or second-line treatment of HER2-negative MBC (NCT03650894). The primary endpoint is iRECIST 24-week clinical benefit rate (CBR), evaluated separately for HR+ MBC (n=15) and AR+/HR- MBC (n=15). An optimum Simon 2-stage design (80% power, 5% one-sided alpha) is employed to evaluate an alternative hypothesis of >50% CBR compared to historical control of < 30% CBR for conventional chemotherapy, with expansion of each cohort planned if ≥6/15 responses are observed. Secondary outcomes include best overall objective response rate (ORR), progression-free and overall survival (PFS,OS), and safety. Exploratory endpoints include assessment of peripheral T-cell counts and T cell receptor excision circles (TREC PCR, Mayo Laboratories, a surrogate of thymic T-cell production) over time. Results: Durable responses were observed, with an ongoing complete response at 41+ months in a patient who discontinued due to toxicity (AR+/HR- cohort, PD-L1 CPS score 3%). Therapy was tolerated with a toxicity profile consistent with prior studies of ipilimumab & nivolumab, with five subjects (19%) requiring treatment discontinuation related to toxicity. Outcomes by cohort and PDL1 are summarized in Table 1. Using mixed effects linear models, therapy was associated with a significant expansion of CD8+ T cells (23/mcL/month, p< .01) but not CD3+ T cells (7/mcL/month, p=.59) or CD4+ T cells (4/mcL/month, p=.65). Baseline TREC counts were higher in younger participants (mean: < 50y 2156/mcL; 50-65y 961/mcL; >65y 311/mcL). TRECs did not increase globally, however TREC expansions were observed in several younger participants. Conclusions: The regimen of ipilimumab, nivolumab, plus bicalutamide is safe and clinically active in 1st/2nd-line HER2-negative MBC. Neither cohort crossed the Simon futility barrier for cohort expansion, however durable responses were observed including in PD-L1-negative patients, highlighting the unmet need for biomarkers to identify candidates for chemotherapy-sparing checkpoint blockade. Further research is indicated to evaluate the impact of AR antagonists on T-cell function and thymic stimulation in MBC. Acknowledgements: Drug and study support was provided by Bristol-Myers Squibb and The BMS International Immuno-Oncology Network (II-ON).

Clinical Institute


Clinical Institute

Women & Children




Page D, Hall A, Collins K, Moxon N, Mellinger S, Kelly T, Kelley A, Fredrich N, Seino A, Liberatore G, Conlin A, Topp Z, Perlewitz K, Stanton S, Urba W, Wu Y, Martel M, Sun Z, Kogushi Y, Redmond W, Traina T, Guculp A. SABCS Annual Meeting; December 5-9; San Antonio, TX. 2023: P03-06-09

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