Phase II study of pembrolizumab plus mifepristone in patients with advanced HER2-negative breast cancer.

person Nan Chen University of Chicago, Chicago, IL info_outline Nan Chen, Elena Michaels, Poornima Saha, Murtuza M. Rampurwala, Olwen Mary Hahn, Frederick Matthew Howard, Gini F. Fleming, Theodore Karrison, Suzanne D. Conzen, Rita Nanda

Authors person Nan Chen University of Chicago, Chicago, IL info_outline Nan Chen, Elena Michaels, Poornima Saha, Murtuza M. Rampurwala, Olwen Mary Hahn, Frederick Matthew Howard, Gini F. Fleming, Theodore Karrison, Suzanne D. Conzen, Rita Nanda Organizations University of Chicago, Chicago, IL, University of Chicago Medicine, Chicago, IL, NorthShore University Health System, Evanston, IL, University of Chicago Medical Center, Chicago, IL, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, UT Southwestern Medical Center, Dallas, TX Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Corcept Pharmaceuticals, Merck, U.S. National Institutes of Health Background: Metastatic breast cancer is incurable, and novel treatment (tx) strategies are needed. Single agent immune checkpoint inhibitor (ICI) tx has limited efficacy; combination approaches may yield better results. Multiple mechanisms of glucocorticoid-induced immunosuppression have been proposed, including the suppression of the cytotoxic Th1 cytokine response via glucocorticoid receptor (GR) activation. We hypothesize that pretreatment with a GR antagonist shifts the cytotoxic immune response toward Th1, thus enhancing response to ICIs. We present the safety and efficacy of the combination of pembrolizumab and mifepristone in advanced HER2-negative breast cancer. Methods: This (NCT03225547) was a phase II non-randomized study of pembrolizumab and mifepristone in patients (pts) with advanced HER2-negative breast cancer. Pts with prior ICI tx were excluded. Pts received mifepristone 300mg daily and pembrolizumab 200mg every 3 weeks; mifepristone was started 7 days prior to pembrolizumab. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety and tolerability. Results: 18 patients were enrolled from March 2018 – November 2020; 10 patients with TNBC (cohort 1) and 8 patients with HR+ BC (cohort 2). Mean age was 53 yrs (range 33-74) and 33% of patients were self-reported Black. In cohort 1, 50% of patients were tx naive in this advanced setting, and 90% of patients had < 2 prior lines of tx. In cohort 2, 25% of patients had not received prior chemo in the metastatic setting. The overall ORR was 6%. One pt with TNBC had a complete response (CR). She received 36 cycles of tx; tx was discontinued due to mucositis and rash, and she remains in CR at >48 mos from start of tx. No patients in cohort 2 had a partial or complete response. The most common treatment-related adverse events were rash (61%), thyroid abnormality (17%), and pruritis (17%). 45% of patients experienced a grade 3 or 4 adverse event; all except one (hypokalemia) were due to rash. Rash was described as maculopapular dermatitis. The DCR at 18 weeks was 33.3% in the overall population; it was 44.4% in cohort 1 and 16.7% in cohort 2. Overall median PFS was 1.9 months [95% CI 1.8 – 3.6]. Overall median OS was 12.9 months [95% CI 5.8 – 23.0]. Conclusions: While this regimen demonstrated efficacy in a small subset of patients, including one pt with long-term CR, given the non-randomized design, we cannot determine if mifepristone enhanced the efficacy of ICI. In addition, a higher than anticipated rate of skin toxicity, possibly related to mifepristone enhancing the activity of ICI, was observed in the study, leading to early closure. While the benefit/risk analysis of this combination does not support further evaluation, additional investigation of alternative chemotherapy-free, immunomodulatory strategies is warranted. Clinical trial information: NCT03225547.

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