A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer - PubMed (original) (raw)
Clinical Trial
. 2021 Feb;26(2):99-e217.
doi: 10.1002/onco.13583. Epub 2020 Nov 24.
Jin Sun Lee 1, Susan E Yost 1, Paul H Frankel 2, Christopher Ruel 2, Colt A Egelston 3, Weihua Guo 3, John D Gillece 4, Megan Folkerts 4, Lauren Reining 4, Sarah K Highlander 4, Kim Robinson 1, Simran Padam 1, Norma Martinez 1, Aileen Tang 1, Daniel Schmolze 5, James Waisman 1, Mina Sedrak 1, Peter P Lee 3, Joanne Mortimer 1
Affiliations
- PMID: 33141975
- PMCID: PMC7873338
- DOI: 10.1002/onco.13583
Clinical Trial
A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer
Yuan Yuan et al. Oncologist. 2021 Feb.
Abstract
Lessons learned: The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor-targeted therapy in combination with immune checkpoint inhibitors are warranted.
Background: Luminal androgen receptor is a distinct molecular subtype of triple-negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR). AR-targeted therapy has shown modest activity in AR-positive (AR+) TNBC. Enobosarm (GTx-024) is a nonsteroidal selective androgen receptor modulator (SARM) that demonstrates preclinical and clinical activity in AR+ breast cancer. The current study was designed to explore the safety and efficacy of the combination of enobosarm and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC).
Methods: This study was an open-label phase II study for AR+ (≥10%, 1+ by immunohistochemistry [IHC]) mTNBC. Eligible patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the safety of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis.
Results: The trial was stopped early because of the withdrawal of GTx-024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 (range 36-81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) complete response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16 weeks was 4 of 16 (25%). Median follow-up was 24.9 months (95% confidence interval [CI], 17.5-30.9). Progression-free survival (PFS) was 2.6 months (95% CI, 1.9-3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4-not reached [NR]).
Conclusion: The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16 weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand-1 (PD-L1). Future clinical trials combining AR-targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation.
Keywords: Androgen receptor; Enobosarm; Pembrolizumab; Triple-negative breast cancer.
© AlphaMed Press; the data published online to support this summary are the property of the authors.
Figures
Figure 1
Response to therapy and PFS. Black triangle, response started.Abbreviations: CR, complete response; NA, not applicable; PD, progression of disease; PR, partial response; SD, stable disease; X, off treatment for progression; Y, treatment completed.
Figure 2
CT imaging of exceptional response. (A): Baseline CT on July 24, 2017, showed subcarinal and right hilar conglomerate lymph adenopathy (the red arrows pointing the target lesions). (B): The bulky subcarinal adenopathy and right hilar is no longer seen on August 24, 2018. Patient continues to have no evidence of disease as of July 2020.Abbreviation: CT, computed tomography.
Figure 3
Kaplan‐Meier survival analysis. (A): Median PFS was 2.6 months (95% CI, 1.9.–3.1). (B): Median OS was 25.5 months (95% CI, 10.4–NR).Abbreviations: CI, confidence interval; OS, overall survival; NR, not reached; PFS, progression‐free survival.
Figure 4
Tumor biomarkers. Established biomarkers of response to immune checkpoint blockade were examined in pretreatment tumors. (A): Stromal TILs were evaluated by pathologists at City of Hope (n = 13). (B): Tumor mutation burden, depicted as m/MB, was evaluated by the TEMPUS xT genome alteration panel (n = 14). Statistics were assessed by two‐tailed Mann‐Whitney test. For both graphs, the median is represented by a line. Nonresponders (progressive disease + stable disease) in red, responders (complete response + partial response) in blue.Abbreviations: m/MB, mutations per megabase; NR, nonresponders; R, responders; TIL, tumor infiltrating lymphocyte.
Figure 5
Principal component analysis (PCA) of whole transcriptome gene expression in tumor tissues. (A): Heat map showing scaled expressions of top 10 genes with significantly differential expressions (false discovery rate ≤ 0.10) for responders versus nonresponders . (B): PCA diagram with type of specimen and response to treatment.Abbreviations: CR, complete response; LN, lymph node; NR, nonresponders; PC1, principle component 1; PC2, principle component 2; PD, progressive disease; PR, partial response; Pre‐Tx, pretreatment; R, responders; SD, stable disease.
Figure 6
Androgen receptor signaling pathway. Baseline tumor biopsies were assessed for gene differential gene expression of a defined AR signature. (A): Heatmap of gene expression of AR signature. Row orders are based on hierarchical clustering. Column orders are based on the specific response groups. (B): AR signature scores between responder and nonresponder groups. Statistics assessed by two‐tailed Mann‐Whitney test. Nonresponders (PD + SD) in red, responders (CR + PR) in blue.Abbreviations: AR, androgen receptor; CR, complete response; LN, lymph node; NR, nonresponders; PD, progressive disease; PR, partial response; R, responders; SD, stable disease.
Figure 7
CIBERSORT analysis of immune subsets. (A): Overall immune infiltration levels between responders and nonresponders. (B): Relative abundance of 18 immune cell types using CIBERSORTx with LM22 signature. The p values from two‐tailed Mann‐Whitney Nonresponders (progressive disease + stable disease) in red, responders (complete response + partial response) in blue.Abbreviations: NR, nonresponders; R, responders.
Figure 8
Peripheral immune characteristics. Peripheral blood mononuclear cells were evaluated by flow cytometry for immune phenotype distributions. (A): CD4+ T cells and (B) CD8+ T cells were evaluated for distribution of naive (CD45RA+ CCR7+), CM (CD45RA− CCR7+), EM (CD45RA− CCR7−), and EMRA (CD45RA+ CCR7−) subsets in pretreatment samples (n = 15). Within (C) non‐naive CD4+ T cells and (D) non‐naive CD8+ T cells, expression of molecules PD‐1, TIGIT, TIM‐3, KLRG1, and CD137 were evaluated in addition to fractions of Tregs (CD25+ CD127−) and Tfh (PD‐1+, CXCR5+) at pretreatment (n = 15). Fold change in expression of depicted molecules and cell subsets relative to pretreatment is shown for (E) CD4+ T cells, cycle 2; (F) CD8+ T cells, cycle 2; (G) CD4+ T cells, cycle 4; (H) CD8+ T cells cycle 4 (cycle 2, n = 15; cycle 4, n = 11). For all graphs, the median is represented by a line. Nonresponders (progressive disease + stable disease) in red, responders (complete response + partial response) in blue.Abbreviations: CM, central memory; EM, effector memory; EMRA, effector memory RA+; NR, nonresponder; R, responder; Tfh, follicular helper CD4+ T cell; Treg, regulatory CD4+ T cell.
Figure 9
Tumor genomic mutations (n = 13). Exome sequencing was performed for pretreatment specimens using Tempus (n = 12) and Foundation Medicine (n = 1).Abbreviations: CR, complete response; LN, lymph node; PD, progressive disease; PFS, progressive‐free survival; PR, partial response; Pre‐Tx, pretreatment; SD, stable disease.
Figure 10
Gut Microbiome Analysis. (A): Hierarchical clustering of species classified by MetaPhlAn2 by patient. (B): Shannon diversity by patient and day of collection. (C): Significant organisms determined by linear discriminant analysis effect size per survival outcomes (blue, progression‐free survival [PFS] >6 months; red, PFS <6 months).Abbreviations: CR, complete response; LDA, linear discriminant analysis; PD, progressive disease; PR, partial response; SD, stable disease.
References
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