A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer

Abstract

Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune-gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline. Eighteen evaluable patients were accrued (11 ER-positive; seven TNBC). Only three patients had a response (ORR = 17%), thus the study did not proceed to the second stage. Responses were only observed in patients with TNBC (ORR = 43%). Responders versus non-responders had upregulation of CD8, granzyme A, and perforin 1 gene expression, and higher mutational and neoantigen burden. Patients with TNBC had an oligoclonal shift of the most abundant TCR-beta clonotypes compared to those with ER-positive disease, p = 0.004. We conclude responses are low in unselected metastatic breast cancer, however, higher rates of clinical benefit were observed in TNBC. Immunogenomic dynamics may help identify phenotypes most likely to respond to immunotherapy.

In silico simulation of a clinical trial with anti-CTLA-4 and anti-PD-L1 immunotherapies in metastatic breast cancer using a systems pharmacology model

“…Since the model aims at predicting patients' responses to immunotherapies, we define the main outputs to be: analysis of time-dependent tumour size change, effector T-cell production and antigen-presenting cell maturation in TDLNs. To illustrate the predictions, we first consider a baseline case and show the dose response to each monotherapy, anti-CTLA-4 and anti-PD-L1, and to their combination, following the regimen of the clinical trial [20]. In characterizing tumour growth, we use RECIST criteria [39], as was done in the clinical trial.…”

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

“…Studies in breast cancer with dual immune checkpoint blockade have been limited, though preclinical studies have shown promise with this combination in TNBC [39]. 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].…”

Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations

“…Detailed information on the tumor microenvironment may serve as a predictive marker for immunomodulatory therapies and may also be useful for development of new treatment strategies, including personalized T cell‐mediated cancer immunotherapy and neoantigen vaccine therapy . TCR repertoire analyses could be used to monitor the dynamics of T cell clonality and the individual tumor‐reactive T cell clones in cancer patients treated with ICI . Profiling the immune repertoire by quantifying the TCR composition in tumor tissues enables assessment of T cell diversity and immune‐related characteristics.…”