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I-SPY2 TRIAL predictive biomarker analysis shows promise to improve targeted therapy for high-risk breast cancers

New Data Analyses Presented at San Antonio Breast Cancer Symposium Spotlight Predictive Response to Pembrolizumab and MK-2206, and Demonstrate Improved Predictive Performance of Breast MRI

SAN FRANCISCO, C.A., December 7, 2017 – Investigators with the I-SPY TRIALs for Breast Cancer, sponsored and managed by Quantum Leap Healthcare Collaborative, presented analyses today at the 2017 San Antonio Breast Cancer Symposium (SABCS) detailing four promising new or improved pathways for predicting response to therapeutic agents in the neoadjuvant setting. Three of the analyses provide new insights into biomarkers associated with the triple negative breast cancer subset, and a fourth concludes that combining measurement of functional tumor volume (FTV) and apparent diffusion coefficient (ADC) improves the predictive performance of breast MRI.

The I-SPY TRIAL was designed to rapidly screen promising experimental treatments and identify those most effective in specific patient subgroups based on molecular characteristics (biomarker signatures). The multi-center, adaptively randomized I-SPY 2 platform trial uses pathological complete response (pCR) as the primary endpoint to identify investigational agents that will improve outcomes in women with stage II/III breast cancer at high risk for early recurrence. The trial investigates all signatures based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status.

“In-depth biological and imaging analyses comparing patients who respond to an investigational regimen versus those who do not respond, reveals the mechanisms of response and resistance,” said Dr. Esserman, I-SPY 2 Principal Investigator. “This new knowledge provides critical insights for adapting I-SPY 2 so that we can give the right therapy to the patient.”

In the first analysis, expression of PI3K/AKT pathway genes were evaluated as specific predictive markers of the AKT-inhibitor MK-2206 in the I-SPY 2 TRIAL. MK-2206 graduated from the trial in 2015 in three biomarker signatures: all hormone receptor (HR)-negative, all HER2-positive, and HR-negative/HER2-positive. While none of the candidate markers tested succeed as specific predictors of response to MK-2206 in the population as a whole, PIK3CA levels within the triple-negative subset associate with pCR specifically in the MK2206 arm, and may merit further evaluation in future trials. Abstract: P2-09-08.

In a second analysis, diffusion-weighted MRI measurements were shown to improve predictive performance of breast MRI for predicting pCR. By combining apparent diffusion coefficient (ADC) with standard functional tumor volume (FTV) MRI measurement, investigators were able to demonstrate a statistically significant improvement over the model using FTV alone. Further improvement can be achieved by adjusting the combined model with breast cancer subtype defined by HR and HER2 status. Abstract: P2-09-23.

Data from a third analysis looked at immune infiltrates (assessed through multiplex fluorescence immunohistochemistry) and immune gene expression signatures as predictors of response to the anti-PD-1 therapy pembrolizumab. Fourteen expression signatures representing different immune cell types (TILs, T cells, CB8 T cells, exhausted T cells, Th1, Tregs, cytotoxic cells, NK, NK CD56dim, dendritic cells, mast cells, B cells, macrophages, and neutrophils) were evaluated.

Ten out of the 14 were associated with a response in the pembrolizumab arm. Higher expression levels of nine of these cell-type signatures were associated with higher pCR rates (T cells, exhausted T cells, Th1, cytotoxic cells, NK, NK CD56dim, dendritic cells, B cells, and macrophages), whereas higher mast cell signature expression is associated with non-pCR. Of these, three signatures (Th1, B cells and dendritic cells) showed significant interaction with response to pembrolizumab. Of note, dendritic cells and Th1 cells may be specific predictors for Pembro in both the population as a whole, and the triple negative subtype. The presence of mast cells was shown to possibly impede response, especially in HR+HER2- patients. Abstract: PD6-08.

Note: Pembrolizumab is marketed by Merck & Co., Inc., Kenilworth, N.J., USA under the brand name KEYTRUDA®.