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Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Additive Clinical Utility of Microsatellite Instability and Tumor Mutational Burden to Predict Immune Checkpoint
Nicolas Sayegh1,2, Ryon P Graf3, Umang Swami1
1Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Purpose:
Immune checkpoint inhibitors (ICI) have shown limited efficacy in unselected patients with metastatic castration-resistant prostate cancer (mCRPC). However, ICIs are approved for biomarker-defined subsets: microsatellite instability-high (MSI-H) and/or high tumor mutational burden (TMB-H). The efficacy of ICIs in TMB-H but not MSI-H disease remains unclear, and limited data exist evaluating ICI outcomes associated with blood-based MSI (bMSI) in mCRPC.
Experimental Design:
This study used the United States-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database. Patients with tissue-assessed MSI (tMSI) and TMB (tTMB) status by an algorithm supporting an FDA-approved CDx for pembrolizumab were included if treated with single-agent ICI. Separately, outcomes on ICI associated with bMSI were assessed, including if treated with single-agent ICI or taxane.
Results:
Among 2,965 patients with mCRPC, tMSI-H (3.2%) was nearly always also tTMB ≥10 mut/Mb (4.7%). In 84 ICI-treated patients, time to next treatment (TTNT) and overall survival (OS) were more favorable in tMSI-H with any TMB [TTNT HR, 0.18; 95% confidence interval (CI), 0.09-0.37 and OS HR, 0.32; 95% CI, 0.15-0.66] and tTMB ≥10 without tMSI-H (TTNT HR, 0.18; 95% CI, 0.04-0.48 and OS HR, 0.20; 95% CI, 0.05-0.77) compared with tTMB <10 without tMSI-H group. In intrapatient assessments, patients with tTMB ≥10 had more favorable TTNT with subsequent ICI versus prior taxane. Detection of bMSI-H was associated with more favorable TTNT on ICI (HR, 0.34; 95% CI, 0.14-0.83) and OS (HR, 0.21; 95% CI, 0.06-0.75) when tumor fraction ≥1%.
Conclusions:
These findings add support for tTMB and tMSI in predicting ICI monotherapy benefit in mCRPC and provide evidence supporting bMSI testing when tissue is unavailable.
Insights
Immune checkpoint inhibitors (ICIs) show improved outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients with high tumor mutational burden (tTMB) or microsatellite instability-high (MSI-H) disease. Blood-based MSI (bMSI) also predicts favorable ICI response when tissue testing is unavailable.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) demonstrate limited efficacy in unselected metastatic castration-resistant prostate cancer (mCRPC) patients.
- Current approvals for ICIs in mCRPC are restricted to biomarker-defined subsets, specifically microsatellite instability-high (MSI-H) and/or high tumor mutational burden (TMB-H).
- The efficacy of ICIs in TMB-H but not MSI-H disease, and outcomes associated with blood-based MSI (bMSI) in mCRPC, remain incompletely understood.
Purpose of the Study:
- To evaluate the efficacy of ICIs in mCRPC based on tissue-assessed MSI (tMSI) and TMB (tTMB) status.
- To assess ICI outcomes in relation to blood-based MSI (bMSI) status.
- To compare ICI efficacy with taxane treatment in patients with tTMB ≥ 10.
Main Methods:
- Utilized the US-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database (FH-FMI CGDB).
- Included patients with tMSI and tTMB status treated with single-agent ICI, or ICI or taxane for bMSI assessment.
- Analyzed time to treatment failure (TTNT) and overall survival (OS) based on biomarker status.
Main Results:
- Among 2,965 mCRPC patients, tMSI-H (3.2%) frequently overlapped with tTMB ≥ 10 mut/Mb (4.7%).
- In 84 ICI-treated patients, tMSI-H and tTMB ≥ 10 (without tMSI-H) were associated with significantly more favorable TTNT and OS compared to tTMB < 10.
- Blood-based MSI-H detection correlated with improved TTNT and OS on ICI when tumor fraction was ≥ 1%.
Conclusions:
- Tissue-assessed TMB and MSI are valuable biomarkers for predicting ICI monotherapy benefit in mCRPC.
- Blood-based MSI testing offers a viable alternative for predicting ICI response when tissue is unavailable.
- These findings support expanded use of genomic biomarkers to guide ICI treatment selection in mCRPC.
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