Blood-based tumor mutational burden from circulating tumor DNA and immune checkpoint inhibitors in advanced prostate cancer.

Abstract

165 Background: A prior study of patients with advanced cancers treated with immune checkpoint inhibitors (ICI) associated improved overall survival with tissue tumor mutational burden above the 80th percentile in each histology (tTMB-H). TMB can also reliably be calculated via liquid biopsy (bTMB), and trends higher than tTMB in analogous tumors. Here, we generate a plasma-informed benchmark for bTMB-H in advanced prostate cancer and report preliminary data from an ongoing multi-institutional case series of patients treated with ICI. Methods: Circulating tumor DNA (ctDNA) next generation sequencing (NGS) results from 3,504 patients with advanced prostate cancer who received a Guardant360 liquid biopsy within a 12-month period were analyzed. The 80th percentile of TMB was defined as the benchmark for bTMB-H in this cohort, and prevalence of microsatellite instability (MSI-H) was determined. Subsequently, clinical data were collected from patients across five institutions who received pembrolizumab based on bTMB scores or other tumor characteristics (i.e. CDK12 mutation). Results: Overall, mean and median bTMB were calculated as 12.34 mut/Mb and 8.61 mut/Mb, respectively (range: 0 – 1164.75 mut/Mb). The 80th percentile of bTMB was 13.4 mut/Mb and the 90th percentile was 16.6 mut/Mb. 2.6% of patients were both MSI-H and bTMB-H. No patients with bTMB < 13.4 mut/Mb (TMB-L) were found to be MSI-H. Ten patients from five institutions received pembrolizumab (8 monotherapy) after a median of 4.5 lines of prior therapy (Table). Four patients were MSI-H. The 3 patients in the cohort with PSA decreases > 50% had both MSI-H and bTMB ≥ 13.4 mut/Mb. Per RECIST criteria, disease was controlled (CR, PR, SD) in 6 of 7 (86%) patients with bTMB scores ≥ 13.4 mut/Mb. Conclusions: These data continue to affirm that ctDNA NGS is a practical and cost-effective means of assessing potential predictors of ICI activity in patients with advanced prostate cancer. Preliminary data from this growing cohort of patients who have received ICI guided by bTMB scores and other molecular parameters identified via ctDNA NGS, including MSI-H, demonstrate a clinical benefit from therapy. Further studies are warranted for contextualizing individual tumor bTMB scores with established, pathology-specific benchmarks.[Table: see text]

A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis

“…The TMB 80th percentile differs between cancer types and has been described based on bTMB with bTMB-H for prostate cancer based on ctDNA being 13.4 mut/Mb [17]. Rauterkus et al [5] showed pembrolizumab used in mCRPC patients with bTMB ≥ 13.4 mut/Mb had disease control in 86% of patients demonstrating the ability of bTMB to predict response. However, this also included patients who had concurrent MSI-H status.…”

“…The o cial companion diagnostic test for assessing tissue TMB (tTMB) and microsatellite status for pembrolizumab is FoundationOne®CDx using tumor tissue [3]. However, circulatory DNA via blood plasma (ctDNA) represents a convenient and non-invasive analysis for determining microsatellite status and blood TMB (bTMB) with bTMB values in the 80th percentile demonstrating e cacy across tumor types [4,5,6]. It remains unknown if TMB should be interpreted differently across tumor types.…”

“…Based on the above, pembrolizumab has a modest e cacy in a tTMB-driven patient population. Rauterkus et al [5] showed 3 504 patients with advanced prostate cancer underwent Guardant360 testing and the 80th percentile bTMB was ≥ 13.4 mut/Mb. In the study [5], six of the seven patients (86%) with bTMB ≥ 13.4 had disease control when treated with pembrolizumab demonstrating the ability of bTMB to predict response to immunotherapy.…”

“…Rauterkus et al [5] showed 3 504 patients with advanced prostate cancer underwent Guardant360 testing and the 80th percentile bTMB was ≥ 13.4 mut/Mb. In the study [5], six of the seven patients (86%) with bTMB ≥ 13.4 had disease control when treated with pembrolizumab demonstrating the ability of bTMB to predict response to immunotherapy. However, co-occurring MSI-H status was not clearly de ned in this patient population.…”