Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab

Abstract

Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.

Efficacy of nivolumab and ipilimumab in patients with malignant pleural mesothelioma is related to a subtype of effector memory cytotoxic T cells: Translational evidence from two clinical trials

“…Recently, the first positive results were announced for the Checkmate-743 trial, demonstrating that combining aPD-1 and aCTLA-4 therapy led to improved OS in MPM, as compared to chemotherapy [19] . In contrast, aPD-1 monotherapy failed to improve PFS and OS [9] .…”

“…Phase II trials in MPM also suggest improved clinical responses upon combination ICI treatment, as the MAPS2 trial (nivolumab plus ipilimumab), the NIBIT-MESO trial (durvalumab (aPD-L1) plus tremelimumab (aCTLA-4)) and the INITIATE trial (nivolumab plus ipilimumab) reported better clinical responses upon combination ICI treatment than reported by trials that investigated monotherapy (nivolumab or pembrolizumab) [16] , [17] , [18] . Recently, the first positive results were announced for the Checkmate-743 [19] , a phase III trial that combined aPD-1 (nivolumab) with aCTLA-4 (ipilimumab) treatment in previously untreated MPM patients. These results are very promising, although the magnitude of the benefit is still awaited.…”

Clinically relevant prognostic and predictive markers for immune-checkpoint-inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC)

“…Longitudinal ctDNA analyses are also in the focus of translational research during ICI therapy. In the recently published INSPIRA trial, a prospective phase II study, 94 patients with solid tumors treated with pembrolizumab where included and serial plasma samples were obtained before and during therapy [ 66 ]. Baseline ctDNA concentrations below the mean were correlated with an increased response rate and better outcome in terms of PFS and OS.…”

Longitudinal Multi-Parametric Liquid Biopsy Approach Identifies Unique Features of Circulating Tumor Cell, Extracellular Vesicle, and Cell-Free DNA Characterization for Disease Monitoring in Metastatic Breast Cancer Patients

“…In breast cancer (BC), the leading cancer in women worldwide [ 5 ], an increase in circulating tumor cell (CTC) count [ 6 ] and an increase in circulating tumor DNA (ctDNA) concentration have been shown to correlate with disease progression [ 7 , 8 ]. More specifically, in metastatic BC (MBC) patients, a reduction of the apoptotic CTC count by ≥50% (after one completed treatment cycle) correlated with stable disease, while a reduction of apoptotic CTCs ≤ 10% was specific for early disease progression in 74% of the cases [ 9 ].…”