Alexey Aleshin

Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab

PURPOSE Immune gene expression signatures are emerging as potential biomarkers for immunotherapy (IO). VIGex is a 12-gene expression classifier developed in both nCounter (Nanostring) and RNA sequencing (RNA-seq) assays and analytically validated across laboratories. VIGex classifies tumor samples into hot, intermediate-cold (I-Cold), and cold subgroups. VIGex-Hot has been associated with better IO treatment outcomes. Here, we investigated the performance of VIGex and other IO biomarkers in an independent data set of patients treated with pembrolizumab in the INSPIRE phase II clinical trial (ClinicalTrials.gov identifier: NCT02644369 ). MATERIALS AND METHODS Patients with advanced solid tumors were treated with pembrolizumab 200 mg IV once every 3 weeks. Tumor RNA-seq data from baseline tumor samples were classified by the VIGex algorithm. Circulating tumor DNA (ctDNA) was measured at baseline and start of cycle 3 using the bespoke Signatera assay. VIGex-Hot was compared with VIGex I-Cold + Cold and four groups were defined on the basis of the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). RESULTS Seventy-six patients were enrolled, including 16 ovarian, 12 breast, 12 head and neck cancers, 10 melanoma, and 26 other tumor types. Objective response rate was 24% in VIGex-Hot and 10% in I-Cold/Cold. VIGex-Hot subgroup was associated with higher overall survival (OS) and progression-free survival (PFS) when included in a multivariable model adjusted for tumor type, tumor mutation burden, and PD-L1 immunohistochemistry. The addition of ΔctDNA improved the predictive performance of the baseline VIGex classification for both OS and PFS. CONCLUSION Our data indicate that the addition of ΔctDNA to baseline VIGex may refine prediction for IO.

Using Circulating Tumor DNA–Based Molecular Residual Disease Detection for Postoperative Monitoring in Early-Stage Uterine Cancer

PURPOSE Clinical decision making for adjuvant treatment in early-stage uterine cancer (UC) following surgery is typically directed by clinicopathological risk factors. There is an unmet need for a clinically relevant biomarker to improve individualized risk stratification and help monitor response to adjuvant therapy. Here, we sought to analyze circulating tumor DNA (ctDNA) as a prognostic biomarker in patients with early-stage UC. METHODS Retrospective analysis of ctDNA results from real-world data was performed for 61 patients (233 plasma time points) diagnosed with early-stage UC. ctDNA status and dynamics were assessed using a clinically validated, personalized, tumor-informed ctDNA assay (Signatera), and its association with recurrence-free survival (RFS) was evaluated. RESULTS ctDNA positivity was associated with significantly reduced RFS postoperatively (hazard ratio [HR], 7.6; P = .003) and postdefinitive therapy (HR, 25.4; P = .0009) and was the most significant factor associated with recurrence when compared with other clinicopathological and molecular risk factors. Notably, of patients who recurred and for whom clinical outcomes were available, 100% were ctDNA-positive before or at the time of recurrence, whereas none of the serially ctDNA-negative patients experienced relapse. CONCLUSION Our data demonstrate the feasibility of monitoring ctDNA in the postoperative and adjuvant settings in early-stage UC. Analysis of ctDNA, in addition to other risk factors, may help identify patients at the highest risk of recurrence, inform surveillance strategies, and support treatment decision-making for these patients.

Study of the Effects of Pembrolizumab in Patients With Advanced Solid Tumors

This is a phase 2 study whose main purpose is to evaluate gene changes and immune biomarkers in patients with solid tumors during treatment with pembrolizumab and in relation to response to treatment. Pembrolizumab is a monoclonal antibody that is designed to block a protein called programmed cell death 1 ligand 1 (PD-L1) which will allow the body's immune system to kill the cancer cells.