Philippe L. Bedard

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.

Randomized Phase II Study of Bevacizumab with Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant/Refractory High-Grade Ovarian Cancer (NCI Trial)

Abstract Purpose: Mesothelin (MSLN) is highly expressed in high-grade serous/endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody–drug conjugate directed at the MSLN antigen with a tubulin polymerization inhibitor. We assessed the safety, activity, and pharmacokinetics of the combination AR/bevacizumab (Bev; ARB) versus weekly paclitaxel/Bev (PB) in patients with platinum-resistant/refractory HGOC (prrHGOC). Patients and Methods: Following a run-in phase I study to assess ARB safety, patients with prrHGOC with centrally confirmed MSLN-positive expression were randomized to ARB or PB (weekly paclitaxel 80 mg/m2 with Bev 10 mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate, safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events. Results: The combination of Bev (10 mg/kg) biweekly with AR (2.2 mg/kg) weekly was well tolerated. About phase II results, MSLN positivity was 88%, and 57 patients were randomized (28 ARB and 29 PB). Forty-two percentage of patients received prior Bev, and 23% were platinum-refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB, respectively [P = 0.03; HR = 2.02 (1.06–3.86)]. The overall response rate was 21% with ARB and 65% with PB. The most common treatment-related grade ≥3 adverse events were anemia (18%) with ARB and neutropenia (24%) with PB. Higher baseline levels of circulating IL6 were associated with worse PFS, and its levels decreased with PB treatment. Conclusions: Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as the standard of care.

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.