Improved overall survival in an anti-PD-L1 treated cohort of newly diagnosed glioblastoma patients is associated with distinct immune, mutation, and gut microbiome features: a single arm prospective phase I/II trial
Shiao‐Pei Weathers, Xiqi Li, Haifeng Zhu, Ashish Damania, Mark Knafl, Brian McKinley, Heather Lin, Rebecca A. Harrison, Nazanin Majd, Barbara O’Brien, Marta Peñas-Prado, Monica Loghin, Carlos Kamiya Matsuoka, W.K. Alfred Yung, Luisa M. Solis Soto, Dipen M. Maru, Ignacio Wistuba, Edwin R. Parra, Sharia Hernandez, P. Andrew Futreal, Jennifer A. Wargo, Katja Schulze, Walter C. Darbonne, Nadim J. Ajami, Scott E. Woodman, John de Groot
Abstract
This phase I/II trial aims to evaluate the efficacy of concurrent atezolizumab with radiation therapy and temozolomide (TMZ) followed by adjuvant atezolizumab and TMZ in newly diagnosed glioblastoma (GBM) patients and to identify pre-treatment correlates with outcome (N = 60). Trial number: NCT03174197. The primary outcome was overall survival (OS) whereas secondary outcomes were retrospective global–omics analyses to identify pre-treatment immune and genetic tumor features that correlated with survival. Concurrent use of atezolizumab with radiation and TMZ demonstrated OS in line with published trials for newly diagnosed GBM. Tumor genomic (WES and/or targeted NGS panel), transcriptomic (RNAseq) and tissue microenvironment imaging, as well as fecal metagenomic sequencing were conducted. Gene set enrichment analysis of tumors identified multiple immune-based transcriptomic programs to distinguish patients with longer versus shorter survival (p ≤ 0.01). GBM immune enrichment was highly associated with the pre-treatment tumor mesenchymal subtype and patient gastrointestinal bacterial taxa profile. Checkpoint inhibitor (CPI) therapy is modestly effective in Glioblastoma patients, with some patients not benefitting at all. Authors here present the outcomes of single arm prospective clinical trial employing combination CPI therapy in newly diagnosed GBM and identify the pre-treatment genetic, microbiome and immunological factors that might contribute to sensitivity.