Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma

Abstract

Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma. We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome sequencing and tumor RNA sequencing were performed to identify molecular targets for potential matched therapy. A multidisciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood-brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed. Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome sequencing was completed for all patients, and RNA sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression free 21 months after surgery, 3 times longer than the patient's previous time to progression. Analysis of matched nonenhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations. Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma. .

Phase 1 lead‐in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma

“…There is increased interest in the use of repurposed or “repositioned” drugs selected based on molecular analysis of brain tumors …”

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma—PNOC003: A report from the Pacific Pediatric Neuro‐Oncology Consortium

“…Tumor RNAseq was used to identify RNA fusions and to perform differential expression analysis. Somatic variant detection, copy number analysis and translocation and RNA fusion detection were performed as previously described . Differential expression analysis was performed using Cuffdiff and DESeq2 and utilizing RNAseq data generated from five separate commercially purchased RNA controls (cerebellum, occipital cortex, brain homogenate, brain stem and fetal brain).…”

“…Specific alterations were matched to potential therapeutics in the study pharmacopeia using a custom set of drug rules and a heuristic approach, as previously described . The study pharmacopeia included all oncology drugs in the US Pharmacopeia, as well as select noncancer drugs (herein referred to as repositioned agents).…”

“…Diffuse intrinsic pontine glioma (DIPG) arise in the brainstem and predominantly affect children, with less than 10% of patients surviving more than 2 years, despite decades of research . Recent advances in molecular profiling of tumors through whole exome sequencing (WES) and RNA sequencing (RNAseq) support the development of personalized, genome‐guided clinical trials that may foster the development of new therapeutic interventions for DIPG …”

Reply to Lu: Connecting the dots between metformin and high‐grade glioma

“…In fact, one clinical trial is currently recruiting patients with IDH1 or IDH2 mutated solid tumors including gliomas for treatment with metformin and chloroquine (NCT02496741) . Also, one prospective feasibility trial for genomics‐informed treatment of recurrent and progressive glioblastoma even went so far as to recommend metformin treatment in patients with rare IDH1 or two mutated glioblastomas in their molecular tumor board …”