Groot, John F. de

Abstract Purpose While immunotherapy has transformed treatment in multiple solid tumors, its efficacy in high-grade glioma remains limited. Understanding the molecular and clinical factors that influence glioma’s response to immunotherapy is essential to improving outcomes. Methods We identified patients with recurrent glioblastoma or astrocytoma, IDH-mutant grade 4, who had been treated with checkpoint inhibitor (CPI), virus therapy, or cell therapy and determined the association between their molecular, clinical, and demographic characteristics and survival outcomes. Results We identified 66 patients, 57 glioblastoma and 9 astrocytoma, IDH-mutant grade 4; 38 were treated with CPI, 22 with virus therapy, and 6 with cell therapy. PIK3CA mutation was associated with shorter PFS and OS (p = 0.022, 0.073, respectively) among all patients and a shorter OS among CPI-treated patients (p = 0.004). Tumor tissue without the mutation had less PD-1 expression in CD3+/CD8 + T cells. In CPI-treated patients, IDH1/2 mutation was associated with a shorter OS (p = 0.002), and mutations in RB1 and TERT promoter were associated with a shorter PFS (p-value = 0.00056, 0.022, respectively). Length of CPI therapy of more than 6 months was associated with increased PFS and OS (p = 0.048, 0.062, respectively), while steroid use at baseline was associated with a shorter OS (p = 0.00023). Multifocal disease was associated with shorter PFS and OS durations (p = 0.0017, 0.0013, respectively) among all patients. Conclusions In high-grade glioma, PIK3CA, IDH1/2, RB1, and TERT promoter mutations may be associated with a poor response to immunotherapy. Our results may provide the rationale for clinical trials combining PI3K and IDH inhibitors with CPI in high-grade glioma.

Abstract Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 24(2); 295–305. ©2017 AACR. See related commentary by Wick and Kessler, p. 256