Genome-driven medicine for patients with recurrent glioma enrolled in early phase trials.

BACKGROUND

Recent studies showed that patients with glioma can safely participate in early phase clinical trials; however, clinical benefits in this population were limited. We aimed to evaluate the benefit of molecular profiling to guide enrolment in early phase trials for patients with recurrent glioma.

METHODS

Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2018 were reviewed for clinico-pathological characteristics, toxicity, response, progression-free survival and overall survival (OS). The primary objective was to evaluate response rates in molecularly-oriented versus non-molecularly-oriented patients.

RESULTS

Eighty-eight patients were enrolled, of whom 45 (51.1%) patients were molecularly-oriented. Targets included IDH1/2 (n = 15), BRAF (n = 11), and FGFR1 (n = 3) mutations, FGFR2-3 fusions (n = 9), and mismatch repair deficiency (n = 7). Among patients with high-grade glioma (n = 74), the rate of stable disease ≥6 months and partial or complete response was 25.7% in molecularly-oriented versus 5.1% in non-molecularly-oriented patients (p = 0.02). Upon multivariable adjustment, baseline steroid use ≥20 mg prednisone equivalent per day was associated with shorter OS (OR 3.15 [95% CI 1.62-6.13], p = 0.0008), while molecular enrichment strategy was associated with longer OS (OR 0.40 [95% CI 0.22-0.73], p = 0.003). Nine (10.2%) patients experienced grade 3-4 toxicity and no dose limiting toxicity (DLT) occurred in both cohorts.

CONCLUSION

The use of molecular profiling to guide enrolment in early phase trials is feasible and might provide benefits to selected patients with glioma. Further studies are warranted to confirm these results in larger randomised settings and identify the patients most likely to benefit from this approach.

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest statement CB reports personal fees from BMS, Sanofi, Abbvie, Roche, Astra Zeneca. As a subinvestigator at the DITEP: Abbvie, Aduro biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Aeneca, Astra Zeneca Ab, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingel-heim, Boston Pharmaceuticals, Inc, Bristol Myers Squibb, Bristol-Myers Squibb Inter-national Corporation, Ca, Celgene Corpo-ration, Cephalon, Chugai Pharmaceutical Co, Clovis Oncology, Daiichi Sankyo, Debiopharm S.a, Eisai, Eli lilly, Exelixis, Forma, Gamamabs, Genentech, Inc, Gilead Sciences, Inc, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Incyte Corpora-tion, Innate Pharma, Institut De Recher-che Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev., Inc, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Kgaa, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Mil-lennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Nerviano Medical Sciences, Novartis Pharma, Octimet Onco-logy Nv, Oncoethix, Oncomed, Oncopep-tides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre Medicament, Plexxikon, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Tioma Therapeutics, Wyeth Pharma-ceuticals France, Xencor, Y's Therapeutics. JCS is an employee of Amgen and former employee of AstraZeneca. FB reports research funding from Abbvie and Sanofi; employment from Celgene (I); stocks from Crossject (I); travel, accommodations, expenses from Bristol-Myers Squibb for travel expenses, outside the submitted work. KHX reports consulting fees and research grant from BTG, outside the submitted work. AI reports grants and other from Carthera (September 2019); research grants from Transgene; grants from Sanofi, and Air Liquide; and travel funding from Leo Pharma, outside the submitted work. MT reports research funding from Sanofi; consulting or advisory role from Agios Pharmaceutical, Integragen, Taiho Oncology, and Servier, outside the submitted work; travel, accommodations, expenses from Merck Sharp & Dome and Servier, outside the submitted work. All remaining authors have declared no conflicts of interest.