Plasma YKL-40 as a biomarker for bevacizumab efficacy in patients with newly diagnosed glioblastoma in the phase 3 randomized AVAglio trial

// Mogens K. Boisen 1 , Camilla B. Holst 2 , Nicola Consalvo 3 , Olivier L. Chinot 4 and Julia S. Johansen 1, 2, 5 1 Department of Oncology, Herlev University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark 2 Department of Medicine, Herlev University Hospital, Herlev, and Gentofte Hospital, Copenhagen, Denmark 3 Biostatistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland 4 Department of Neuro-Oncology, Aix-Marseille University, Marseille, France 5 Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Correspondence to: Mogens K. Boisen, email: mogens.karsboel.boisen@regionh.dk Keywords: bevacizumab; YKL-40; newly-diagnosed; glioblastoma; AVAglio Received: May 07, 2017 Accepted: November 14, 2017 Published: December 04, 2017 ABSTRACT YKL-40 is a glycoprotein with pro-angiogenic functions. We hypothesized that patients with newly diagnosed glioblastoma and low baseline plasma YKL-40 levels derive greater benefit from first-line bevacizumab. Plasma samples were collected from 563 patients in the randomized, phase 3 AVAglio trial who received bevacizumab or placebo plus radiotherapy/temozolomide. Raw plasma YKL-40 concentrations were converted to age-corrected percentiles of normal healthy YKL-40 levels and divided into quartiles (Q). The impact of baseline plasma YKL-40 level on survival was investigated using Cox regression analyses. Patients with low baseline plasma YKL-40 (≤Q1) had an improved progression-free survival hazard ratio (HR) for bevacizumab versus placebo (0.37, 95% confidence interval [CI]: 0.25–0.55) compared with high plasma YKL-40 (> Q1) (0.71, 95% CI: 0.57–0.87). Overall survival HRs were comparable between the subgroups (≤ Q1: 0.69, 95% CI: 0.44–1.09; (> Q1: 0.88, 95% CI: 0.68–1.13). A trend for improved progression-free survival HR with low versus high YKL-40 was observed in proneural glioblastoma (0.41, 95% CI: 0.13–1.28 vs 0.80, 95% CI: 0.45–1.40, respectively), but not for proliferative/mesenchymal subtypes. Elevated plasma YKL-40 (> 90th percentile of normal) was an independent negative prognostic factor. In conclusion, the predictive value of baseline plasma YKL-40 level as a biomarker for bevacizumab efficacy in glioblastoma may be limited to patients with proneural tumors. Independent validation studies are required to confirm these results.