Use of cytokines to predict on-target toxicity in patients with recurrent glioblastoma treated with aflibercept.

Abstract

e12507 Background: On-target toxicity related to antiangiogenic therapy may be severe and limit treatment duration. Treatment-related changes in circulating cytokine and angiogenic proteins may reveal the mechanism of specific toxicities, potentially predict toxicity to antiangiogenic agents and permit tailored therapy. Methods: In a single-arm phase II study (NABTC 0601) we measured circulating cytokine and angiogenic factors in 29 pts with recurrent GBM treated with 4 mg/kg aflibercept iv every two wks. Plasma samples were analyzed at baseline, 24 hrs and at 28 days. 41 circulating factors were measured using suspension bead multiplex assays or ELISA. Grade II and higher toxicities were assessed using CTCAE v3.0 and correlated with cytokine expression. Results: Log-transformed baseline expressions were used and evaluated with Cox proportional hazard regression models to assess the effect of biomarkers on any grade II-IV (GII-IV) toxicity or any GII-IV on-target toxicity (HTN, proteinuria, thrombosis). All tests were two-sided with a statistical significance level of p = 0.05. Among 29 pts, there were 46 GII-IV events. Low baseline levels of IL-7 (HR = 0.30, 95%CI 0.10-0.91, p = 0.033) and elevated levels of CTACK (4.12, 1.14-15. 0, 0.031) and SDF1a (4.02, 1.07-15.0, 0.039) were predictive of any GII-IV toxicity. An increase in IL-13 (2.37, 1.34-4.18, 0.003), G-CSF (5.7, 1.00-32.4, 0.050) and bFGF (1.69, 1.04-2.74, 0.035) from baseline to 24 hrs was significantly associated with the development of any GII-IV toxicity. An increase in IL-13 from baseline to 24 hrs and 28 days trended towards significance in predicting on-target toxicities (1.52, 0.94-2.46, 0.09 at 24 hrs and 4.69, 0.92-23.9, 0.063 at 28 days). Conclusions: Toxicity remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Low baseline levels of proinflammatory cytokines such as IL-7 are associated with a decreased risk of toxicity. Increased IL-13, a profibrotic cytokine, at 24 hrs significantly predicts any toxicity and strongly correlates with on-target toxicity at 24 hrs and 28 days. Profiling of IL-13 as a surrogate for endothelial dysfunction could individualize pt risk during antiangiogenic therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Genentech, Merck, Novartis, Pfizer, Schering-Plough Merck, Novartis, Schering-Plough Genentech, Novartis, Schering-Plough