Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib

Lokesh Jain, Tristan M Sissung, Romano Danesi, Elise C Kohn, William L Dahut, Shivaani Kummar, David Venzon, David Liewehr, Bevin C English, Caitlin E Baum, Robert Yarchoan, Giuseppe Giaccone, Jürgen Venitz, Douglas K Price, William D Figg, Lokesh Jain, Tristan M Sissung, Romano Danesi, Elise C Kohn, William L Dahut, Shivaani Kummar, David Venzon, David Liewehr, Bevin C English, Caitlin E Baum, Robert Yarchoan, Giuseppe Giaccone, Jürgen Venitz, Douglas K Price, William D Figg

Abstract

Background: Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.

Methods: Toxicities (> or = grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes.

Results: Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136).

Conclusions: This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.

Figures

Figure 1
Figure 1
Kaplan-Meier curve of progression-free survival following treatment with bevacizumab in combination with docetaxel and thalidomide, n = 60 (A), or bevacizumab in combination with sorafenib, n = 27 (B), or sorafenib alone or in combination with bevacizumab, or cetuximab in patients with prostate cancer, various solid tumors, colon cancer, or NSCLC n = 113 (C), or overall survival following treatment with bevacizumab in combination with sorafenib, n = 26 (D) versus development of ≥ Grade 2 toxicity - - or < Grade 2 toxicity ------ as indicated on each respective figure. Respective P = 0.0009, P = 0.052, P = 0.0003, and P = 0.0068 by a two-tailed log-rank test.

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