Vandetanib Versus Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Two-Part, Double-Blind, Randomized Phase II Study

Natale, Ronald B.; Bodkin, David; Govindan, Ramaswamy; Sleckman, Bethany G.; Rizvi, Naiyer A.; Capó, Adolfo; Germonpré, Paul; Eberhardt, Wilfried; Stockman, Paul K.; Kennedy, S.; Ranson, Malcolm R

doi:10.1200/jco.2008.18.6015

Cited by 197 publications

(139 citation statements)

References 25 publications

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“…A meta‐analysis of 9 randomized trials with 4813 patients estimated a risk ratio for QTc prolongation versus control of 7.90 (95% confidence interval, 4.03–15.50) 154. In our review, the weighted incidence of any vandetanib‐related QTc prolongation was 8.6%, with QTc >500 ms in 2.6% 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70155, 156, 157 Because of its long half‐life (19 days), special care is needed when monitoring patients with QTc prolongation.…”

Section: Resultsmentioning

confidence: 75%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

159

142

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BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario.Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare.ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

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Section: Resultsmentioning

confidence: 75%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

159

142

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“…Phase III clinical studies are now underway with vandetanib in non-small-cell lung cancer following promising results in phase I and II studies (Holden et al, 2005;Natale et al, 2006;Tamura et al, 2006;Heymach et al, 2007a, b). We have reported earlier that both EGFR and VEGF overexpressions are associated with progression of cholangiocarcinoma (Yoshikawa et al, 2008), and hypothesised that simultaneously blocking the EGFR and VEGF pathways might have synergistic therapeutic effects against cholangiocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

Yoshikawa

Ojima²,

Kokubu³

et al. 2009

Br J Cancer

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Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses X12.5 mg kg À1 day À1 (Po0.05), but higher doses (50 mg kg À1 day À1 , Po0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg À1 day À1 ) also significantly (P ¼ 0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.

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“…† Vandetanib induced manageable normal tissue toxicities related to inhibition of EGFR and VEGFR signaling such as diarrhea, rash, and hypertension. 19,20 The effect of combining radiation and vandetanib on normal tissue is currently unknown, however it has been shown in both preclinical and clinical trials that use of VEGF inhibitors with radiation may result in higher rates of normal tissue toxicity such as induction of thrombosis, hemorrhage, and bowel toxicities. [21][22][23] In contrast, it was postulated that combination of radiotherapy with inhibitors of angiogenesis may actually decrease these risks because radiotherapy has been used to prevent hemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

Wachsberger

Burd

Ryan

et al. 2009

International Journal of Radiation Oncology*Biology*Physics

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Vandetanib Versus Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Two-Part, Double-Blind, Randomized Phase II Study

Abstract: The primary efficacy objective was achieved, with vandetanib demonstrating a significant prolongation of PFS versus gefitinib. Vandetanib 300 mg/d is currently being evaluated as a monotherapy in two randomized phase III studies in advanced NSCLC.

Cited by 197 publications

References 25 publications

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

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