Randomized Phase II Study of Vandetanib Alone or With Paclitaxel and Carboplatin as First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

Heymach, John V.; Paz‐Ares, Luis; Braud, Filippo de; Sebastian, Martin; Stewart, David J.; Eberhardt, Wilfried; Ranade, Anantbhushan; Cohen, G.; Trigo, José; Sandler, Alan; Bonomi, Philip; Herbst, Roy S.; Krebs, A; Vasselli, James R.; Johnson, Bruce E.

doi:10.1200/jco.2008.17.3138

Cited by 216 publications

(159 citation statements)

References 26 publications

(2 reference statements)

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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

154

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

154

142

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“…PFS was superior with docetaxel + vandetanib 100 mg/d versus docetaxel alone. In study 7, combining vandetanib 300 mg/d with carboplatin-paclitaxel produced a greater PFS benefit than carboplatin-paclitaxel alone (17). In this study, the vandetanib 300 mg/d monotherapy arm was inferior to carboplatin-paclitaxel alone.…”

mentioning

confidence: 62%

“…In studies 6 and 7, the addition of vandetanib 300 mg/d to docetaxel and carboplatin-paclitaxel, respectively, yielded modest PFS benefits compared with chemotherapy alone (HR, 0.83 and 0.76, respectively), and the greatest PFS benefit was seen when vandetanib 100 mg/d was added to docetaxel (HR, 0.64; refs. 16,17). As shown in four randomized phase III studies, the addition of EGFR TKIs to chemotherapy for NSCLC does not improve outcome (22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

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Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non–Small Cell Lung Cancer

Hanrahan

Ryan

Mann

et al. 2009

Clinical Cancer Research

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Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progressionfree survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: vandetanib versus gefitinib (study 3), docetaxel ± vandetanib (study 6), and carboplatin-paclitaxel and/or vandetanib (study 7). In study 7, vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving vandetanib versus gefitinib or vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either vandetanib monotherapy or carboplatin-paclitaxel.

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“…Although the compound was also known to be a sub-micromolar inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, the early preclinical evidence suggested that this activity is not essential for antitumour effects in vivo since vandetanib demonstrated significant inhibitory activity against a histologically diverse panel of human tumour xenografts, including models insensitive to gefitinib, a highly selective EGFR tyrosine kinase inhibitor (TKI) (1,3). In the clinic, vandetanib has shown activity in non-small cell lung cancer (NSCLC) both as monotherapy and in combination with chemotherapy (4)(5)(6). Vandetanib monotherapy has an acceptable safety and tolerability profile at doses of up to 300 mg/day, where the steady-state mean plasma drug concentration is approximately 1000 ng/ml (2.2 µM; range 1.6-6.3 µM), and where adverse events included hypertension, rash and diarrhoea (7,8) which is consistent with pharmacological inhibition of both VEGFR receptor-2 (VEGFR-2) and EGFR in normal tissues.…”

Section: Introductionmentioning

confidence: 99%

Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer

Ryan

2011

Int J Oncol

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Abstract.Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and their contribution to direct and indirect antitumour effects of vandetanib. For in vitro studies, receptor phosphorylation was assessed by Western blotting and ELISA, cell proliferation was assessed using a cell viability endpoint, and effects on cell cycle determined using flow cytometry. For in vivo studies, Western blotting, ELISA and immunohistochemistry (IHC) were used to assess receptor phosphorylation. Cell culture experiments demonstrated that anti-proliferative effects of vandetanib resulted from inhibition of either EGFR or VEGFR-2 signalling in endothelial cells, but were associated with inhibition of EGFR signalling in tumour cells. Vandetanib inhibited both EGFR and VEGFR-2 signalling in normal lung tissue and in tumour xenografts. In a lung cancer model expressing an activating EGFR mutation, the activity of vandetanib was similar to that of a highly selective EGFR inhibitor (gefitinib), and markedly greater than that of a highly selective VEGFR inhibitor (vatalanib). These data suggest that at the plasma exposures achieved in the clinic, vandetanib will significantly inhibit both VEGFR-2 and EGFR signalling, and that both inhibition of angiogenesis and direct inhibition of tumour cell growth can contribute to treatment response. IntroductionVandetanib (ZD6474) was identified as a potent nanomolar inhibitor of vascular endothelial growth factor (VEGF) signalling with pharmacokinetic properties compatible with chronic, once daily, oral dosing (1,2). Although the compound was also known to be a sub-micromolar inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, the early preclinical evidence suggested that this activity is not essential for antitumour effects in vivo since vandetanib demonstrated significant inhibitory activity against a histologically diverse panel of human tumour xenografts, including models insensitive to gefitinib, a highly selective EGFR tyrosine kinase inhibitor (TKI) (1,3). In the clinic, vandetanib has shown activity in non-small cell lung cancer (NSCLC) both as monotherapy and in combination with chemotherapy (4-6). Vandetanib monotherapy has an acceptable safety and tolerability profile at doses of up to 300 mg/day, where the steady-state mean plasma drug concentration is approximately 1000 ng/ml (2.2 µM; range 1.6-6.3 µM), and where adverse events included hypertension, rash and diarrhoea (7,8) which is consistent with pharmacological inhibition of both VEGFR receptor-2 (VEGFR-2) and EGFR in normal tissues.Although there has been some success in identifying biomarkers of differential benefit to selective EGFR signalling inhibitors (9), no predictive biomarkers have yet been identified for VEGF-signalling inhibitors (10). Identifying biomarkers of benefit fr...

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Randomized Phase II Study of Vandetanib Alone or With Paclitaxel and Carboplatin as First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

Cited by 216 publications

References 26 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

Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non–Small Cell Lung Cancer

Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer

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