Vandetanib Versus Placebo in Patients With Advanced Non–Small-Cell Lung Cancer After Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: A Randomized, Double-Blind Phase III Trial (ZEPHYR)

Lee, Jin Soo; Hirsh, Vera; Park, Keunchil; Qin, Shukui; Blajman, C.; Perng, Reury-Perng; Chen, Yuh‐Min; Emerson, Laura; Langmuir, Peter; Manegold, Christian

doi:10.1200/jco.2011.36.1709

Cited by 204 publications

(130 citation statements)

References 23 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: 70%

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: 70%

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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“…Furthermore, in a phase iii trial of vandetanib (an inhibitor of the vascular endothelial growth factor receptor and egfr) compared with placebo, a significant improvement in pfs (hr: 0.63) again was not associated with an os benefit. However, the actual difference in pfs benefit was only 0.1 months, and the study drug failed to show in an improvement in time to deterioration as a marker for qol, suggesting that the pfs benefit was not clinically meaningful 43 . In contrast, br.21, a study of erlotinib, the absolute pfs benefit was only 0.4 months (albeit statistically significant), but it was associated with a statistically significant 2-month os benefit 18 .…”

Section: Pfs As a Surrogate For The Os Endpoint Beyond First-line Trementioning

confidence: 93%

“…The relationship of pfs to os therefore remains unclear in this setting. With limited effective subsequent lines of treatment in this patient population, and a short median os (4-11 months) [38][39][40][41][42][43] , the argument for a dilution effect on os by subsequent therapies and longer follow-up times is weak, and a surrogate for os beyond first-line treatment may be unnecessary.…”

Section: Pfs As a Surrogate For The Os Endpoint Beyond First-line Trementioning

confidence: 96%

“…Beyond first-line treatment in advanced nsclc, os has remained the primary endpoint in most of the practice-changing trials, with pfs as a secondary endpoint (Table ii) [38][39][40][41][42][43] . Clinical trials of second-line treatment using chemotherapy agents such as docetaxel and pemetrexed reported both pfs and os benefits (tax 317 reported time to progression only) [38][39][40] .…”

Section: Pfs As a Surrogate For The Os Endpoint Beyond First-line Trementioning

confidence: 99%

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Overall Survival Should Be the Primary Endpoint in Clinical Trials for Advanced Non-Small-Cell Lung Cancer

Cheema

Burkes

2013

Current Oncology

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An article in a recent edition of Current Oncology explored the validation of progression-free survival (pfs) as an endpoint in clinical trials of antineoplastic agents for metastatic colorectal cancer, metastatic renal cell carcinoma, and ovarian cancer. The support for pfs as a surrogate endpoint for overall survival (os) was elucidated. As with the aforementioned tumour types, advanced non-small-cell lung cancer (nsclc) has seen a rise in active agents since the year 2000. Those agents range from improved cytotoxics such as pemetrexed, to targeted therapies such as tyrosine kinase inhibitors of the epidermal growth factor receptor and agents that target the EML4–ALK gene mutation. More recently, it has also become apparent that histology plays an important role in the response to and outcomes of treatment. With the therapeutic options for patients with advanced nsclc increasing, concerns are being raised that the efficacy of drugs measured by os may be diluted in clinical trials, thereby underestimating their true clinical benefit. That possibility, together with the need to have efficacious drugs available to patients earlier, has resulted in the search for a surrogate to the os endpoint in advanced nsclc. The present article follows up the recent article on pfs as a surrogate. Although advances in identifying pfs as a valid surrogate endpoint for os have been made in other tumour types, in advanced nsclc, such surrogacy has not been formally validated. Until it has, os should remain the primary endpoint of clinical trials in advanced nsclc.

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“…Observed peculiar toxicities include prolonged QT interval, torsade de pointes, and sudden death. Thus, vandetanib is not indicated in patients suffering from congenital long QT syndrome and frequent monitoring of ECG and of serum potassium, calcium, magnesium, and TSH levels are recommended [79,80].…”

Section: Vandetanibmentioning

confidence: 99%

Novel anti-angiogenic therapeutic strategies in colorectal cancer

Tampellini

Sonetto

Scagliotti

2016

Expert Opinion on Investigational Drugs

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Vandetanib Versus Placebo in Patients With Advanced Non–Small-Cell Lung Cancer After Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: A Randomized, Double-Blind Phase III Trial (ZEPHYR)

Abstract: The study did not demonstrate an overall survival benefit for vandetanib versus placebo. There was a higher incidence of some adverse events with vandetanib.

Cited by 204 publications

References 23 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

Overall Survival Should Be the Primary Endpoint in Clinical Trials for Advanced Non-Small-Cell Lung Cancer

Novel anti-angiogenic therapeutic strategies in colorectal cancer

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