Phase II, open-label trial to assess QTcF effects, pharmacokinetics and antitumor activity of afatinib in patients with relapsed or refractory solid tumors

Molife, L. Rhoda; Alam, Salma; Tan, Daniel S.W.; Kristeleit, Hartmut; Middleton, Gary; Propper, David; Bent, Liz; Stopfer, Peter; Uttenreuther-Fischer, Martina; Wallenstein, Gudrun; Bono, Johann S. de; Spicer, James

doi:10.1007/s00280-013-2286-7

Cited by 15 publications

(12 citation statements)

References 27 publications

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“…The afatinib concentrations required for those effects are lower than the maximal plasma concentrations reported in patients of one study [42]. However, lower maximal concentrations have been reported in other studies [43][44][45][46][47][48][49][50] and the vast majority of patients are probably not going to reach afatinib plasma levels of 1000 ng/ml and above and are therefore not prone to develop the effects analyzed in this paper. Nevertheless, those high concentrations could be reached following accidental overexposure to afatinib.…”

Section: Discussioncontrasting

confidence: 43%

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

Cao

Bhuyan

Umbach

et al. 2017

Cell Physiol Biochem

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Background/Aims: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is used for the treatment of several malignancies. Afatinib is at least partially effective by triggering apoptosis of tumor cells. Platelets may similarly undergo apoptosis, which is characterized by caspase 3 activation, cell shrinkage and phosphatidylserine translocation. However, an effect of afatinib on platelets has never been reported. The present study explored whether treatment of platelets with afatinib modifies platelet activation and apoptosis in the absence and presence of platelet activators thrombin or collagen related peptide (CRP). Methods: Platelets isolated from wild-type mice were exposed for 30 minutes to afatinib (18 µg/ml) without or with subsequent treatment with thrombin (0.005 U/ml or 0.01 U/ml) or CRP (2 µg/ml or 5 µg/ml). Flow cytometry was employed to estimate Orai1 abundance at the platelet surface with specific antibodies, cytosolic Ca 2+ -activity ([Ca 2+ ] i ) from Fluo-3 fluorescence, platelet degranulation from P-selectin abundance, integrin activation from α IIb β 3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, platelet volume from forward scatter and aggregation utilizing staining with CD9-APC and CD9-PE. Results: In the absence of thrombin and CRP, the administration of afatinib (18 µg/ml) slightly, but significantly, increased [Ca 2+ ] i and annexin-V-binding, but did not significantly modify Orai1 abundance, P-selectin abundance, activated α IIb β 3 integrin, cell volume, caspase activity and aggregation. Exposure of platelets to 0.005 U/ml or 0.01 U/ml thrombin or 2 µg/ml or 5 µg/ ml CRP was followed by a significant increase of Orai1 abundance, increase of [Ca 2+ ] i , P-selectin abundance, α IIb β 3 integrin activity, annexin-V-binding, caspase activity, and aggregation, as well as a significant decrease of forward scatter, all effects significantly blunted (thrombin) or virtually abolished (CRP) by afatinib. Conclusions: Afatinib is a powerful inhibitor of platelet activation, platelet apoptosis and platelet aggregation.H. Cao and A. Al Mamun Bhuyan contributed equally and thus share first authorship.

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Section: Discussioncontrasting

confidence: 43%

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

Cao

Bhuyan

Umbach

et al. 2017

Cell Physiol Biochem

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“…QTc prolongation was common (37%) in patients with hepatic impairment treated with bosutinib,10 but this was not seen in other smaller studies 11, 12. QTc prolongation was infrequent or absent with afatinib, crizotinib, ceritinib, dovitinib, imatinib, lapatinib, lenvatinib, nintedanib, pazopanib, and ponatinib 9, 14, 16, 17, 19, 24, 26, 27, 29, 30, 31, 32, 33, 35, 36, 38, 39, 72, 78, 81, 161, 162, 163, 164…”

Section: Resultsmentioning

confidence: 94%

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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“…Based on the current analyses, afatinib does not appear to be associated with significant toxicity of either the Type I or Type II form. Furthermore, preclinical and clinical data indicate that afatinib does not have an effect on the QTc interval [22]. The TAR-adjusted CF-AE rates for afatinib did not vary significantly from those of the comparator Trial day Relative LVEF change from baseline (%) LL1 afatinib 50 mg LL1 placebo Fig.…”

Section: Discussionmentioning

confidence: 90%

“…A phase II trial of afatinib utilized electrocardiograms (ECGs) to assess possible QTcF (QT interval corrected by the Fridericia formula) effects and found no afatinib effect on cardiac repolarization [22]. The analyses reported herein were conducted to further characterize the cardiac safety of afatinib, based on cardiac failure AEs (CF-AEs), including symptomatic cardiac failure and LVEF reductions, reported from LL1 and LL3, as well as patient information available from a large number of additional trials that was derived from the broader clinical databases.…”

Section: Introductionmentioning

confidence: 99%

Cardiac safety of afatinib: a review of data from clinical trials

et al. 2015

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Background: Afatinib is an oral irreversible ErbB family blocker that targets epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and HER4 (ErbB4) and is approved for the first-line treatment of advanced non-small cell lung cancer (NSCLC) with certain sensitizing EGFR mutations. As anti-HER2 therapies have been associated with cardiac dysfunction, we report cardiac safety data for afatinib. Methods: Cardiac data were analyzed from phase III trials of afatinib 40 mg in treatment-naive patients with EGFR mutation-positive NSCLC (LUX-Lung 3 [LL3]; n = 229 afatinib, n = 111 chemotherapy) and afatinib 50 mg in EGFR tyrosine kinase inhibitor-pretreated NSCLC patients (LUX-Lung 1 [LL1]; n = 390 afatinib, n = 195 placebo). Additional pooled data from 49 trials (n = 3865 afatinib-treated patients) is reported. Cardiac failure adverse events (CF-AEs), including symptomatic cardiac failure and depressed left ventricular ejection fraction (LVEF), were analyzed. Results: Time at risk-adjusted CF-AE rates (events/100 patient-years) were similar for afatinib versus placebo in LL1 (2.40 vs 2.23) and versus chemotherapy in LL3 (2.28 vs 2.92); the pooled afatinib CF-AE rate (2.88) was consistent with that for both trials. The frequency of clinically significant LVEF reductions was higher for chemotherapy in LL3

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Phase II, open-label trial to assess QTcF effects, pharmacokinetics and antitumor activity of afatinib in patients with relapsed or refractory solid tumors

Abstract: Afatinib had no impact on cardiac repolarization, had a manageable safety profile and demonstrated antitumor activity in this uncontrolled study.

Cited by 15 publications

References 27 publications

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

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

Cardiac safety of afatinib: a review of data from clinical trials

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