Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: A randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie

Lorenzen, Sylvie; Knorrenschild, Jorge Riera; Haag, Georg-Martin; Pohl, Michael; Thuss‐Patience, Peter; Bassermann, Florian; Helbig, Ulrike; Weißinger, Florian; Schnoy, Elisabeth; Becker, Klaus; Stocker, Gertraud; Rüschoff, Josef; Eisenmenger, Andreas; Karapanagiotou‐Schenkel, Irini; Lordick, Florian

doi:10.1016/j.ejca.2015.01.059

Cited by 55 publications

(45 citation statements)

References 21 publications

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“…SD). With lapatinib monotherapy, when administered to the previously treated HER2-positive GC patients, there were no cases of PR; the disease control rate was only 10 %, the median PFS was 1.3 months (95 % CI, 1.2-1.7 months), and the median OS was 4.7 months (95 % CI, 1.8 months-NA), which led to the conclusion Phase II trial of dacomitinib in patients with HER2-positive gastric cancer that lapatinib failed to show sufficient activity as a monotherapy in HER2-positive GC [18]. Taken together, the findings regarding the activity of dacomitinib monotherapy are encouraging in HER2-positive GC patients.…”

Section: Discussionmentioning

confidence: 99%

Phase II trial of dacomitinib in patients with HER2-positive gastric cancer

Lee

Cho

et al. 2015

Gastric Cancer

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Section: Discussionmentioning

confidence: 99%

Phase II trial of dacomitinib in patients with HER2-positive gastric cancer

Lee

Cho

et al. 2015

Gastric Cancer

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“…The concentrations required for those effects are well in the range of lapatinib concentrations determined in patients [61]. Thus, the observed effect of lapatinib on eryptosis may well contribute to or even account for its effect on anemia, a major side effect of the drug [9,11,25,26,61,62]. The sensitivity to lapatinib may be enhanced by clinical conditions known to enhance the susceptibility to triggers of eryptosis, such as dehydration [68], hyperphosphatemia [69], chronic kidney disease (CKD) [70][71][72][73], hemolytic-uremic syndrome [74], diabetes [75], hepatic failure [76], malignancy [63], sepsis [77], sickle-cell disease [63], beta-thalassemia [63], Hb-C and G6PD-deficiency [63], as well as Wilsons disease [78].…”

Section: Discussionmentioning

confidence: 90%

“…On the other hand, lapatinib could counteract apoptosis induced by excessive glucose concentrations [58]. Side effects of lapatinib include skin rash, hand foot skin reaction and pruritus [8,9,11,16,23,25,26,30,59], alopecia [9,23], leukopenia [9,16,25,30], diarrhea, nausea and vomiting [9,11,16,23,25,26,30,38,59,60], fatigue [11,23,30], peripheral neuropathy [9,30], and anemia [9,11,25,26,61,62].…”

Section: Introductionmentioning

confidence: 99%

Lapatinib Induced Suicidal Death of Human Erythrocytes

Zierle

Bissinger

Egler

et al. 2015

Cell Physiol Biochem

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Background/Aims: The human epidermal growth factor receptors tyrosine kinase inhibitor lapatinib has been shown to trigger suicidal death or apoptosis of tumor cells and is thus used for the treatment of malignancy. Side effects of lapatinib include anemia, which could, at least in theory, result from stimulation of eryptosis, the suicidal death of erythrocytes which is characterized by cell shrinkage and phospholipid scrambling of the cell membrane leading to phosphatidylserine translocation to the erythrocyte surface. Mechanisms involved in the triggering of eryptosis include oxidative stress, increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), and ceramide. The present study explored, whether lapatinib induces eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from DCFDA dependent fluorescence, and ceramide abundance utilizing labelled specific antibodies. Results: A 48 hours exposure of human erythrocytes to lapatinib (≥ 1 µg/ml) significantly increased the percentage of annexin-V-binding cells, and significantly decreased forward scatter. Lapatinib (7.5 µg/ml) did not significantly modify DCFDA fluorescence and ceramide abundance. Lapatinib slightly, but significantly decreased Fluo3-fluorescence (≥ 5 µg/ml). Lapatinib (7.5 µg/ml) enhanced the annexin-V-binding in the presence of the Ca²⁺ ionophore ionomycin (1 µM) without significantly modifying Fluo3 fluorescence in the presence of ionomycin. The effect of lapatinib on forward scatter but not on annexin-V-binding was significantly blunted by removal of extracellular Ca²⁺. Conclusion: Lapatinib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect occurring despite decrease of cytosolic Ca²⁺ activity.

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“…In contrast, the EGFR/HER2 small-molecule inhibitor lapatinib showed only limited efficacy in treating advanced gastric cancer (Hecht et al 2016; Lorenzen et al 2015; Satoh et al 2014). EGFR-targeted therapeutics have been ineffective so far: the addition of the EGFR-targeted antibody cetuximab to chemotherapy failed to show any significant benefit in the phase III EXPAND trial (Lordick et al 2013), the addition of the anti-EGFR antibody panitumumab to chemotherapy did not improve overall survival of patients in the phase III REAL3 trial (Waddell et al 2013), and in the SWOG 0127 trial, the small-molecule inhibitor erlotinib did not improve the outcome of patients with metastatic or unresectable gastric cancer (Dragovich et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines

Kneissl

Hartmann

Pfarr

et al. 2016

J Cancer Res Clin Oncol

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PurposeGastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFα) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab.MethodsA panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity.ResultsWe found no correlation between TGFα secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab.ConclusionsOur data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s00432-016-2308-z) contains supplementary material, which is available to authorized users.

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Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: A randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie

Cited by 55 publications

References 21 publications

Phase II trial of dacomitinib in patients with HER2-positive gastric cancer

Phase II trial of dacomitinib in patients with HER2-positive gastric cancer

Lapatinib Induced Suicidal Death of Human Erythrocytes

Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines

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