Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HeadHER1/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to 80% of NSCLCs. The study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV open-label, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV) NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H) were selected from two Clinical centres (Sarajevo and Banja Luka). The aim of study was to evaluated efficacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of 14th May 2008 were included in analysis of data (n = 19). This population is defined as the Intent to Treat (ITT) population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. The findings are consistent with the results of the randomized, placebo-controlled BR.21 study. Indicating that erlotinib is an effective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost 84%, and PFS was approximately 24,7 weeks (compared with 44% and 9,7 weeks for erlotinib reported in phase III). Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions. 24% of patients experienced an SAE (most commonly gastrointestinal (GI) disorders).
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PMID:Our experiences with erlotinib in second and third line treatment patients with advanced stage IIIB/ IV non-small cell lung cancer. 1912 14

Lung cancer is the leading cause of cancer-related death worldwide. Despite several chemotherapeutic agents, a survival plateau has been reached, so new treatment strategies are clearly needed. A strong interest is now focused on the use of targeted therapies for the management of non-small-cell lung cancer. Monoclonal antibodies against the epidermal growth factor receptor (EGFR; cetuximab) or vascular endothelial growth factor receptor (VEGFR; bevacizumab) and EGFR tyrosine kinase inhibitors (gefitinib, erlotinib) are generally well tolerated and do not have the severe systemic side effects usually seen with cytotoxic drugs. A considerable number of treated patients develop dermatologic side effects, such as acneiform eruption, xerosis, and eczema, and unfortunately, this is often one cause of negative impact on a patient's quality of life. No controlled clinical trials have been performed to manage rash, so it is necessary to provide suggestions for managing this frequent side effect. The main problems related to the class of angiogenesis inhibitors affecting VEGFRs are the exclusion of patients with brain metastases and/or squamous histology, and vascular adverse effects, such as hypertension, proteinuria, thrombosis, and hemorrhage. There are other new agents in clinical development, such as sorafenib, sunitinib, vorinostat, vandetanib, everolimus, panobinostat, and ASA404. They are all associated with a spectrum of toxicities, often reversible with interruption of dosing. Further research is required to clarify the role of targeted therapies and toxicities management.
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PMID:Toxicity of targeted therapy in non-small-cell lung cancer management. 1928 69

Among the many chemotherapeutic options for metastatic colorectal cancer, none has shown clear superiority in efficacy. All pharmacologic agents in current use have been associated with adverse events. Frequently reported adverse events associated with the chemotherapeutic agents oxaliplatin, irinotecan, 5-fluorouracil, and capecitabine include acute and chronic neuropathy, hypersensitivity reactions, diarrhea, neutropenia, and hand-foot syndrome. Although biologic agents are seemingly less toxic, toxic effects can also arise with their use; antiangiogenic agents result in hypertension, and EGFR inhibitors can cause severe hypersensitivity, paronychial infections, and more commonly, dermatologic rash. Furthermore, a correlation has been reported for the efficacy of anti-EGFR agents and development of rash. Data indicate that elderly patients with colorectal cancer who have adequate function and performance status, who may previously have been dissuaded from pursuing active therapy solely on the basis of age, should receive the same treatment as younger patients. To enhance the survival of patients with metastatic colorectal cancer, many therapies are administered. Recognition of treatment-emergent toxic effects will, therefore, aid the design and implementation of management strategies that minimize treatment interruption and/or discontinuation, and enhance quality of life for patients.
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PMID:Toxic effects and their management: daily clinical challenges in the treatment of colorectal cancer. 1933 27

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses < or =300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.
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PMID:Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. 1934 11

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).
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PMID:Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. 1956 54

Lapatinib is an oral, small-molecule, dual kinase inhibitor that targets both HER2 and the EGF receptor. Lapatinib was approved in June 2008 in Europe for the treatment of advanced HER2-positive breast cancer. Promising results in trastuzumab-refractory metastatic breast cancer were obtained from Phase I, II and III studies in combination with chemotherapy. Diarrhea and rash are the most common side-effects and are mostly moderate and treatable. Cardiac toxicity occurs rarely and mostly as an asymptomatic and reversible decrease of left ventricular ejection fraction. Unlike trastuzumab, some data show that lapatinib could cross the blood-brain barrier, with some evidence of activity in treating or preventing brain metastases. Its evaluation is actively ongoing, in combination with trastuzumab and in the adjuvant setting.
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PMID:Lapatinib in metastatic breast cancer. 1986 62

Angiogenesis is essential for normal tissue and even more so for solid malignancies. At present, inhibition of tumor angiogenesis is a major focus of anticancer drug development. Bevacizumab, a humanized antibody against VEGF, was the first antiangiogenic agent to be approved for advanced non-small cell lung cancer, breast cancer and colorectal cancer. The most commonly observed adverse events are hypertension, proteinuria, bleeding and thrombosis. Sunitinib, a small molecule blocking intracellular VEGF, KIT, Flt3 and PDGF receptors, which regulate angiogenesis and cell growth, is approved for the treatment of advanced renal cell cancer (RCC) and malignant gastrointestinal stromal tumor. The most frequent adverse events include hand-foot syndrome, stomatitis, diarrhea, fatigue, hypothyroidism and hypertension. Sorafenib, an oral multikinase inhibitor, is approved for the second-line treatment of advanced RCC and upfront treatment of advanced hepatocellular carcinoma. Most common adverse events with sorafenib are dermatologic (hand-foot skin reaction, rash, desquamation), fatigue, diarrhea, nausea, hypothyroidism and hypertension. More recently, cardiovascular toxicity has increasingly been recognized as a potential adverse event associated with sunitinib and sorafenib treatment. Elderly patients are at increased risk of thromboembolic events when receiving bevacizumab, and potentially for cardiac dysfunction when receiving sunitinib or sorafenib. The safety of antiangiogenic drugs is of special concern when taking these agents for longer-term adjuvant or maintenance treatment. Furthermore, newer investigational antiangiogenic drugs are briefly reviewed.
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PMID:Antiangiogenic drugs in oncology: a focus on drug safety and the elderly - a mini-review. 1994 Apr 66

Herein, we report a case of bullous dermatitis that occurred in a 61-year-old woman 5 days after beginning therapy with erlotinib for the treatment of stage IV pulmonary adenocarcinoma with metastases at the hypophyseal level. Skin reactions are the most common adverse drug reactions (ADRs) associated with epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors, and acneiform rash is the most frequently reported ADR in patients treated with erlotinib. To our knowledge, this is the first case of bullous dermatitis induced by erlotinib. This report highlights the need for additional research in the field of skin toxicity of EGFR-TK inhibitors.
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PMID:A case of bullous dermatitis induced by erlotinib. 1996 13

Erlotinib is increasingly being used for the treatment of non-small cell lung cancer. The recommended dose is 150 mg/day and no efficacy data is available for lower doses. We describe a case of dramatic tumor response to 50 mg erlotinib in a patient with EGFR mutation positive NSCLC who developed a severe rash on full dose erlotinib. Rash is known to correlate with response and survival in patients treated with erlotinib. Our case suggests that in the presence of rash, dose reductions to "subtherapeutic" levels remain effective and may prevent unnecessary early treatment termination.
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PMID:Dramatic response to low-dose erlotinib of epidermal growth factor receptor mutation-positive recurrent non-small cell lung cancer after severe cutaneous toxicity. 2000 14

PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.
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PMID:Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. 2006 89


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