A phase Ib/II study of XL184 (BMS 907351) with and without erlotinib (E) in patients (pts) with non-small cell lung cancer (NSCLC).

Wakelee, Heather A.; Gettinger, Scott; Engelman, J. A.; Jänne, Pasi A.; West, Howard; Subramaniam, Deepa; Leach, Joseph W.; Wax, Michael; Yaron, Yifah; Lara, Primo N.

doi:10.1200/jco.2010.28.15_suppl.3017

Cited by 50 publications

(38 citation statements)

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“…Another drug, ARQ197, which is a selective non ATP competitive inhibitor of c-MET, when combined with erlotinib in the second/third-line treatment of EGFR inhibition naïve NSCLC patients showed increased PSF, mainly among patients with non-squamous histology, K-Ras mutations, and EGFR wild-type status [73] . Other drugs targeting MET pathways, such as AMG102 [74] , a monoclonal antibody against HGF, and MetMab (Genentech) [77] , a human recombinant agonist of the HGF-Met signaling pathway, are still in phaseⅠstudies and show promise in the treatment of NSCLC patients [76][77][78] .…”

Section: The Role Of Met Targeted Inhibitionmentioning

confidence: 99%

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

Mello

Marques²,

Medeiros³

et al. 2011

WJCO

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Lung cancer is currently the leading cause of cancer death in Western nations. Non-small cell lung cancer (NSCLC) represents 80% of all lung cancers, and adenocarcinoma is the predominant histological type. Despite the intensive research carried out on this field and therapeutic advances, the overall prognosis of these patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Nowadays, pharmacogenetics and pharmacogenomics represent the key to successful treatment. Recent studies suggest the existence of two distinct molecular pathways in the carcinogenesis of lung adenocarcinoma: one associated with smoking and activation of the K-Ras oncogene and the other not associated with smoking and activation of the epidermal growth factor receptor (EGFR). The K-ras mutation is mainly responsible for primary resistance to new molecules which inhibit tyrosine kinase EGFR (erlotinib and gefitinib) and most of the EGFR mutations are responsible for increased tumor sensitivity to these drugs. This article aims to conduct a systematic review of the literature regarding the molecular pathways involving the EGFR, K-Ras and EGFR targeted therapies in NSCLC tumor behavior.

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Section: The Role Of Met Targeted Inhibitionmentioning

confidence: 99%

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

Mello

Marques²,

Medeiros³

et al. 2011

WJCO

View full text Add to dashboard Cite

show abstract

“…Cabozantinib has entered a combination regimen with erlotinib as a phase Ib/II trial. Very little is known about the results of this trial, with the exception of a partial response by patients who have MET amplification or EGFR T790M mutation [Wakelee et al 2010]. Foretinib (XL880) is a multikinase inhibitor that targets c-MET and VEGFR2 at nanomolar concentrations [Qian et al 2009].…”

Section: Plexins: Modulators Of C-met Activationmentioning

confidence: 99%

c-MET as a potential therapeutic target and biomarker in cancer

2011

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Abstract:The receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. This review provides an overview of the evidence to support c-MET or the HGF/c-MET signaling pathway as relevant targets for personalized cancer treatment based on high frequencies of c-MET and/or HGF overexpression, activation, amplification in non-small cell lung carcinoma (NSCLC), gastric, ovarian, pancreatic, thyroid, breast, head and neck, colon and kidney carcinomas. Additionally, the current knowledge of small molecule inhibitors (tivantinib [ARQ 197]), c-MET/HGF antibodies (rilotumumab and MetMAb) and mechanisms of resistance to c-MET-targeted therapies are discussed.

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“…In addition, HGF-c-MET signaling is also implicated in resistance to EGFR TKI therapy, and rational combinations with anti-EGFR therapies have also been tested. Other c-Met inhibitors such as tivantinib, cabozantinib, and onartuzumab have been combined with erlotinib to try to overcome this HGF-c-MET-mediated resistance to EGFR TKI therapy (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

A Phase I, Dose-Escalation Study of the Multitargeted Receptor Tyrosine Kinase Inhibitor, Golvatinib, in Patients with Advanced Solid Tumors

Molife

Dean

Blanco-Codesido

et al. 2014

Clinical Cancer Research

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Purpose: Receptor tyrosine kinases c-Met and Ron transduce signals regulating cell migration and matrix invasion. This phase I dose-escalation trial tested golvatinib, a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron.Experimental Design: Patients with advanced solid tumors received golvatinib orally, once daily, continuously. Using a "3þ3" design, dosing started at 100 mg once daily, escalating to the maximum tolerated dose (MTD) defined by dose-limiting toxicities. Pharmacokinetic, pharmacodynamic, and preliminary antitumor activity was assessed during dose escalation and in a MTD expansion cohort.Results: Thirty-four patients were treated at six dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased g-glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (50.0%). Frequent treatment-related adverse events (with incidence >10%) included diarrhea (58.8%), nausea (50%), vomiting (44.1%), fatigue (41.2%), decreased appetite (32.4%), elevated alanine aminotransferase (32.4%), elevated aspartate aminotransferase (20.6%), dry skin (11.8%), and dysgeusia (11.8%). Best overall response was stable disease (median duration 85 days, range 85-237). Pharmacokinetics demonstrated high variability, although maximum plasma concentration and area under the plasma concentration-time curve increased with dose. Soluble urokinase-type plasminogen activator receptor, VEGFR2, c-Met, and angiopoietin-2 levels increased after dose. Posttreatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD.Conclusions: Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation. Clin Cancer Res; 20(24); 6284-94. Ó2014 AACR.

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A phase Ib/II study of XL184 (BMS 907351) with and without erlotinib (E) in patients (pts) with non-small cell lung cancer (NSCLC).

Cited by 50 publications

References 0 publications

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

c-MET as a potential therapeutic target and biomarker in cancer

A Phase I, Dose-Escalation Study of the Multitargeted Receptor Tyrosine Kinase Inhibitor, Golvatinib, in Patients with Advanced Solid Tumors

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