Reference Detail

Ref Type Journal Article
PMID (25363205)
Authors Falchook GS, Wheler JJ, Naing A, Piha-Paul SA, Fu S, Tsimberidou AM, Hong DS, Janku F, Zinner R, Jiang Y, Huang M, Lin Q, Parkhurst K, Kurzrock R
Title Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumors.
Journal Investigational new drugs
Vol 33
Issue 1
Date 2015 Feb
URL
Abstract Text Angiogenesis plays a pivotal role in tumor growth and metastasis. Sorafenib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF-A), would vertically inhibit VEGF/VEGFR signaling. A phase I trial was performed to assess safety, maximum tolerated dose (MTD), and clinical correlates.Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received sorafenib daily for 28 days and bevacizumab every two weeks. Clinical correlates included VEGF polymorphisms. Expansion cohorts of responding tumor types were enrolled.One hundred fifteen patients were treated, and the MTD was identified as 200 mg twice daily sorafenib and 5 mg/kg bevacizumab every two weeks. Median number of prior therapies was four. Twenty-nine patients (25 %) achieved stable disease ≥6 months; six patients (5 %) achieved a partial response (total SD ≥ 6 months/PR=35 (30 %)). 76 patients (66 %) experienced adverse events of grade 2 or higher, most commonly hand and foot syndrome (n = 27, 24 %) and hypertension (n = 24, 21 %). Dose-limiting toxicity occurred in eight patients (7 %), and 45 patients (39 %) required dose reduction for toxicity. Grade 3 and 4 hypertension was associated with longer time to treatment failure, overall survival, and higher response rate.Combination sorafenib and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced solid tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT L576P melanoma sensitive Bevacizumab + Sorafenib Clinical Study Actionable In a clinical case study, a melanoma patient harboring KIT L576P demonstrated sensitivity to the combination treatment of Nexavar (sorafenib) and Avastin (bevacizumab), resulting in a partial response for 8 months (PMID: 25363205). 25363205
MET N375S ovarian carcinoma sensitive Bevacizumab + Sorafenib Clinical Study Actionable In a clinical case study, a patient with ovarian cancer harboring MET N375S demonstrated sensitivity to the combination treatment, Nexavar (sorafenib) and Avastin (bevacizumab), resulting in stable disease for greater than six months (PMID: 25363205). 25363205
KIT S476I MET R988C gastrointestinal stromal tumor sensitive Bevacizumab + Sorafenib Clinical Study Actionable In a clinical case study, a GIST patient harboring KIT S476I and MET R988C demonstrated sensitivity to the combination treatment, Nexavar (sorafenib) and Avastin (bevacizumab), resulting in stable disease for 6 months (PMID: 25363205). 25363205
Unknown unknown Advanced Solid Tumor not applicable Bevacizumab + Sorafenib Phase I Actionable In a Phase I trial, the treatment combination of Avastin (bevacizumab) and Nexavar (sorafenib) in patients with advanced solid tumors resulted in stable disease in 25% (29/115) of patients and a partial response in 5% (6/115) of patients (PMID: 25363205). 25363205
KRAS Q61H ovarian carcinoma sensitive Bevacizumab + Sorafenib Clinical Study Actionable In a clinical case study, a patient with ovarian carcinoma harboring KRAS Q61H demonstrated sensitivity to treatment with the combination of Nexavar (sorafenib) and Avastin (bevacizumab), resulting in 62% tumor regression (PMID: 25363205). 25363205