The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors – Is there more to come?

2013 ◽  
Vol 49 (11) ◽  
pp. 2504-2511 ◽  
Author(s):  
Viktor Grünwald ◽  
Axel Stuart Merseburger
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Vascular Endothelial ◽  
Free Survival ◽  
To Come ◽  
Endothelial Growth Factor

T-cell receptor (TCR) repertoire in metastatic renal cell carcinoma (RCC) patients treated with first-line vascular endothelial growth factor receptor blockade.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 501-501
Author(s):  
Thai Huu Ho ◽  
Robert Charles Gagnon ◽  
Yuan Liu ◽  
F. Stephen Hodi ◽  
Sabina Signoretti ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
T Cell ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Treated Group ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Cell Repertoire ◽  
Endothelial Growth Factor

501 Background: Reports have demonstrated an inverse relationship between suppression of immune surveillance mechanisms and activation of the vascular endothelial growth factor receptor (VEGFR) pathway suggesting that T cell repertoires may impact response to VEGFR blockade. We evaluated the association between clinical outcomes and T cell repertoire in metastatic RCC patients receiving a front-line anti-VEGFR, pazopanib. Methods: Pre-treatment RCC tumors were analyzed from VEG105192, a phase III study of mRCC patients randomized (2:1) to pazopanib (paz) 800 mg daily vs placebo (pbo) for TCR gamma (TCRG) and TCR beta (TCRB) CDR3 regions. Using the Adaptive Biotechnologies immunoSEQ Assay, we assessed TCR clonality, a measure of total repertoire represented by expanded clones, and entropy, a measure of evenness and diversity. PD-L1 was evaluated by immunohistochemistry (IHC) H-Scores. The goal of the study was to determine if the repertoire of T cell clones was associated with progression-free survival as a clinical endpoint. Results: In the cohort with available tissue, the median PFS was 10.8 and 5.5 months (mos) for paz and pbo, respectively. TCRB (n = 114) and TCRG (n = 43 pbo, 109 paz) clonality ranged from 0-0.31 and 0-0.98, and entropy from 1-12.1 and 0-10.37, respectively. TCRB and TCRG entropy were highly correlated (Spearman’s R = 0.92, n = 114). Samples from the pbo-treated group with higher TCRG entropy, defined as the top 25th percentile, were associated with an improved median PFS (12.8 months) when compared to the lower 75th percentile (3.1 months, P = 0.023); similar trends were seen for TCRB entropy. Neither entropy nor clonality was associated with maximal reduction in tumor volume in the paz-treated group. PD-L1 H-scores were not associated with entropy or clonality (P > 0.05). Conclusions: Our data suggests that RCC samples with higher entropy are associated with a favorable prognosis. Identification of tumors with restricted TCRB/G chain usage and less diverse repertoire, as represented by lower entropy and higher clonality, may impact responses to VEGFR blockade and requires further study. Clinical trial information: NCT00334282.

scholarly journals Ramucirumab – egy új gyógyszer az onkológiában

2016 ◽  
Vol 157 (40) ◽  
pp. 1587-1594 ◽  
Author(s):  
András Telekes ◽  
Dániel Deme
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Local Relapse ◽  
Vascular Endothelial ◽  
Previously Treated ◽  
And Migration ◽  
Endothelial Growth Factor

Ramucirumab is a humanized monoclonal antibody against vascular endothelial growth factor receptor-2, which inhibits the binding of vascular endothelial growth factor-A, -C and -D ligands. Furthermore it blocks the ligand stimulated activation of p44/p42 mitogen activated protein kinases, thus neutralizing the ligand induced proliferation and migration of human endothelial cells. Based on the results of the REGARD (Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma) and the RAINBOW (Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma) studies ramucirumab was approved for 2nd line treatment as monotherapy and in combination with paclitaxel for patients with local relapse and unresectable or metastatic gastric cancer (including gastro-esophegal junction adenocarcinoma). Based on the results, in advanced solid malignancies, ramucirumab may prolong progression free survival and overall survival, although it may increase the risk of all adverse events (fatigue, neutropenia, haemorrhage, nausea, stomatitis). The authors review the clinical studies of ramucirumab. Orv. Hetil., 2016, 157(40), 1587–1594.

scholarly journals Pazopanib as first-line therapy for patients with metastatic kidney cancer

2018 ◽  
pp. 70-76
Author(s):  
B. Ya. Alekseev ◽  
I. M. Shevchuk
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Vascular Endothelial ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Endothelial Growth Factor

Pazopanib (Votrient®) is an oral small-molecule multi-kinase inhibitor that predominantly inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β and the stem cell factor receptor c-Kit. In preliminary experiments using mouse and rabbit models of angiogenesis, pazopanib inhibited angiogenesis caused by a combined vascular endothelial growth factor and a major fibroblast growth factor. Although the drug was developed as a therapeutic multi-tumour agent, it is currently approved in many countries for the treatment of advanced soft tissue sarcoma and renal cell carcinoma (RCC). In multicentre, randomized trials of the efficacy of pazopanib as a first-line therapy in patients with metastatic RCC, progression-free survival (PFS) was significantly greater in pazopanib recipients than in cytokine recipients and pazopanib was noninferior to sunitinib with respect to time to disease progression. In addition, side effects such as liver dysfunction and hypertension can be usually managed, and pazopanib is likely to be a more preferred cost-effective option and shows better quality-of-life compared to other alternative drugs.

Functional and prognostic influence of receptor polymorphisms in the vascular endothelial growth factor system in colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15032-e15032
Author(s):  
T. Hansen ◽  
K. G. Spindler ◽  
D. A. Olsen ◽  
R. F. Andersen ◽  
J. Lindebjerg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Protein Concentration ◽  
Progression Free Survival ◽  
Vascular Endothelial ◽  
Malignant Tumours ◽  
Free Survival ◽  
Endothelial Growth Factor

e15032 Background: The vascular endothelial growth factor (VEGF) system plays a key role in the angiogenic process ensuring a sufficient blood supply to the growth of malignant tumours. The clinical importance of single nucleotide polymorphisms (SNP's) in the VEGF receptors is still unknown. The aim of this study was to investigate the functional and prognostic influence of the V297I C/T and the -604 T/C SNP's in the VEGFR-2 gene, in tumour and normal tissue from colorectal cancer patients. Methods: Blood samples and tissue were collected from 110 patients, surgically resected for colorectal cancer. Genomic DNA was isolated from whole blood, and SNP's were analysed by PCR. Gene expression analysis was performed by RT-PCR and protein analysis was performed by ELISA. Progression free survival according to genotypes was compared using the Kaplan-Meier method and the logrank test. Results: Median gene expression according to the CC genotype of the -604 T/C SNP, were significantly higher than the median gene expression of the TT genotype (p = 0.045) and the TC genotype (p = 0.033) in CRC tissue. Regarding the V297I C/T SNP, median protein concentration according to the CT genotype was significantly higher than the median protein concentration of the CC genotype, p = 0.005. The CC genotype held prognostic information compared to CT and TT genotypes for both SNP's, p<0.05. Conclusions: The V297I C/T SNP seems to have a functional influence on the VEGFR-2 protein level, and the -604 T/C SNP on the gene expression level in CRC patients. The results furthermore indicate a prognostic influence of both SNP's on progression-free survival. No significant financial relationships to disclose.

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