Study and research of Foretinib in Renal Cell Carcinoma

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Study and research of Foretinib in Renal Cell Carcinoma

Posted On : Jan-13-2012 | seen (3903) times | Article Word Count : 715 |

Foretinib, in advanced metastatic solid tumors. Foretinib was identified by high-throughput screening and rationally developed to act as both a proliferation inhibitor (Met) and an angiogenesis inhibitor (VEGFR) in order to test the hypothesis that antitumor activity could be combined in a single agent.

INTRODUCTION

Yesterday’s post described the results of a Phase I clinical trial of the mesechymal-epithelial transition (Met) tyrosine kinase inhibitor, Foretinib, in advanced metastatic solid tumors. Foretinib was identified by high-throughput screening and rationally developed to act as both a proliferation inhibitor (Met) and an angiogenesis inhibitor (VEGFR) in order to test the hypothesis that antitumor activity could be combined in a single agent. In that trial, 10% of the enrolled patients had papillary renal cell carcinoma. The results showed that half of those (5% of the full enrollment) had a partial response to foretinib. These findings prompted a Phase II clinical trial of the efficacy of foretinib in patients with papillary renal cell carcinoma. While the trial is not yet complete and final results are unavailable, the preliminary results that have been released are promising.

The Phase II trial enrolled 50 patients who were assigned to two cohorts. The first cohort was on an intermittent dosing schedule similar to that described for the Phase I trial. These patients received a dose of 240mg daily for the first five days of a 14 day cycle. The second cohort was on a continuous dosing regimen of 80mg daily. The most common adverse events that were observed included hypertension (27%), aspartate aminotransferase (AST) increase (22%), and diarrhea (11%). The patients in the second cohort of continuous dosing demonstrated fewer adverse events than those in the intermittent cohort.

Confirmed partial responses were observed in four patients (11%) in the intermittent dosing cohort. There were also two patients with unconfirmed partial response, 28 with stable disease, and 2 who experienced disease progression. The median progression-free survival in this group was 7.9 months, which is similar to the upper end of the range of overall survival for patients with papillary renal cell carcinoma. In the daily dosing cohort, 3 patients (21%) demonstrated a confirmed partial response. Another 11 patients had stable disease and none had progressive disease.

These findings are most interesting in the context of papillary renal cell carcinoma because the vast majority of these patients, approximately 80-90%, do not harbor any known mutation in the c-Met gene. In this particular trial 57% of patients in the intermittent dosing group and 31% of patients in the continuous dosing group demonstrated evidence of c-Met activation. Of the four patients in the intermittent dosing cohort who demonstrated a confirmed partial response, two showed c-Met activation. Additionally, both patients who showed an unconfirmed partial response had c-Met activation as did 15 of the 28 patients with stable disease. The investigators claim that this indicates a total clinical benefit rate of 92% in the intermittent group. In the daily dosing cohort, one of the three confirmed partial response patients had c-Met activation. When combined with the 11 patients who had stable disease, the investigators claim that this results in a total clinical benefit rate of 98%.

SUMMARY

This Phase II trial of the efficacy of foretinib in treating patients with papillary renal cell carcinoma is still ongoing and the data analysis remains incomplete. Nonetheless, these preliminary results strongly suggest that for some papillary renal cell carcinoma patients, foretinib is a successful chemotherapeutic treatment. The question remains, however, whether foretinib will prove to be effective only in cases where c-Met is activated. The findings so far in this study would suggest that c-Met activity is not required for foretinib to be effective. Perhaps the action of foretinib on VEGFR can provide some benefit for papillary renal cell carcinoma patients even in the absence of c-Met. Further analysis of the patients enrolled in this trial and which of them responded to foretinib treatment will aid investigators in framing a Phase III trial for foretinib in the context of this disease.

REFERENCES

1. Srinivasan R, et al “A phase II study of two dosing regimens of foretinib (GSK1363089), a dual MET/VEGFR2 inhibigtor, in patients with papillary renal carcinoma” KCA 2009; Final program.
2. Eder JP, Shapiro GI, Appleman LJ, et al. (2010) A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2. Clin Cancer Res July 1, 2010 16; 3507

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<h1>Study and research of Foretinib in Renal Cell Carcinoma</h1> Author: <a href='http://www.articleseen.com/profile_Dr.Rabia.aspx'>Dr.Rabia</a> INTRODUCTION

Yesterday’s post described the results of a Phase I clinical trial of the mesechymal-epithelial transition (Met) tyrosine kinase inhibitor, Foretinib, in advanced metastatic solid tumors. Foretinib was identified by high-throughput screening and rationally developed to act as both a proliferation inhibitor (Met) and an angiogenesis inhibitor (VEGFR) in order to test the hypothesis that antitumor activity could be combined in a single agent. In that trial, 10% of the enrolled patients had papillary renal cell carcinoma. The results showed that half of those (5% of the full enrollment) had a partial response to foretinib. These findings prompted a Phase II clinical trial of the efficacy of foretinib in patients with papillary renal cell carcinoma. While the trial is not yet complete and final results are unavailable, the preliminary results that have been released are promising.

The Phase II trial enrolled 50 patients who were assigned to two cohorts. The first cohort was on an intermittent dosing schedule similar to that described for the Phase I trial. These patients received a dose of 240mg daily for the first five days of a 14 day cycle. The second cohort was on a continuous dosing regimen of 80mg daily. The most common adverse events that were observed included hypertension (27%), aspartate aminotransferase (AST) increase (22%), and diarrhea (11%). The patients in the second cohort of continuous dosing demonstrated fewer adverse events than those in the intermittent cohort.

Confirmed partial responses were observed in four patients (11%) in the intermittent dosing cohort. There were also two patients with unconfirmed partial response, 28 with stable disease, and 2 who experienced disease progression. The median progression-free survival in this group was 7.9 months, which is similar to the upper end of the range of overall survival for patients with papillary renal cell carcinoma. In the daily dosing cohort, 3 patients (21%) demonstrated a confirmed partial response. Another 11 patients had stable disease and none had progressive disease.

These findings are most interesting in the context of papillary renal cell carcinoma because the vast majority of these patients, approximately 80-90%, do not harbor any known mutation in the c-Met gene. In this particular trial 57% of patients in the intermittent dosing group and 31% of patients in the continuous dosing group demonstrated evidence of c-Met activation. Of the four patients in the intermittent dosing cohort who demonstrated a confirmed partial response, two showed c-Met activation. Additionally, both patients who showed an unconfirmed partial response had c-Met activation as did 15 of the 28 patients with stable disease. The investigators claim that this indicates a total clinical benefit rate of 92% in the intermittent group. In the daily dosing cohort, one of the three confirmed partial response patients had c-Met activation. When combined with the 11 patients who had stable disease, the investigators claim that this results in a total clinical benefit rate of 98%.

SUMMARY

This Phase II trial of the efficacy of foretinib in treating patients with papillary renal cell carcinoma is still ongoing and the data analysis remains incomplete. Nonetheless, these preliminary results strongly suggest that for some papillary renal cell carcinoma patients, foretinib is a successful chemotherapeutic treatment. The question remains, however, whether foretinib will prove to be effective only in cases where c-Met is activated. The findings so far in this study would suggest that c-Met activity is not required for foretinib to be effective. Perhaps the action of foretinib on VEGFR can provide some benefit for papillary renal cell carcinoma patients even in the absence of c-Met. Further analysis of the patients enrolled in this trial and which of them responded to foretinib treatment will aid investigators in framing a Phase III trial for foretinib in the context of this disease.

REFERENCES

1. Srinivasan R, et al “A phase II study of two dosing regimens of foretinib (GSK1363089), a dual MET/VEGFR2 inhibigtor, in patients with papillary renal carcinoma” KCA 2009; Final program.
2. Eder JP, Shapiro GI, Appleman LJ, et al. (2010) A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2. Clin Cancer Res July 1, 2010 16; 3507

Phase I trail of Foretinib in Metastatic Solid Tumors
Met Inhibitors: Targeted therapies for multiple cancersAbout the Author: We pays great attention to the purity, stability and activity of the products like <a rel="nofollow" href="http://www.selleckchem.com/products/PHA-739358(Danusertib).html">Danusertib</a>, <a rel="nofollow" href="http://www.selleckchem.com/products/Tipifarnib(R115777).html">Tipifarnib</a>, <a rel="nofollow" href="http://www.selleckchem.com/products/SB-431542.html">SB 431542</a> & more. Article Source: <a href='http://www.articleseen.com/Article_Study-and-research-of-Foretinib-in-Renal-Cell-Carcinoma_133381.aspx'> http://www.articleseen.com/Article_Study and research of Foretinib in Renal Cell Carcinoma_133381.aspx</a>

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