New trial results on pazopanib have important implications for patients with advanced renal cell carcinoma

COMPARZ, INTORSECT & INTORACT - Three phase III studies investigating treatments of renal cell carcinoma reported at ESMO 2012

Design of the COMPARZ study

Design of the COMPARZ study
Credit:Dr Robert Motzer
Restrictions for use:ESMO website only

Three urgently awaited and highly ranked randomised phase III trials in the area of advanced renal cell carcinoma are being presented at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna. All three studies are important, although only one of is positive. The COMPARZ trial allows defining a standard option in the front line treatment of renal cell carcinoma, because the study data prove that pazopanib is non-inferior to sunitinib. In addition, being treated with pazopanib, patients experienced fewer side-effects and an increased quality of life.

According to Prof. Maria De Santis from Kaiser Franz Josef-Spital, Vienna, Chair of the ESMO 2012 Genitourinary cancers programme track, and who was not involved in the studies, the COMPARZ, INTORACT and INTORSECT are significant studies because they increase the knowledge about the use of targeted treatment options, in particular temsirolimus, sorafenib, bevacizumab and pazopanib.

Design of the INTORSECT study

Design of the INTORSECT study

Credit:Dr Thomas Hutson
Restrictions for use:ESMO website only

COMPARZ trial: pazopanib and sunitinib similarly effective in first line treatment of metastatic renal cell carcinoma

The new drug pazopanib has similar efficacy to sunitinib in controlling metastatic renal cell carcinoma, the results of the phase III randomised, open-label COMPARZ trial show.
 
Sunitinib and pazopanib are both targeted drugs and sunitinib has been considered as the reference standard, although non-randomised trials have suggested similar efficacy with pazopanib, and less incidence of some side effects.
 
Dr Robert Motzer from Memorial Sloan Kettering Cancer Center, New York, USA and colleagues set out to compare the efficacy, safety, and quality of life for pazopanib and sunitinib in a global, 1100-patient phase III trial. The primary endpoint was to establish non-inferiority of progression-free survival, and safety and quality of life were evaluated as secondary endpoints, as well.

Progression-free survival in the INTORACT study according to independent committee review

Progression-free survival in the INTORACT study according to independent committee review

Credit:Dr Brian Rini
Restrictions for use:ESMO website only 

The trial showed that pazopanib had similar efficacy (i.e. non-inferiority) compared to sunitinib in first-line treatment of metastatic renal cell carcinoma. The main endpoint for assessment was progression-free survival, and the researchers looked at other endpoints as well, including response, overall survival, safety and quality of life.
 
For both drugs, the median progression-free survival by the treating physician’s assessment was slightly more than 10 months.
Both drugs resulted in side effects, but fatigue and skin sores, occurred with less frequency for pazopanib than with sunitinib, the researchers found.
The quality-of-life questionnaires were in favour of pazopanib over sunitinib, and suggested improved tolerability for pazopanib over sunitinib, Dr Motzer reported.

INTORSECT trial: Temsirolimus does not demonstrate superiority in survival over sorafenib in second-line treatment

The results of a phase III trial comparing two commonly used drugs in the second-line treatment of renal cell carcinoma suggest that temsirolimus does not improve survival over sorafenib in the second line setting.

The two drugs inhibit different targets: temsirolimus targets mTOR, which regulates cell growth and proliferation, while sorafenib inhibits several tyrosine kinases, including VEGF receptors.

This is the first head-to-head phase III trial comparing a VEGF inhibitor to an mTOR inhibitor in renal cell carcinoma, reporting final results. Hence, this trial will have important treatment implications for patients and physicians, noted Dr Thomas Hutson from Texas Oncology-Baylor Charles A Sammons Cancer Center in Texas, USA.

Temsirolimus had demonstrated an overall survival benefit compared to interferon alfa in previously untreated patients with advanced renal cell carcinoma and poor prognostic features, but the drug's efficacy after treatment with a VEGF inhibitor was not known, Dr Hutson explained.

The INTORSECT trial included 511 renal cell carcinoma patients from 112 sites, whose disease progressed after first-line sunitinib therapy and who had an ECOG performance status of 0 or 1. Median progression-free survival with temsirolimus was 4.28 months compared to 3.91 months with sorafenib. Median overall survival for the temsirolimus group was 12.27 months compared to 16.64 months for those who received sorafenib.

Based on these results, the researchers found that temsirolimus did not show superiority to sorafenib in the primary end point of progression-free survival or in the secondary end point of overall survival.

This trial shows drugs that inhibition of the VEGF pathway may be a better option than mTOR inhibitors for patients progressing on sunitinib, Dr Hutson reported. In addition, mTOR inhibitors may be appropriate for first line use for a select group of non-clear cell renal cell carcinoma patients and/or those patients with poor performance status.

INTORACT trial: bevacizumab plus temsirolimus offers no advantage over bevacizumab plus interferon

A phase III trial has failed to confirm early clinical results with the combination of bevacizumab and temsirolimus in renal cell carcinoma, investigators from the INTORACT trial reported.

The two drugs target separate molecular pathways involved in renal cell carcinoma, and early results had seemed promising, according to Prof. Brian Rini, a staff physician at the Cleveland Clinic's Taussig Cancer Institute in Cleveland, Ohio and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Cleveland, Ohio.

The INTORACT trial, a global phase IIIb, randomised, open-label, multi-centre study, compared temsirolimus plus bevacizumab with interferon plus bevacizumab as first-line treatment in 791 patients with predominantly clear cell metastatic renal cell carcinoma.

At the data cutoff for final analysis, 489 patients had independently assessed progression-free survival events. Median progression-free survival with the temsirolimus combination was 9.1 months, compared to 9.3 months in the interferon group. Median overall survival was 25.8 months in the temsirolimus group and 25.5 months for the interferon group.

This study failed to find an advantage to the combination of bevacizumab and temsirolimus over bevacizumab and interferon, therefore did not confirm preliminary results of this combination, Prof. Rini concluded.