International
Conference on Molecular Targets and Cancer Therapeutics
Several plasma biomarkers have been identified that may be predictive of
OS in advanced renal cell carcinoma, according to the results of the TARGET
study.
As an exploratory component of the TARGET study, researchers examined
plasma biomarkers for possible prognostic value. The phase-3 TARGET trial found
that sorafenib (Nexavar, Bayer), a multikinase inhibitor with activity against
RAF kinase and a number of receptor tyrosine kinases, was safe and effective
for patients with advanced renal cell carcinoma in whom one prior systemic
treatment had failed.
In the study, 903 patients with advanced clear cell renal cell carcinoma
were randomly assigned 1:1 to sorafenib or placebo. The results indicated that
those patients assigned sorafenib had double the PFS as those assigned placebo.
Researchers then conducted a secondary analysis that measured plasma
VEGF, soluble VEGFR-2, CAIX, TIMP-1 and p21 RAS by ELISA at baseline, three
weeks and 12 weeks after treatment in order to determine if any of these
biomarkers predicted outcome.
“The biomarker component of TARGET was intended to utilize this
valuable study to search for biomarkers — in this case, proteins we can
measure in plasma — that would help determine renal cell carcinoma
prognosis, and predict patients who would benefit from treatment with
sorafenib,” according to Coral Peña, PhD, associate director for
Clinical Cancer Biomarkers at Bayer HealthCare Pharmaceuticals.
A previous report had shown that baseline VEGF was prognostic and
possibly predictive of sorafenib benefit. However, results from this study
indicate that there was no correlation between levels of plasma soluble
VEGFR-2, CAIX, TIMP-1 or RAS and the efficacy of sorafenib.
In univariate analyses, patients with higher levels of CAIX (HR=2.26),
TIMP-1 (HR=3.34) or RAS (HR=2.49) at the start of the trial had poorer OS when
treated with placebo. An analysis of CAIX, TIMP-1, RAS and VEGF together with
clinical variables in a group of 59 patients from the placebo group showed that
TIMP-1 was independently prognostic for survival (P<.001).
In addition, the researchers found no correlation between the use of
sorafenib and baseline levels of soluble VEGFR-2, CAIX, TIMP-1, or RAS. There
was also no correlation found between outcome and change from baseline at three
or 12 weeks for VEGF, soluble VEGFR-2, CAIX, TIMP-1 or RAS.
“For the moment, these findings are preliminary, but
promising,” Pena said. “Although the analysis included a relatively
small number of patients, the strength of TIMP-1 as a prognostic marker for
renal cell carcinoma is remarkable. It would be interesting to see further
studies of TIMP-1 in RCC to confirm this finding and evaluate its potential for
clinical application.”
For more information:
- Pena C. #A36. Presented at: AACR-NCI-EORTC International Conference
on Molecular Targets and Cancer Therapeutics; Nov. 15-19, 2009; Boston.