Abstract
Simple SummaryTreatment of metastatic renal cell carcinoma (mRCC) remains a challenge due to the lack of biomarkers indicating the optimal drug for each patient. This study analyzed blood samples of patients with predominant clear cell mRCC who were treated with the mTOR inhibitor everolimus after failure of one prior tumor therapy. In an exploratory approach, predictive blood biomarkers were searched. We found lower levels of the protein thrombospondin-2 (TSP-2) at the start of the therapy and higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation to be associated with therapy response. Of note, these blood biomarkers had a higher predictive value than baseline patient parameters or risk classifications. Polymorphisms in the mTOR gene appeared to be associated with therapy response, but were not significant. To conclude, it seems feasible to identify patients showing longtime responses to everolimus and possible to increase tumor therapy response rates based on biomarkers for individual therapy selection.There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.
Highlights
The introduction of targeted therapies, including tyrosine kinase inhibitors (TKI, such as sorafenib, sunitinib, pazopanib, axitinib, cabzoantinib, tivozanib); anti-VEGF antibodies, such as bevacizumab; and mammalian target of rapamycin inhibitors has revolutionized the treatment of metastatic renal cell carcinoma in recent years [1,2,3]
The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell metastatic renal cell carcinoma (mRCC) who benefit from second-line treatment with everolimus
In order to screen for biomarker candidates associated with angiogenesis, antibody arrays were performed in a test cohort comprising eight responders and four non-responders
Summary
The introduction of targeted therapies, including tyrosine kinase inhibitors (TKI, such as sorafenib, sunitinib, pazopanib, axitinib, cabzoantinib, tivozanib); anti-VEGF antibodies, such as bevacizumab; and mammalian target of rapamycin (mTOR) inhibitors (everolimus, temsirolimus) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) in recent years [1,2,3]. Patients were treated with everolimus (Afinitor®), which was considered as the standard of care in second- or third-line therapy of clear cell mRCC after the failure of VEGF-targeted therapies at the time of the study initiation in 2011 [3,6]. During this era of TKI treatment, the only registered drugs in this setting besides everolimus were axitinib and sorafenib [7]. Patients aged ≥65 years (6-month progression-free survival (PFS) 54.4% (95% confidence interval (95% CI) 35.2–70.1) vs. 23.7% (95% CI 10.5–39.9)) and with a BMI >25 kg/m2 (6-month PFS 51.4% (95% CI 34.7–65.7) vs. 18.2% (95% CI 5.7–36.3)) gained the most benefit [7]
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