Predictive Markers for Outcome with Pazopanib in Metastatic Renal Cell Cancer

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Several targeted drugs are approved for treatment of metastatic renal cell cancer, but no validated biomarkers are available for prediction of clinical outcome of treatment with these agents. In a recent study, Tran and colleagues from The University of Texas MD Anderson Cancer Center in Houston, GlaxoSmithKline in Research Triangle Park, North Carolina, and Collegeville, Pennsylvania, Cedars-Sinai Medical Center in Los Angeles, California, Baylor-Sammons/Texas Oncology in Dallas, and San Carrillo and Forlanini Hospitals in Rome identified baseline cytokine and angiogenic factors that predicted outcome in patients receiving pazopanib (Votrient) in clinical trials.

Screening of 17 cytokine and angiogenic factors in 129 patients with greatest and least tumor shrinkage in a phase II trial yielded the candidate markers interleukin (IL)-6, IL-8, hepatocyte growth factor (HGF), tissue inhibitor of metalloproteinases (TIMP)-1, and E-selectin. Confirmatory analysis in the same population identified IL-6, IL-8, VEGF, osteopontin, E-selectin, and HGF as having an association with continuous tumor shrinkage or progression-free survival.

In the validation study in samples from 344 patients enrolled in a phase III trial, pazopanib-treated patients with high concentrations (relative to median) of IL-8 (P = .006), osteopontin (P = .0004), HGF (P = .010), and TIMP-1 (P = .006) had shorter progression-free survival than did those with low levels of these markers. In placebo-treated patients, high concentrations of IL-6 (P < .0001), IL-8 (P = .002), and osteopontin (P < .0001) were associated with shorter progression-free survival.

These factors were stronger prognostic markers than were standard clinical classifications (Eastern Cooperative Oncology Group, Memorial Sloan-Kettering Cancer Center, and Heng criteria). High IL-6 was associated with greater relative progression-free survival benefit from pazopanib vs placebo (P = .009 for the interaction), whereas standard clinical classifications did not predict progression-free survival benefit.

As stated by the investigators, “[Cytokine and angiogenic factor] profiles could provide prognostic information beyond that of standard clinical classification and identify markers predictive of pazopanib benefit in patients with metastatic renal cell carcinoma. Further studies of the predictive effects of these markers in different populations and with different drugs (eg, mTOR inhibitors) are warranted.”

Funding for the study was provided by GlaxoSmithKline. ■

Tran HT, et al: Lancet Oncol 13:827-837, 2012.




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