The standard frontline therapy for patients with metastatic renal cell carcinoma (mRCC) is sequential sunitinib, a VEGF inhibitor, followed by everolimus, an mTOR inhibitor. However, several effective targeted therapies are now available in the frontline setting, primarily those that target VEGF and mTOR, warranting a comparison of these modalities to determine an optimal sequence.

The phase II RECORD-3 study compared the standard approach of sunitinib followed by everolimus to sequential everolimus and sunitinib. In the trial, 471 patients with both clear and non-clear cell mRCC were evenly randomized between the two treatment arms. A majority of patients (86%) presented with favorable or intermediate prognoses.

Overall, the trial did not demonstrate that first-line everolimus was noninferior to first-line sunitinib, further solidifying sunitinib as the preferred choice for patients with a favorable to intermediate prognosis, explains Robert A. Figlin, MD. However, since only a small subpopulation of high-risk patients were enrolled, it may still be appropriate to utilize the mTOR inhibitor temsirolimus in this setting. Unfortunately, Figlin adds, the trial design made an overall survival comparison complex, since several patients were allowed to drop out of the trial.

Looking deeper into the subpopulations, Brian I. Rini, MD, notes that a portion of patients had non-clear cell histology. For these patients, the results still seem to indicate that a VEGF inhibitor should be the preferred first-line treatment. However, this theory will need to be validated in a prospective trial.

Summarizing his thoughts on the RECORD-3 trial, Thomas E. Hutson, DO, PharmD, remarks that mTOR inhibitors seem to have no role for the vast majority of patients with mRCC in the frontline setting. However, data still suggests that mTOR inhibitors are optimal in high-risk patients.