Formal discussant of the RECORD-3 trial, Toni K. Choueiri, MD, Associate Professor of Medicine at Harvard Medical School and Director of the Kidney Cancer Center at Dana-Farber Cancer Institute, Boston, said that the focus of the research concerns how to move forward in the treatment of metastatic renal cell carcinoma.

The trial by Motzer et al addresses an important question on the sequential use of tyrosine kinase inhibitors and mTOR inhibitors. “The study did not meet its primary endpoint, and therefore, for the average metastatic renal cell carcinoma patient, I would not start with everolimus [Afinitor] as first-line therapy,” he stated.

Another important finding of the trial is that less than 50% of patients are unable to cross over to second-line treatment, he noted.

Dr. Choueiri had several reservations about the study results. “The analysis assumes patients were able to cross over, and I would strongly argue that the [combined progression-free survival data for first-line and second-line therapy] may not be relevant for patient care, because of the high number of censored patients, the uncertainty of how [progression-free survival] was calculated after second-line therapy, and the [progression-free survival] from start of second-line therapy was not presented,” he commented.

Major Implication

The major clinical implication of RECORD-3 is that first-line vascular endothelial growth factor (VEGF)-targeted therapy remains the standard of care in metastatic renal cell carcinoma. A potential use of first-line mTOR inhibition includes temsirolimus (Torisel) in poor-risk disease and in patients with cardiovascular disease.

“In my practice, I may use an mTOR inhibitor as first-line therapy in some patients with poor-risk disease and patients with recent acute arterial vascular events or cardiomyopathy, after consultation with my cardiologist,” he said.

Future research directions should include identification of tumors addicted to mTOR pathway signaling and evaluation of results from the ongoing phase III SWITCH-1 and SWITCH-2 sequencing trials of sunitinib followed by sorafenib or vice versa and pazopanib (Votrient) followed by sorafenib and vice versa. “However, the small percentages of patients able to go on second-line therapy in the same clinical trial may limit applicability of all of these trials,” he cautioned. ■

Disclosure: Dr. Choueiri has served in a consultant/advisory role for AVEO, GlaxoSmithKline, Novartis, Pfizer, and Exelixis, and has received research funding from Pfizer.