Everolimus (Afinitor, Novartis) is not as effective as sunitinib (Sutent, Pfizer) in the first-line setting for patients with metastatic renal cell carcinoma, and it has a different toxicity profile, according to a phase 2 randomized direct comparator trial.
The study, known as RECORD-3, was published online July 21 in the Journal of Clinical Oncology.
"The hope was that everolimus would be better tolerated and as good as sunitinib in first-line treatment," said lead investigator Robert Motzer, MD, attending physician in the genitourinary oncology service at the Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Medical College at Cornell University in New York City.
However, "in first-line therapy, the efficacy of sunitinib appeared to be better than everolimus. It is clear that sunitinib remains the standard first-line therapy," he explained.
"The current paradigm of sunitinib followed by everolimus at progression should be maintained. The experimental sequence of everolimus first followed by sunitinib second did not appear to be as effective," Dr. Motzer reported.
RECORD-3 was sponsored by Novartis, the maker of everolimus. It is the first head-to-head comparison of the mTOR inhibitor everolimus and the VEGF tyrosine kinase inhibitor (TKI) sunitinib, both of which are orally administered. RECORD-3 is the first study of its kind to look at sequence therapy in renal cell carcinoma, the investigators note.
The standard first-line treatment for metastatic renal cancer is VEGF TKI therapy, such as sunitinib. If a patient progresses, the next step is to switch to everolimus.
Previous studies suggested that everolimus had a "very favorable" safety profile and "good activity" in patients who had progressed on first-line therapy with sunitinib, Dr. Motzer explained. After this is established, the next step in drug development is often a head-to-head comparison with the reference standard.
The RECORD-3 study set out to determine how the efficacy and safety of everolimus compares with sunitinib in the first-line setting, and how the standard sequence of sunitinib followed by everolimus compares with everolimus followed by sunitinib. Quality-of-life issues were also assessed.
At the beginning of the trial, "our opinion was that everolimus was better tolerated by most patients than sunitinib," Dr. Motzer explained.
Crossover Trial Design
The open-label crossover study was conducted at 83 sites in 19 countries from October 2009 to June 2011. Participants were randomized to first-line everolimus (n = 238) or sunitinib (n = 238) until disease progression or discontinuation. At disease progression, patients could crossover to second-line treatment with the other drug.
Median progression-free survival was shorter with first-line everolimus than with first-line sunitinib (7.9 vs 10.7 months; hazard ratio [HR], 1.4). Likewise, median progression-free survival was shorter with everolimus followed by sunitinib than with sunitinib followed by everolimus (21.1 vs 25.8 months; HR, 1.3).
Median overall survival was also shorter with everolimus followed by sunitinib than with sunitinib followed by everolimus (22.4 vs 32.0 months; HR, 1.2).
Different Safety Profiles
Although the safety profiles of the 2 drugs are different, the investigators could not conclude that everolimus is better tolerated than sunitinib, Dr. Motzer reported. Some adverse effects, like hypertension and fatigue, occurred more frequently with sunitinib. Others, like stomatitis, were more common with everolimus. In fact, there was no clear distinction between the drugs regarding quality of life.
"For the common type of kidney cancer, clear cell carcinoma, this study showed that sunitinib is the preferred first-line treatment over everolimus," Dr. Motzer concluded.
The study was funded by Novartis, the manufacturer of everolimus. Dr. Motzer reports financial relationships with Novartis, Pfizer, Genentech, Aveo, and GlaxoSmithKline. Several of the study coauthors report financial relationships with various pharmaceutical companies, and some are employed by Novartis, as detailed in the publication.
J Clin Oncol. Published online July 21, 2014. Abstract
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Cite this: Sunitinib or Everolimus First-Line for Kidney Cancer? - Medscape - Jul 24, 2014.