A Head-to-Head Trial of Efficacy: Pazopanib Versus Sunitinib

A recent trial supports noninferiority of pazopanib and sunitinib in terms of efficacy, with fewer adverse events associated with patient discomfort occurring with pazopanib than with sunitinib.

A recent trial supports noninferiority of pazopanib and sunitinib in terms of efficacy, with fewer adverse events associated with patient discomfort occurring with pazopanib than with sunitinib.

Researchers have tested the comparative efficacy of pazopanib (PZ) and sunitinib (SB) in promoting progression-free survival in patients with metastatic renal-cell carcinoma. The phase-3 trial compared efficacy by randomizing over 1110 patients in equal proportions to receive either 800 mg of PZ orally daily or a regimen of 50 mg of SB orally daily every 4 weeks, alternating with a 2-week gap in therapy, over several back-to-back 6-week cycles of treatment. Investigators prespecified progression-free survival as the primary endpoint, and secondary endpoints as quality of life, safety, and overall survival.

Patients taking SB have a 51% probability of experiencing a longer time to progression of disease than patients taking PZ, although the advantage of SB is not statistically significant (hazard ratio: 1.05; 95% CI, 0.90 to 1.22). In terms of overall survival, patients receiving PZ had a 52% probability of longer overall survival than patients receiving SB. A significant difference in overall survival was not proven (hazard ratio: 0.91; 95% CI, 0.76 to 1.08). By the end of the 3-year trial, researchers confirmed noninferiority between the 2 products.

Investigators found an advantage of PZ in terms of a lower likelihood of fatigue (55% with PZ versus 63% with SB), hand-and-foot syndrome (29% with PZ versus 50% with SB), and thrombocytopenia (41% with PZ versus 78% with SB) over the roughly 40 months of follow-up. To quantify the clinical significance of these results, switching ≈13 patients from SB to PZ should prevent 1 instance of fatigue, switching ≈5 patients from SB to PZ should prevent 1 instance of hand and foot syndrome, and switching ≈3 patients from SB to PZ should prevent 1 instance of thrombocytopenia. In 11 of 14 comparisons of health-related quality of life, results favored a significant advantage of PZ over SB (P <.05).

Investigators stressed that the efficacy of the products was similar, but stressed that the tolerability of PZ was superior to the tolerability of SB, stating, "When agents with similar efficacy are options for first-line therapy, the safety profile assumes greater importance in determining treatment choice." Elaborating on the adverse events of PZ versus SB, the investigators wrote, "Elevations in liver-function tests, weight loss, and changes in hair color were more common with pazopanib than with sunitinib. Most adverse events, particularly those associated with discomfort, such as fatigue, the hand-foot syndrome, and mouth sores, occurred more frequently with sunitinib than with pazopanib." Improvements in health-related quality of life with PZ show that the improved safety profile of PZ over SB translates to better outcomes for patients and a demonstrated reduction in use of medical resources.

Comparative efficacy trials, such as this comparison of PZ with SB, have been a goal of the FDA since April 2010, when Robert J. Temple, the deputy center director for clinical science at the Center for Drug Evaluation and Research (CDER) stated a preference for phase-3 trials that not only offer proof of effectiveness but also demonstrate superior efficacy or a safety advantage compared with older products for new product approvals. Pazopanib may be the first of many products submitted for FDA review with results of a head-to-head phase-3 trial.