Advanced renal cell carcinoma agent doubles progression-free survival

Milan, Italy-A multi-targeted angiogenesis inhibitor more than doubled progression-free survival (PFS) in patients with advanced renal cell carcinoma, a recent study indicates.

However, the improved PFS did not lead to an overall survival advantage.

Pazopanib, which was granted FDA approval for treatment of advanced RCC in 2009, is an oral agent that targets vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit.

Dr. Sternberg presented final results from a multicenter study involving 435 patients with advanced RCC with clear-cell histology. Patients were randomized 2:1 to pazopanib or placebo. Treatment continued until disease progression, at which time all patients on the placebo arm had the option to receive open-label pazopanib.

The patients had a median age of approximately 60 years, and the two treatment groups did not differ significantly with respect to baseline characteristics. Dr. Sternberg reported that 53% to 54% of the patients had no prior exposure to cytokine therapy.

Pazopanib treatment led to a median PFS of 11.1 months in treatment-naïve patients and 7.4 months in cytokine-pre-treated patients. That compared with 2.8 months and 4.2 months, respectively, in the placebo group (p<.001 for both comparisons).

Crossover affects overall survival

The study had statistical power to detect 50% improvement in overall survival with pazopanib. An interim analysis at the time of the final PFS analysis showed a trend toward improved survival, but not a statistically significant difference. The final analysis showed an overall survival of 22.9 months in the pazopanib group and 20.5 months in the placebo group, also a nonsignificant difference.

Reiterating the effect of crossover on survival, Dr. Sternberg said, "Crossover occurred as early as 6 weeks after beginning randomized treatment. Many patients who crossed over to pazopanib continued treatment for prolonged periods of time."

More than half (54%) of placebo patients crossed over to pazopanib. In contrast, only 22% of patients in the pazopanib group received additional anti-VEGFR or mammalian target of rapamycin inhibitor therapy.

In two post hoc analyses, investigators analyzed overall survival after adjustment for crossover from the placebo group. Two separate analyses showed 50% or greater improvement in overall survival with pazopanib versus placebo.

Overall, 93% of patients in the pazopanib group had adverse events, compared with 74% of the placebo group. Grade 3 adverse events occurred in 36% of the pazopanib arm and 17% of the placebo group, and grade 4 events occurred in 9% and 6%, respectively. The most common adverse events in the pazopanib arm were diarrhea (52%), hypertension (40%), and hair color changes (38%). No significant changes to the type, frequency, or severity of adverse events were observed with longer follow-up.

Dr. Sternberg and several of her co-authors disclosed a financial and/or other relationship with GlaxoSmithKline.