Cytokine Refractory

Sorafenib

Sorafenib has been approved for the treatment of mRCC patients after failure of cytokine therapy.¹⁹The median PFS was 5.5 months in the sorafenib group and 2.8 months in the placebo group (HR = 0.44; 95% CI, 0.35 to 0.55; P <0.01). The first interim analysis of OS in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (HR = 0.72; 95% CI, 0.54 to 0.94; P = 0.02), although this benefit was not statistically significant according to the O'Brien-Fleming threshold. The comparison of sorafenib with best supportive care produced a base-case ICER of USD $139,182 per QALY gained for the combined group.⁹

Sorafenib was also found to be superior to temsirolimus in the INTORSECT study which enrolled patients who had failed VEGF TKI.²⁰

Axitinib

Axitinib has been approved for the treatment of mRCC patients after cytokine failure.²¹Median OS was 20.1 months (95% CI, 16.7 to 23.4) with axitinib and 19.2 months (95% CI, 17.5 to 22.3) with sorafenib (HR = 0.969; 95% CI, 0.800 to 1.174; one-sided P = 0.3744). Median investigator-assessed PFS was 8.3 months (95% CI, 6.7 to 9.2) with axitinib and 5.7 months (95% CI, 4.7 to 6.5) with sorafenib (HR = 0.656; 95% CI, 0.552 to 0.779; one-sided P <0.0001).

Pazopanib

Pazopanib was approved for use in the second-line after cytokine failure based on the study by Sternberg et al, comparing it to placebo.⁴

Prior VEGF TKI

Axitinib

Axitinib has been approved for the treatment of mRCC patients after VEGF TKI failure.²¹

Everolimus

Everolimus has been approved for the treatment of mRCC patients after VEGF TKI failure.²²The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (HR = 0.33; P <0.001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR = 0.32; P <0.001) by investigators review.²³The base-case ICER of everolimus versus best supportive care alone was reported as 89,547 per QALY gained.²⁴

Recommendations for Second-line Treatment of mRCC

The workgroup voted 5 to 2 in support of the adaptation of the Canadian guideline (Supplementary Table 1), with the exclusion of tivozanib. The group suggested using the word anti-VEGF targeted therapy to make it clearer that drugs like 5-fluorouracil (5-FU) and tamoxifen should not be used. Besides the treatment options listed in the Canadian guidelines, it was also decided that best supportive care and clinical trials should be considered as part of the local treatment practice (Table 1).