Renal Cell Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage IV and Recurrent Renal Cell Cancer
Sunitinib and the combination of bevacizumab plus interferon-alpha have each been associated with longer PFS than interferon-alpha alone in randomized controlled trials. Sunitinib is an orally available multikinase inhibitor (VEGFR-1, VEGFR-2, PDGFR, c-Kit). In 750 previously untreated patients, all of whom had clear cell kidney cancer, a phase III trial compared sunitinib with interferon-alpha. Sunitinib as first-line systemic therapy was associated with a median PFS of 11 months compared with 5 months for interferon-alpha. The HR for progression was 0.42 (95% CI, 0.32–0.54; P < .001).[Level of evidence: 1iiDiii] However, the analysis for OS showed a strong but statistically nonsignificant trend to improved survival (26.4 months vs. 21.8 months, HR, 0.82; 95% CI, 0.669–1.001; P = .051).[Level of evidence: 1iiDiii] Bevacizumab, a monoclonal antibody that binds to and neutralizes circulating VEGF protein, delayed progression of clear cell renal cell carcinoma when compared with placebo in patients with disease refractory to biological therapy. Similarly, bevacizumab plus interferon-alpha as first-line therapy resulted in longer PFS but not OS compared with interferon alpha alone in two similarly designed randomized controlled trials.[28,29]
Axitinib was shown to prolong progression of disease when used as second-line systemic therapy. A randomized controlled trial of 723 patients conducted at 175 sites in 22 countries evaluated axitinib versus sorafenib as treatment for renal cell carcinoma with a clear cell component that had progressed during or after first-line treatment with sunitinib (54%), cytokines (35%), bevacizumab plus interferon (8%), or temsirolimus (3%). The primary endpoint was PFS, and the data were analyzed when disease in 61% of the axitinib patients and 71% of the sorafenib patients had progressed.
Median PFS was 6.7 months for axitinib and 4.7 months for sorafenib (HR, 0.665; 95% CI, 0.544–0.812, P < .0001 for progression of death using a one-sided log-rank test and a threshold of P < .025 for significance). However, the largest benefit was seen in patients who received cytokines as first-line therapy and whose median PFS was 12.1 months with axitinib versus 6.5 months with sorafenib (P < .0001). In patients who had previously received sunitinib, axitinib was associated with a 1.4-month increase in PFS compared to sorafenib (4.8 months compared to 3.4 months, one-sided P = .0107). There were not enough deaths (n = 223 compared to 417 needed as per protocol) at the time of publication to report results on OS. Comparing the toxicity of the two regimens is complicated because the axitinib arm included a dose-escalation component such that only those patients who tolerated the lower dose were subsequently given the higher doses. Hypertension, nausea, dysphonia, and hypothyroidism were more common with axitinib, whereas palmar-plantar erythrodysesthesia, alopecia, and rash were more common with sorafenib.