Treatment Options in Metastatic Renal Carcinoma: An Embarrassment of Riches

This issue of the Journal of Clinical Oncology contains the first full report of a major advance in the treatment of metastatic renal cell carcinoma (RCC). Using SU11248 (sunitinib), an inhibitor of the vascular endothelial growth factor (VEGF) tyrosine kinase and the newest member of the class of tyrosine kinase inhibitors (TKIs; which also includes imatinib, erlotinib, and gefitinib), Motzer et al show that 45 of 53 patients treated after failure of first-line cytokine therapy had some degree of minor or major regression of disease accompanied by a median survival of 16.4 months. The expected median survival is 8 to 9 months. With sunitinib rapidly moving toward full US Food and Drug Administration review and with an Expanded Access Program soon in place, this drug should be ready for use by patients and their oncologists by the end of 2005 or early 2006. It is a welcome and sorely needed addition to the oncologist’s armamentarium. There is little to be skeptical about in this report. The remarkable, well-documented, and long-term responses (Figs 2 and 3 in Motzer et al) seen across multiple treatment centers and the high frequency of the responses lend strong credence to the activity of the agent. Although this was not a controlled trial, the response and median survival results are substantially better than any published data of second-line therapy in metastatic renal cancer. Furthermore, if this were the only TKI showing activity in RCC and if the data were the first to be reported, such a report would require urgent confirmation before being embraced. However, this article was one of several “firsts.” At the June 2004 meeting of the American Society of Clinical Oncology (ASCO; in New Orleans, LA), Ratain et al, simultaneously with Motzer at al, reported on the activity of sorafenib in RCC, a similar new TKI also targeting, in part, the VEGF receptor (VEGFR). Ratain et al reported that in a phase II, placebo-controlled, randomized discontinuation trial of sorafenib, 30% of patients with heavily pretreated metastatic RCC had a 25% regression of disease. An update of the completed trial was reported in 2005; it enrolled 202 patients in a period of only 16 months. All patients were treated with 12 weeks of sorafenib; given that tumor shrinkage occurred in 73 patients (30%), they continued receiving open-label sorafenib with a median progression-free survival of 10 months. Disease progression or tumor growth greater than 25% occurred in 51 patients, who came off study. Sixty-nine patients, whose tumors did not shrink by more that 25% or grow by more that 25%, were then randomly assigned either to placebo or to sorafenib. Ratain et al reported that the median progression-free survival of the 32 patients randomly assigned to continue sorafenib was 24 versus only 6 weeks for those 33 patients (four were not assessable) who were randomly assigned to placebo (P .0087). That result was confirmed at the 41st Annual Meeting of the American Society of Clinical Oncology (Orlando, FL, May 13 to 17, 2005) when Escudier et al reported on an 884-patient randomized phase III trial of second-line therapy for metastatic RCC. Patients were randomly assigned to either sorafenib 400 mg bid or placebo. The time to progressive disease for patients receiving sorafenib was 24 weeks, whereas time to progressive disease in placebo-treated patients was 12 weeks (P .01 10 ). Surprisingly, only 2% of patients had partial responses to sorafenib on central review, whereas 78% of patients had a minor response or stable disease. Escudier et al concluded that sorafenib significantly improves progression-free survival compared with placebo. Also at the 2005 ASCO meeting, Motzer et al reported on preliminary data from a second phase II trial of sunitinib in 106 patients with metastatic RCC. Using virtually identical study designs and eligibility criteria, they reported responses in 29% of patients. Rini et al reported on another new TKI inhibiting the VEGF/platelet-derived growth factor receptor, AG-013736. At 5 mg orally bid, 46% of 52 patients with RCC who had experienced treatment failure after one prior cytokine therapy had a partial response, and another 40% (21 patients) had stable disease (however, 20 of those 21 had some degree of tumor shrinkage). Only 8% of patients had progressive disease. These AG-013736 data are almost identical to that of sunitinib, and suggest that each molecule, although different structurally, is targeting a similar set of receptors necessary for the growth of RCC. Single-agent bevacizumab, which targets VEGF itself, first opened this field of study when Yang et al reported responses in 10% of RCC patients and an improvement in the median time to progression from 2 to approximately 6 months (P .0011). Also at the 2004 ASCO meeting, Hainsworth et al built on the Yang et al data by adding erlotinib 150 mg per day (a nearly inactive single agent) to bevacizumab. Striking responses were seen and the data were updated by Spigel et al at the 2005 ASCO meeting. Of 58 assessable, mostly previously untreated patients, there was a complete response rate of 3%, a partial response rate of 22%, and a minor/stable response rate of 44%/40%, respectively; only eight of the 58 patients (13%) had progressive disease. The median survival time for the combination of bevacizumab and erlotinib is now 23 months. Adding imatinib as a third agent added toxicity without improving the response proportion, and a randomized phase II trial of bevacizumab erlotinib has completed accrual. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 1 JANUARY 1 2006