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Originally published as JCO Early Release 10.1200/JCO.2005.03.7234 on December 5 2005 © 2006 American Society of Clinical Oncology.
Treatment Options in Metastatic Renal Carcinoma: An Embarrassment of RichesUniversity of Nevada School of Medicine, and Nevada Cancer Institute, Las Vegas, NV 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).1 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),2 Motzer et al1 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 al1) 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,3 simultaneously with Motzer at al,4 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 Also at the 2005 ASCO meeting, Motzer et al7 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 al8 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 al9 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 al10 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 al11 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,12 and a randomized phase II trial of bevacizumab ± erlotinib has completed accrual. There is now an "embarrassment of riches"13 for treating metastatic RCC. The single agents (sunitinib, sorafenib, bevacizumab, and AG 013736) are active but in phase I/II trials, other TKIs such as AZ 2171 and PTK 767 are also active. Furthermore, the older agents, interleukin-2 and interferon, still have important roles (albeit less defined now). This wealth of single agents (and the potential differences and similarities between them) has led to impressive numbers of phase II and III trials for RCC. There is a sunitinib versus interferon trial and a sorafenib versus interferon trial, both underway in first-line therapy. The Cancer and Leukemia Group B has recently completed a first-line trial in more than 700 patients who were randomly assigned to either interferon 9 million units 3 times per week or interferon 9 million units 3 times per week plus bevacizumab (10 mg/kg every 2 weeks).14 Phase II trials include bevacizumab plus interleukin-2, bevacizumab plus sorafenib, among many others. This large number of phase II and III trials (many with translational end points nested at cancer centers throughout the United States) provides widespread opportunities for patient and oncologist participation. Virtually all patients with RCC should now, or in the near future, be able to receive these exciting new drugs. A word of caution is still warranted. The precise clinical mechanism by which these drugs act and the mechanism by which tumors become resistant to them remains poorly understood. Motzer et al1 showed data that placental growth factor (a VEGF family member which is a specific ligand for VEGFR-1) levels increase during treatment. During the period of 2 weeks without treatment, there is decline back to baseline. There is no obvious correlation with progressive disease and increasing baseline levels of PlGF, although those data have not been reported fully in the Motzer et al article.1 In Figure 6D of the article, we see an interesting new piece of biology regarding metastatic RCC. Circulating levels of VEGFR-2, a new biomarker, are strikingly elevated at the start of cycle 1 (perhaps a new biomarker for RCC) and decline rather precipitously by day 28 or the end of cycle 1. There is then an increase of the VEGFR-2 concentrations before the start of cycle 2; this seesaw pattern continues throughout the eight cycles. However, note that the VEGFR-2 concentrations begin to plateau at the fourth to fifth cycle—is this the point at which drug resistance is beginning? One can only speculate what a continuous dosing of SU11248 would do to VEGFR-2 concentrations, and whether continuous dosing of SU11248 should be considered for additional development of this novel agent. In conclusion, this full report by Motzer et al (along with those full reports soon to be published by Ratain et al3 and Hainsworth et al10) represents a breakthrough in the treatment of metastatic RCC. All three studies build on the bevacizumab data first reported by Yang et al9 and bring closer to reality simpler, outpatient, life-prolonging therapy for patients with this otherwise deadly disease. Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Author Contributions
REFERENCES
1. Motzer R, Michaelson MD, Redman BG, et al: SU11248, a multi-targeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, demonstrates antitumor activity in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24, 2006 2. Krause DS, Van Etten RA: Tyrosine kinases as targets for cancer therapy. N Engl J Med 353:172-187, 2005 3. Ratain MJ, Flaherty KT, Stadler WM, et al: Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT). J Clin Oncol 22:14, 2004 (suppl; abstr 4501) 4. Motzer RJ, Rini BI, Michaelson MD, et al: SU011248, a novel tyrosine kinase inhibitor, shows antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma: Results of a phase 2 trial. J Clin Oncol 22:382, 2004 (suppl; abstr 4500) 5. Ratain MJ, Eisen T, Stadler WM, et al: Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 23:388, 2005 (suppl; abstr 4544) 6. Escudier B, Szczylik C, Eisen T, et al: Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 23:380s, 2005 (abstr 4510) 7. Motzer RJ, Rini BI, Michaelson MD, et al: Phase 2 trials of SU11248 show antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma (RCC). J Clin Oncol 23:380, 2005 (suppl; abstr 4508) 8. Rini B, Rixe O, Bukowski R, et al: AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC). J Clin Oncol 23:380, 2005 (suppl; abstr 4509) 9. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003 10. Hainsworth JD, Sosman JA, Spigel DR, et al: Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma (RCC). J Clin Oncol 22:382, 2004 (suppl; abstr 4502) 11. Spigel DR, Hainsworth JD, Sosman JA, et al: Bevacizumab and erlotinib in the treatment of patients with metastatic renal carcinoma (RCC): Update of a phase II multicenter trial. J Clin Oncol 23:387, 2005 (suppl; abstr 4540) 12. Hainsworth JD, Sosman JA, Spigel DR, et al: Bevacizumab, erlotinib, and imatinib in the treatment of patients (pts) with advanced renal cell carcinoma (RCC): A Minnie Pearl Cancer Res Network phase I/II trial. J Clin Oncol 23:388, 2005 (suppl; abstr 4542) 13. Schama S: Embarrassment of Riches: An Interpretation of Dutch Culture in the Golden Age. Berkeley, CA, University of California Press, 1988 14. Rini BI, Small EJ: Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 23:1028-1043, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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25% regression of disease. An update of the completed trial was reported in 2005
