First-Line Therapy
Please describe current medical oncology approaches to first-line therapy for metastatic renal cell carcinoma.
The current first-line therapy for most patients with good- to intermediate-risk metastatic renal cell carcinoma is a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. A small group of patients with good performance status should consider high-dose interleukin 2 (IL-2, Proleukin) therapy, but the toxicity and commitment to inpatient administration precludes this approach in many patients.
The selection of the specific VEGF receptor tyrosine kinase inhibitor used for first-line therapy has evolved. Level 1 evidence has been established for sunitinib (Sutent) in this setting since 2007, but more recently, data from the COMPARZ study1 suggests that pazopanib (Votrient) has similar efficacy to sunitinib with a better side-effect profile in many patients. Lower levels of evidence support the use of other VEGF receptor tyrosine kinase inhibitors such as sorafenib (Nexavar) and axitinib (Inlyta) as well as the VEGF ligand inhibitor bevacizumab (Avastin), in the first-line setting.
For patients with poor-risk metastatic renal cell carcinoma, there is level 1 evidence to support use of an intravenous mTOR inhibitor over interferon alfa. Lower-level evidence supports the use of VEGF receptor tyrosine kinase inhibitors in the poor-risk setting also.
Second-Line Therapy
What about second-line therapy for metastatic or recurrent disease?
Second-line therapy selection depends on the first-line approach that preceded it, and some would argue that the efficacy and tolerability of the first-line agent should also inform second-line selection. For patients who received first-line high-dose IL-2, level 1 evidence supports the use of VEGF receptor tyrosine kinase inhibitors in the second-line setting, with axitinib being the common choice based on data from the AXIS study.2
Patients who received a VEGF receptor tyrosine kinase inhibitor in the first line can be treated with either another VEGF receptor tyrosine kinase inhibitor or an mTOR inhibitor in the second line. Renal cell carcinoma experts are divided over this choice, which represents an area of equipoise and debate.
Data from the RECORD-1 study provides level 1 evidence for the oral mTOR inhibitor everolimus (Afinitor) over best supportive care alone after a VEGF receptor tyrosine kinase inhibitor. Data from the AXIS study supports the use of axitinib over sorafenib in this setting. Interestingly, the progression-free survival for everolimus and axitinib after sunitinib therapy in these different trials was approximately 4 months. A trial of everolimus vs axitinib after a single VEGF receptor tyrosine kinase inhibitor might be definitive but has not been undertaken.
The INTORSECT trial3 compared the intravenous mTOR inhibitor temsirolimus (Torisel) to the VEGF receptor tyrosine kinase inhibitor sorafenib after sunitinib therapy. There was minimal difference in progression-free survival between the two agents, but patients given sorafenib in this trial had a 4-month better overall survival.
Extrapolating these data to clinical practice has been difficult. Nevertheless, many oncologists have noted a benefit with sorafenib, including improved overall survival in the second-line setting among patients who had received first-line sunitinib for longer than 6 months in the INTORSECT trial. Poor-risk patients given temsirolimus in the first line are routinely given a VEGF receptor tyrosine kinase inhibitor in the second line if their performance status is adequate.
Third Line and Beyond
And what options are appropriate for third-line therapy in these patients?
Third-line therapy is dependent on prior therapy. Both mTOR inhibitors and VEGF receptor tyrosine kinase inhibitors have activity. Based on RECORD-1,4 everolimus has activity compared to best supportive care, whereas the recently reported GOLD study5 showed that use of sorafenib resulted in an overall survival of 11 months in patients treated with prior VEGF- and mTOR-directed therapies.
Treatment beyond third-line therapy may be warranted in some patients who have had good disease control duration or responses to prior VEGF- or mTOR-directed agents and good performance status. Many clinicians use sorafenib or bevacizumab in this setting, although there is no evidence base to support this. ■
Disclosure: Dr. Quinn has received honoraria for scientific advisory board involvement for Pfizer, Bayer, Genentech, and Novartis.
References
1. Motzer RJ, Hutson TE, Cella D, et al: Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369:722-731, 2013.
2. Rini BI, Escudier B, Tomczak P, et al: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 378:1931-1939, 2011.
3. Hutson TE, Escudier B, Esteban E, et al: Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 32:760-767, 2014.
4. Motzer RJ, Escudier B, Oudard S, et al: Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. RECORD-1 Study Group. Lancet 372:449-456, 2008.
5. ESMO @ ECC 2013: Similar phase III results reported for dovitinib vs. sorafenib treatment in patients with metastatic renal cell carcinoma. September 29, 2013. Available at www.esmo.org/Conferences/European-Cancer-Congress-2013/News/Similar-Phase-III-Results-Reported-for-Dovitinib-vs.-Sorafenib-Treatment-in-Patients-with-Metastatic-Renal-Cell-Carcinoma. Accessed February 24, 2014.
