Clear cell (CC)-renal cell carcinoma (RCC), the predominant histologic type of RCC, is highly dependent on angiogenesis, via the vascular endothelial growth factor (VEGF) pathway.1 The mammalian target of rapamycin (mTOR) pathway also appears to play a role in VEGF production, as well as directly promote tumor cell growth.
Sunitinib (Sutent), a multitargeted oral tyrosine kinase inhibitor (TKI) targeting VEGF receptors and multiple other molecular targets, yielded a greater median overall survival (OS) than interferon (IFN)-α in a landmark phase 3 trial (26.4 vs 21.8 mo, respectively; P = .051).2 After censoring patients’ crossing over from IFN-α to sunitinib, the difference was statistically significant. Median progression-free survival (PFS) was 11 months for sunitinib compared with 5 months for IFN-α (P <.001); objective response rate (ORR) was 47% for sunitinib compared with 12% for IFN-α (P <.001). The most common sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). All 3 Memorial Sloan-Kettering Cancer Center clinical risk groups (good, intermediate, and poor) appeared to benefit, although ~93% of patients had good- or intermediate-risk disease. In a presentation at the Genitourinary Cancers Symposium this past February, the renal EFFECT trial demonstrated that the conventional regimen of 50-mg daily 4 weeks on treatment/2 weeks off treatment was statistically superior to 37.5 mg daily given continuously on the composite end point of death, progression, and patient-reported outcomes.3
A phase 3 placebo-controlled study of pazopanib (Votrient), a VEGF receptor TKI, enrolled 435 patients with CCRCC who were treatment-naïve or had received previous cytokine-based therapy. 4 Median PFS was 9.2 months in the pazopanib group compared with 4.2 months in the placebo group (P <.0001). When analyzed according to prior therapy, median PFS for treatment- naïve patients was 11.1 months compared with 2.8 months for placebo (P <.0001); and for cytokine-treated patients, median PFS was 7.4 months versus 4.3 months for placebo (P <.001). The ORR was 30% for the pazopanib arm and 3% for the placebo group. Common pazopanib-related adverse events included diarrhea, hypertension, hair depigmentation, nausea, anorexia, and vomiting. Elevated levels of alanine aminotransferase and aspartate aminotransferase were noteworthy laboratory abnormalities, and these were occasionally severe. Results from the completed phase 3 COMPARZ trial comparing pazopanib with sunitinib are eagerly awaited.
The AVOREN (Avastin and Roferon in Renal Cell Carcinoma) trial randomized 649 patients with CC-RCC to firstline IFN-α-2a plus placebo or IFN-α-2a plus bevacizumab (Avastin), a monoclonal antibody against VEGF, which was administered intravenously every 2 weeks.5 Adding bevacizumab to IFN-α- 2a significantly prolonged median PFS (10.2 vs 5.4 mo, respectively; P <.0001) and ORR (30.6% vs 12.4%, respectively; P <.0001). A trend toward improved OS was also observed with the addition of bevacizumab (P = .3360), but the availability of other active agents confounded the survival analysis. The contribution of IFN-α-2a to the efficacy of the combination is unclear, and the poor-risk subgroup might not benefit from the doublet. A similar Cancer and Leukemia Group B trial demonstrated a comparable extension in median PFS with the combination of bevacizumab and IFN.6
Temsirolimus, an mTOR inhibitor administered via weekly intravenous infusion, prolonged median OS compared with IFN-α (10.9 vs 7.3 mo, respectively; P = .008) in patients with poor-risk RCC, defined as ≥3 poor risk factors by Memorial Sloan-Kettering risk classification.7 Thus, the standard of care has changed relatively rapidly with the advent of these targeted biologic agents, which have generally supplanted cytokines as conventional therapy. High-dose (HD) interleukin (IL)-2 may retain a role in selected patients (good-risk CC-RCC, alveolar features and the absence of papillary or granular features, high CAIX expression, genomic signatures) with good performance status as a result of an ~7% durable complete remission and apparent cures.8,9 The severe cardiovascular, pulmonary, and renal toxicities of HD IL-2 render it as an option only for relatively young patients without significant comorbidities. Unfortunately, the recent prospective SELECT (Selenium and Vitamin E Cancer Prevention Trial) was unable to validate tumor CAIX expression as a predictive factor for response.
To summarize, sunitinib, pazopanib, or bevacizumab-IFN are preferred firstline agents for good- and intermediaterisk CC-RCC, whereas temsirolimus is preferred for patients with poor-risk disease. HD IL-2 retains its role in a wellselected, good-risk subset. Phase 3 trials under way include tivozanib versus sorafenib (Nexavar) and axitinib versus sorafenib. Other ongoing studies are evaluating adjuvant therapy with VEGF and mTOR inhibitors.
For salvage therapy after relapsed/ refractory cytokine-based regimens, the evidence supports using pazopanib or sorafenib, although the other approved agents also demonstrate activity in this setting.10,11 The TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial) trial was limited to good- and intermediate-risk patients and demonstrated superior median PFS for sorafenib compared with placebo (5.5 vs 2.8 mo, respectively; P < .000001).10 The 13.5% improvement in median OS seen with sorafenib over pazopanib was not significant (17.8 vs 15.2 mo, respectively; hazard ratio [HR], 0.88; P = .146). Secondary analysis censoring crossover data showed a significant OS benefit with sorafenib (HR, 0.78; P = .0287). Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib; hypertension and cardiac ischemia were rare. A smaller randomized phase 2 trial in the first-line setting failed to demonstrate improved outcomes with sorafenib versus IFN- α.12 Given the lack of robust frontline data, sorafenib increasingly is being reserved for salvage therapy following other agents.
Everolimus (Afinitor), an orally administered mTOR inhibitor, was recently approved in RCC based on findings from the RECORD (Renal Cell Cancer Treatment with Oral RAD001 Given Daily)-1 trial, which showed improved outcomes in patients previously treated with sunitinib and/or sorafenib.13 Everolimus was associated with significant improvement in median PFS compared with placebo (4.0-1.9 mo; HR, 0.30; P <.001). The probability of 6-month PFS was 26% with everolimus versus 2% with placebo, though the RECIST response rate with everolimus was only 1%. Stomatitis, rash, and fatigue were the most common adverse events, but were mostly mild or moderate in severity. Observed class-specific toxicities consisted of interstitial pneumonitis, hyperlipidemia, and hyperglycemia.
For therapy following previous treatment with mTOR inhibitors, no definitive data exist demonstrating improved outcomes with currently available agents. There is evidence of incomplete cross-resistance between the newly approved agents discussed, with modest activity when switching agents.14,15 Lack of complete cross-resistance occurs when sequentially administering the different antiangiogenic agents; for example, sorafenib → sunitinib, sunitinib → sorafenib, bevacizumab → sunitinib and sorafenib → axitinib.14-17 A phase 3 trial comparing second-line sorafenib with axitinib in patients treated previously with sunitinib reported prolonged PFS with axitinib, but the data have not yet been presented formally. An ongoing phase 3 trial is comparing sorafenib with temsirolimus following previous treatment with sunitinib.
Prognostic and Predictive Factors
Known prognostic factors associated with outcomes in advanced RCC treated with IFN-α include performance status, disease-free interval, number of metastatic sites, hemoglobin, calcium, and lactate dehydrogenase (LDH).18 Recent analysis from trials with anti- VEGF agents shows these factors continue to be of major importance, although notably neutrophilia and thrombocytosis replaced LDH in the newly created (2009) model.19 Future prognostic models will attempt to incorporate molecular markers with clinical variables to refine prognosis prediction in patients with metastatic CC-RCC treated with novel antiangiogenic agents.
Despite providing important incremental improvements in outcomes, the novel antiangiogenic agents have not yielded complete responses or cures and are associated with significant toxicities, implying there is ample room for improvement and the need for continued commitment to clinical trials. Biomarkers potentially predictive of response are emerging and need to be incorporated into the clinical development of agents. Furthermore, the evaluation of adjuvant therapy using VEGF and mTOR inhibitors is ongoing after surgery.
Guru Sonpavde receives research support from Pfizer, Bristol-Myers Squibb, Cephalon, Celgene, and Bellicum and is on the speakers’ bureau for GlaxoSmithKline, Novartis, and sanofi-aventis. Thomas E. Hutson receives research support from Bayer/Onyx, Pfizer, GlaxoSmithKline; is an advisory board/consultant for Bayer/ Onyx, Pfizer, Den dreon, and sanofi-aventis; and is on the speakers’ bureau for Bayer/Onyx, Pfizer, Amgen, sanofi-aventis, Novartis, and Genentech. Lance Cowey has nothing to disclose.
- Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18:338-340.
- Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584-3590.
- Motzer RJ, Hutson TE, Olsen MR, et al. Randomised phase II multicenter study of the efficacy and safety of sunitinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma (Renal EFFECT Trial). J Clin Oncol. 2011;29(suppl 7):LBA308.
- Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061-1068.
- Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28:2144-2150.
- Rini BI, Halabi S, Rosenberg JE et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26:5422-5428.
- Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281.
- Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin- 2 therapy. J Clin Oncol. 1995;13:688-696.
- McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133-141.
- Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. J Clin Oncol. 2009;27:3312-3318.
- Hutson TE, Davis ID, Machiels JP, et al. Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): interim results of a phase II randomized discontinuation trial (RDT). J Clin Oncol. 2007; 25(18S):Abstract 5031.
- Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280-1289.
- Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456.
- Tamaskar I, Garcia JA, Elson P, et al. Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior anti - angiogenic therapy. J Urol. 2008;179:81-86.
- Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. 2009;182:29-34.
- Rini BI, Michaelson MD, Rosenberg JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3743-3748.
- Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27:4462-4468.
- Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-296.
- Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27:5794-5799.