Over the last decade, improved understanding of canonical pathways implicated in the unique biology of renal cell carcinoma (RCC) has fueled the development of several new approaches to treatment for this malignancy. Development of tyrosine kinase inhibitors; mammalian target of rapamycin inhibitors; and, more recently, targeted immunotherapies such as checkpoint inhibitors has had a major impact on the natural history of this disease. Clinical prognostic models also have played a central role in the management of metastatic disease, as well as in the design and interpretation of clinical trials. Currently, 11 regimens are approved by the US Food and Drug Administration for the treatment of advanced RCC, and there is a growing role for localized approaches, including surgery, in appropriately selected patients. This article reviews current registration data for approved agents, and offers an outlook on selected novel strategies. A practical perspective on the multidisciplinary management of advanced RCC is provided, with a focus on systemic therapy.
Renal cell carcinoma (RCC) is characterized by a unique biology and poor response to conventional chemotherapy and radiation therapy. Over the last decade, a growing understanding of the underlying oncogenetic events and relevant molecular pathways has enabled significant advances in therapy for this disease. Inactivation of the von Hippel–Lindau (VHL) gene is the cardinal oncogenetic event in the pathogenesis of clear cell RCC. Loss of function in this tumor suppressor gene results in high levels of hypoxia-inducible factor (HIF) with activation of multiple downstream effectors involved in angiogenesis and cell proliferation, most prominently the vascular endothelial growth factor (VEGF). Further, it is well understood that the phosphoinositide 3-kinase pathway, with its key enzymatic complex involving the mammalian target of rapamycin (mTOR), is commonly upregulated and actionable in this disease. Lastly, a growing understanding of the unique immune microenvironment that is commonly hyperinfiltrated in RCC renders this disease targetable through reinvigoration of the patient’s immune system; this is evident historically by the success of cytokine therapy prior to the advent of molecularly targeted agents, and more recently by the successful application of checkpoint inhibitor blockade in this disease. In addition to the successful development of 11 systemic regimens approved by the US Food and Drug Administration (FDA), a large body of work characterizing the heterogeneous nature of this disease has established clinical, laboratory, and molecular criteria to guide the management of RCC. This information can be integrated with individual patient data to inform decision making regarding the utility of systemic therapies, surgical interventions, and even active surveillance in the metastatic setting. This article provides a practical perspective on the management of advanced RCC, as well as insight into the current models of risk stratification and ongoing clinical trials. The discussion will focus on the currently available systemic therapies; other strategies that are beyond the scope of this article include active surveillance[4,5] and metastasectomy.[6,7]
Risk Stratification of Patients With Advanced RCC
Even in the metastatic setting, the natural history of clear cell RCC is highly variable, and outcomes of systemic therapy are heterogeneous. Therefore, standardized determination of patient and disease characteristics that correlate with clinical outcomes has played a central role in this setting. Currently there are two well-established prognostic models—one from Memorial Sloan Kettering Cancer Center (MSKCC) and the other from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)—that have been developed and validated in large datasets of patients treated for metastatic RCC (Table 1). These have become critical in the design and interpretation of clinical trials and are commonly applied in retrospective analyses of large cohorts. Further, they have also been useful for patient prognostication and counseling. While the MSKCC and IMDC models typically do not facilitate selection of specific agents in the metastatic setting, they can guide decision making in several unique clinical scenarios, as we will outline in this article.
MSKCC and IMDC prognostic risk models for metastatic RCC
In 2002, we reported on the first developed and most widely used prognostic tool, the MSKCC risk criteria. This model incorporates five prognostic factors that correlated independently with overall survival (OS) in patients treated with interferon alfa for metastatic disease: Karnofsky performance status scores of less than 80%, intervals of less than 1 year between diagnosis of RCC and initiation of treatment, lactate dehydrogenase levels more than 1.5 times the upper limit of normal, corrected serum calcium levels greater than 10 mg/dL, and hemoglobin levels below the lower limit of normal. This model was subsequently validated in an independent cohort of patients during the immunotherapy era and ultimately in patients treated with sunitinib. The MSKCC risk model has been applied to large clinical trial datasets multiple times, and it remains the most frequently used source of risk scores for stratification of patients enrolled in randomized clinical trials. Following the advent of targeted therapies, Heng et al, with the IMDC, compiled and retrospectively analyzed a large cohort of 645 patients with metastatic RCC treated with first-line tyrosine kinase inhibitor (TKI) therapy. The resulting clinical prediction model, commonly known as the IMDC model, provides a six-variable score that largely overlaps with the MSKCC model. The IMDC model also stratifies patients into “favorable-,” “intermediate-,” and “poor-risk” categories, while adding high absolute neutrophil and platelet counts as risk factors but excluding high lactate dehydrogenase level as a risk factor.
Applicability of prognostic models beyond the first-line setting in clear cell RCC
Initially, these prognostic models were validated only in patients with metastatic RCC who were receiving first-line therapy. However, in 2004, the Cleveland Clinic group that previously reported on the MSKCC risk criteria conducted a study in which they pooled data from cytokine-pretreated patients receiving additional systemic therapies and proposed a separate model to stratify patients with prior therapies; this MSKCC model included only three factors (Karnofsky performance status score, hemoglobin level below the lower limit of normal, and corrected serum calcium concentration). Similarly, the IMDC model was validated in patients in second-line therapy and in patients with non–clear cell RCC. More recently, use of prognostic gene expression signatures has improved the predictive power of the IMDC model and provided additional prognostic information in the setting of metastatic RCC.
Prognostic models in specific clinical scenarios: active surveillance, cytoreductive nephrectomy, and first-line therapy options
Risk stratification tools have been applied to support decision making in several clinical scenarios. Data from a small trial prospectively studying active surveillance in patients with metastatic RCC suggests that integration of IMDC risk assessment and disease burden may enable clinicians to identify patients who are more likely to remain on active surveillance for a longer period of time. Based on a large retrospective analysis, RCC patients being considered for cytoreductive nephrectomy appeared to gain an OS benefit from undergoing surgery before initiation of systemic therapy if they met three or fewer IMDC criteria preoperatively, whereas those with higher IMDC risk scores did not benefit from this strategy. The only agent currently approved based on a pivotal trial performed in a “risk-defined” setting is temsirolimus, which was found to yield superior OS outcomes compared with interferon alfa in patients with three or more “poor-risk” features (as defined by the MSKCC criteria) and/or the presence of extensive metastatic disease.
TKI registration trials, however, did enroll patients with poor-risk disease and showed clear treatment efficacy; hence, other approved first-line agents (such as sunitinib and pazopanib) are valid options in this setting. In fact, TKIs are commonly used in this setting, given the ease of oral administration (eg, compared with the need for weekly infusions for temsirolimus), the more robust radiographic response rates, and the superior efficacy of TKIs over rapalogs suggested by several randomized studies.[17-19] Finally, a recently published phase II trial in patients with previously untreated metastatic RCC and intermediate- or poor-risk disease per IMDC criteria reported superior progression-free survival (PFS) in those who received the novel TKI cabozantinib compared with those who received sunitinib.
Systemic Therapy for Metastatic RCC: First-Line Options
A better understanding of the canonical pathways in RCC has led to the introduction of several molecularly directed therapies over the last 10 years, with these targeted treatment options replacing cytokine-based strategies as the standard of care in metastatic RCC. The availability of agents with known efficacy and safety profiles, as well as individual patient characteristics and physician preferences, all play a role in the selection of first-line and subsequent therapy (see the section in this article, “Choosing Between First-Line Option” and Table 2).
TKIs as standard of care in the first-line setting
Sunitinib and pazopanib are the most commonly used first-line agents approved for the treatment of advanced RCC. These small, orally available molecules are potent inhibitors of multiple tyrosine kinases, most relevantly VEGF receptor (VEGFR) 2, a key mediator of early-phase angiogenesis expressed on endothelial cells in the tumor microenvironment. In the pivotal phase III trial of first-line sunitinib, patients treated with this agent achieved longer PFS and higher objective response rates (ORRs) compared with those who received interferon alfa (median PFS, 11 months vs 5 months; hazard ratio [HR], 0.42; 95% CI, 0.32–0.54; P < .001; and ORR, 31% vs 6%, respectively). Similarly, in its phase III registration trial, pazopanib demonstrated significant improvement in PFS and ORR when compared with placebo in patients with predominantly untreated advanced RCC (median PFS, 9.2 months vs 4.2 months; HR, 0.46; 95% CI, 0.34–0.62; P < .0001; and ORR, 30% vs 3%, respectively).
A large subsequent phase III trial confirmed PFS noninferiority for pazopanib when compared with sunitinib in treatment-naive patients with metastatic disease (median PFS, 8.4 months vs 9.5 months; HR, 1.05; 95% CI, 0.99–1.22). Similar OS outcomes were also reported in both groups in a subsequent analysis (median OS, 28.3 months vs 29.1 months, respectively; HR, 0.92; 95% CI, 0.79–1.06; P = .24). Secondary analyses of this trial compared patients’ tolerance of pazopanib with that of sunitinib and reported distinctly different safety profiles. Patients receiving pazopanib were more likely to develop liver function test abnormalities, hair color changes, and weight loss. In contrast, adverse events were more frequently seen in the sunitinib-treated patients, including fatigue, hand-foot syndrome, and stomatitis. In the phase III trial, patient-reported quality-of-life scores predominantly favored pazopanib. Similar results were reported in the phase II, randomized, double-blind, cross-over study that evaluated patients’ and physicians’ preferences for pazopanib vs sunitinib, with both groups significantly favoring pazopanib.
Since the initial approval of sunitinib, several retrospective studies have evaluated alternative schedules (compared with the standard regimen of a 50-mg dose, for 4 weeks on treatment followed by 2 weeks off) in an effort to improve tolerance to the medication, optimize drug exposure, and maximize efficacy. While continuous administration of low-dose sunitinib was not found to be more effective than the standard schedule, a growing body of retrospective data shows favorable outcomes with an alternative dosing schedule of 50 mg for 2 weeks on treatment/1 week off.[29-31] A small phase II randomized trial compared traditional sunitinib dosing with this new schedule and reported that the 2 weeks on treatment/1 week off approach was associated with less toxicity and superior failure-free survival at 6 months when compared with the standard schedule of 4 weeks on the drug followed by 2 weeks off.
Emerging data: cabozantinib
Recent reports have prompted discussion of the potential future role of a novel TKI in the frontline setting. Cabozantinib is a small molecule that inhibits VEGFR. Unlike sunitinib, this agent also blocks the tyrosine kinases MET and AXL, which, in addition to being oncoproteins and HIF targets, have been associated with acquired resistance to antiangiogenic therapy. In a recently reported randomized phase II trial, cabozantinib achieved superior PFS and increased ORR when compared with sunitinib in treatment-naive patients with IMDC-designated intermediate- or poor-risk disease. While these are provocative data, it is important to note that this agent is presently FDA-approved in pretreated patients with advanced or metastatic RCC (see the section in this article, “Second-line options”).
Use of mTOR inhibitors in the first-line setting
Temsirolimus, administered intravenously, is an allosteric inhibitor of mTOR. It binds to the intracellular protein FKBP12, forming a complex that inhibits mTOR complex 1 signaling. As previously noted, in a pivotal phase III Global Advanced Renal Cell Carcinoma trial, patients with poor-risk features who were treated with this agent demonstrated prolongation of OS compared with those who received interferon alfa (median OS, 10.9 months vs 7.3 months; HR, 0.73; 95% CI, 0.58–0.92; P = .008) (see the section, “Prognostic models in specific clinical scenarios”). In the same study, the combination of temsirolimus plus interferon did not show additional benefit, likely because of limited drug exposure due to poor tolerance. Key side effects of temsirolimus include hyperglycemia, hyperlipidemia, and fatigue. The drug is used infrequently due to the need for weekly IV infusions. It has not been compared directly with sunitinib or pazopanib in the first line; however, several randomized studies have suggested that VEGF-targeting TKIs achieve an antitumor effect superior to that of mTOR complex 1 inhibitors when given alone in treatment-naive and pretreated patients.[17,18,35]
Bevacizumab plus interferon alfa
Bevacizumab is a monoclonal antibody that binds to VEGF-A and prevents its interaction with VEGFRs, halting angiogenesis. Two phase III clinical trials conducted in untreated patients with advanced clear cell RCC have shown that the combination of interferon alfa with bevacizumab results in significant improvement of PFS vs treatment with interferon alfa alone (median PFS, 10.2 months vs 5.4 months; HR, 0.63; 95% CI, 0.52–0.75; P = .0001). The median PFS (8.5 months vs 5.2 months; HR, 0.71; 95% CI, 0.61–0.83; P < .001) and ORR (25.5% vs 13.1%, respectively) seen in the second trial led to approval of the combination. However, due to the unfavorable adverse event profile and the infusions required for interferon, and the frequent injections (of bevacizumab), the regimen is not commonly used in the clinic.
Cytokine-based immunotherapies: high-dose interleukin-2
High-dose interleukin-2 remains a first-line option in a selected group of patients with metastatic RCC. It was initially approved by the FDA in 1992, based on the results of a pool of seven nonrandomized phase II clinical trials with meaningful, durable response rates in a small portion of patients. Despite this evidence, the potential benefits of high-dose interleukin-2 must be balanced cautiously with the significant morbidity associated with this agent, which requires hospital admission and is frequently administered in the intensive care unit setting to allow close patient monitoring. More recently, the prospective phase II SELECT study reported an ORR of 25% based on World Health Organization criteria in treatment-naive patients, but the investigators failed to confirm certain histopathologic features tested for their utility in selecting patients.
1. Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 2008;8:865-73.
2. Battelli C, Cho DC. mTOR inhibitors in renal cell carcinoma. Therapy. 2011;8:359-67.
3. Carlo MI, Voss MH, Motzer RJ. Checkpoint inhibitors and other novel immunotherapies for advanced renal cell carcinoma. Nat Rev Urol. 2016;13:420-31.
4. Ornstein MC, Wood LS, Elson P, et al. A phase II study of intermittent sunitinib in previously untreated patients with metastatic renal cell carcinoma. J Clin Oncol. 2017;35:1764-9.
5. Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016;17:1317-24.
6. Dabestani S, Marconi L, Hofmann F, et al. Local treatments for metastases of renal cell carcinoma: a systematic review. Lancet Oncol. 2014;15:e549-e561.
7. Karam JA, Rini BI, Varella L, et al. Metastasectomy after targeted therapy in patients with advanced renal cell carcinoma. J Urol. 2011;185:439-44.
8. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-96.
9. Mekhail TM, Abou-Jawde RM, Boumerhi G, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005;23:832-41.
10. Patil S, Figlin RA, Hutson TE, et al. Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2011;22:295-300.
11. 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;27:5794-9.
12. Ko JJ, Xie W, Kroeger N, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 2015;16:293-300.
13. Kroeger N, Xie W, Lee JL, et al. Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: characterization of survival outcome and application of the International mRCC Database Consortium criteria. Cancer. 2013;119:2999-3006.
14. de Velasco G, Culhane AC, Fay AP, et al. Molecular subtypes improve prognostic value of International Metastatic Renal Cell Carcinoma Database Consortium prognostic model. Oncologist. 2017;22:286-92.
15. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2014;66:704-10.
16. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-81.
17. 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. 2014;32:760-7.
18. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32:2765-72.
19. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:917-27.
20. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35:591-7.
21. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 3.2015. J Natl Compr Canc Netw. 2015;13:151-9.
22. Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376:354-66.
23. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-24.
24. 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;28:1061-8.
25. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722-31.
26. Motzer RJ, Hutson TE, McCann L, et al. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014;370:1769-70.
27. Escudier B, Porta C, Bono P, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol. 2014;32:1412-8.
28. Motzer RJ, Hutson TE, Olsen MR, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol. 2012;30:1371-7.
29. Atkinson BJ, Kalra S, Wang X, et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol. 2014;191:611-8.
30. Bracarda S, Iacovelli R, Boni L, et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol. 2015;26:2107-13.
31. Bjarnason GA, Khalil B, Hudson JM, et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol. 2014;32:480-7.
32. Lee JL, Kim MK, Park I, et al. Randomized phase II trial of sunitinib four weeks on and two weeks off versus two weeks on and one week off in metastatic clear-cell type renal cell carcinoma: RESTORE trial. Ann Oncol. 2015;26:2300-5.
33. Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35:2687-97.
34. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814-23.
35. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473-82.
36. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-11.
37. 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;26:5422-8.
38. 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;13:688-96.
39. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207-14.
40. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select” trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2015;21:561-8.
41. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 2.2014. J Natl Compr Canc Netw. 2014;12:175-82.
42. 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. 2011;378:1931-9.
43. Rini BI, Melichar B, Ueda T, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013;14:1233-42.
44. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-64.
45. McDermott DF, Sosman JA, Sznol M, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol. 2016;34:833-42.
46. Choueiri TK, Fishman MN, Escudier B, et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin Cancer Res. 2016;22:5461-71.
47. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33:1430-7.
48. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-13.
49. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35:785-92.
50. Molina AM, Hutson TE, Larkin J, et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol. 2014;73:181-9.
51. George S, Motzer RJ, Hammers HJ, et al. Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol. 2016;2:1179-86.
52. Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients (pts) with advanced renal cell carcinoma (aRCC): preliminary safety and efficacy results. Ann Oncol. 2016;27(suppl 6):abstr 773PD.
53. Choueiri T, Larkin J, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): results from a phase Ib trial. J Clin Oncol. 2017;35(suppl):abstr 4504.
54. Amin A, Plimack E, Infante J, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(suppl 5s):abstr 5010.
55. Chowdhury S, McDermott DF, Voss MH, et al. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2017;35(suppl):abstr 4506.
56. McDermott DF, Atkins MB, Motzer RJ, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). J Clin Oncol. 2017;35(suppl 6):abstr 431.
57. Atkins MB, McDermott DF, Powles T, et al. IMmotion150: a phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol. 2017;35(suppl):abstr 4505.
58. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017 Jul 5. [Epub ahead of print]
59. Choueiri TK, Fay AP, Gagnon R, et al. The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma. Clin Cancer Res. 2013;19:5218-26.
60. Funakoshi T, Lee CH, Hsieh JJ. A systematic review of predictive and prognostic biomarkers for VEGF-targeted therapy in renal cell carcinoma. Cancer Treat Rev. 2014;40:533-47.
61. Schneider BP, Shen F, Miller KD. Pharmacogenetic biomarkers for the prediction of response to antiangiogenic treatment. Lancet Oncol. 2012;13:e427-e436.
62. Castellano D, Virizuela JA, Cruz J, et al. The role of pharmacogenomics in metastatic renal cell carcinoma. Cancer Metastasis Rev. 2012;31(suppl 1):S29-S32.
63. Motzer RJ, Hutson TE, Hudes GR, et al. Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma. Cancer Chemother Pharmacol. 2014;74:739-50.
64. Harmon CS, DePrimo SE, Figlin RA, et al. Circulating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naive patients with metastatic renal cell carcinoma. Cancer Chemother Pharmacol. 2014;73:151-61.
65. Ho TH, Choueiri TK, Wang K, et al. Correlation between molecular subclassifications of clear cell renal cell carcinoma and targeted therapy response. Eur Urol Focus. 2016;2:204-9.
66. Hsieh JJ, Chen D, Wang PI, et al. Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur Urol. 2017;71:405-14.
67. Choueiri TK, Figueroa DJ, Fay AP, et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin Cancer Res. 2015;21:1071-7.
68. Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14:141-8.
69. 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;27:3584-90.
70. Sternberg CN, Hawkins RE, Wagstaff J, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49:1287-96.
71. Motzer RJ, McCann L, Deen K. Pazopanib versus sunitinib in renal cancer. N Engl J Med. 2013;369:1970.
72. Escudier B, Bellmunt J, Negrier 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;28:2144-50.
73. Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28:2137-43.
74. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14:1287-94.
75. Motzer RJ, Hutson TE, Ren M, et al. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016;17:e4-e5.
76. 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. Lancet. 2008;372:449-56.
77. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256-65.