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First-line Treatment Options for Renal Cell Carcinoma

Authors: Ulka Vaishampayan,
Oncology Multidisciplinary Team Chair and Associate Professor, Karmanos Cancer Institute, Wayne State University, Detroit, MI, US
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Published Online: Nov 2nd 2017

The incidence of renal cell carcinoma (RCC) has steadily risen over the past 10 years and accounts for 2–3% of all adult malignancies.1 Metastatic RCC (mRCC) is associated with a poor prognosis; historically, 5-year survival was around 8% but that is rapidly improving.2 For many years, the only treatment for mRCC approved by the US Food and Drug Administration (FDA) was high dose interleukin-2 (HD IL-2; Proleukin®, Prometheus Laboratories Inc., San Diego, CA). The 1992 approval was based on data from a number of clinical trials demonstrating consistent objective response rates, including durable complete responses (CR) in select patients.3 However, the use of HD IL-2 is associated with short-term toxicity, and requires hospitalization and management by specialist teams experienced in HD IL-2 therapy.4 In addition, only a minority (15%) of patients respond to treatment, based on data in the package insert.3



In 2005, elucidation of the pathogenic processes underlying RCC led to the emergence of vascular endothelial growth factor and tyrosine kinase inhibitors (TKIs) and mechanistic target of rapamycin (mTOR) inhibitors. These include sorafenib, sunitinib, axitinib, bevacizumab plus interferon-alpha (IFN-α), temsirolimus, everolimus, pazopanib and, most recently, cabozantinib and lenvatinib.5 Molecular-targeted therapies have become the standard of care for mRCC as a result of their favorable efficacy and tolerability profiles, and many are administered orally. The current recommendation from the National Comprehensive Cancer Network (NCCN) is the use of oral, multi-target, TKIs, specifically sunitinib and pazopanib, in the first-line setting.6 In the recent CABOzantinib versus SUNitinib (CABOSUN) study, cabozantinib showed significant clinical benefit in progression-free survival (PFS) and overall response rate (ORR) compared with sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC, the first time that any agent has demonstrated statistically significant and superior efficacy over sunitinib.7 However, despite encouraging ORRs, the use of targeted therapy has infrequently resulted in CR or durable remissions.8

The emergence of immune checkpoint inhibitors such as the anti-programmed cell death 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking agents has further broadened the therapeutic landscape for mRCC. In the CheckMate 016 phase I study, nivolumab plus ipilimumab therapy demonstrated manageable safety, clinically meaningful antitumor activity, and durable responses with promising overall survival (OS) at 2 years in patients with mRCC.9 Recently reported results evaluated this combination in a phase III randomized trial, Checkmate 14, comparing sunitinib, and the nivolumab plus ipilimumab combination revealed significantly improved PFS and OS in intermediate- or poor-risk RCC.10 Numerous ongoing phase III clinical studies are investigating combination therapies involving immune checkpoint inhibitors and anti-vascular agents in the first-line setting for mRCC (NCT02982954, NCT02420821, NCT02853331, NCT02811861, NCT02684004).

At present, HD IL-2, sorafenib, sunitinib, pazopanib, and bevacizumab + IFN-α, are the only approved agents for previously untreated mRCC. In the randomized Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma (COMPARZ) trial, pazopanib showed superior ORR compared with sunitinib (31% versus 25%), but no difference in PFS (8.4 versus 9.5 months) or OS (28.3 versus 29.1 months).11 The double-blind, randomized, controlled cross-over Patient Preference Study of Pazopanib Versus Sunitinib in Advanced or Metastatic Kidney Cancer (PISCES) study found a significant patient preference for pazopanib over sunitinib (70% versus 22%), with health-related quality of life and safety as key influencing factors.12 However, the study has been criticized for its design with the timing of toxicity assessment being skewed.13 Of the current options, HD IL-2 is currently the only agent with adequate follow up to demonstrate durable responses, with OS extending to decades.14,15

Since 2011, the PROCLAIMSM (Proleukin Observational Registry to Evaluate the Treatment Patterns and Clinical Response in Malignancy) registry has been evaluating current clinical practice of HD IL-2 use. A recent report of PROCLAIM data from 352 patients with RCC showed a CR of 4%, partial response (PR) of 13%, stable disease (SD) in 39%, and progressive disease (PD) in 43% in patients treated with HD IL-2 alone (n=142). The median OS was not reached in patients with CR, PR, or SD (median follow-up, 21 months). Among patients (n=149) that received targeted therapy after HD IL-2, the median OS was 35.5 months. The median OS was 8.5 months in PD patients who received HD IL-2 without follow-on targeted therapy and 29.7 months in PD patients who received follow-on targeted therapy after HD IL-2.16 These data demonstrate that the use of HD IL-2 is appropriate with careful patient selection and has the capacity to impart long-term clinical benefit when administered before targeted therapy.16

The PROCLAIM registry also includes patients with metastatic melanoma. Data from these patients suggest that treatment with HD IL-2 followed by immune checkpoint blockade, is a promising approach; this is currently being investigated in patients with mRCC.17 This supports the findings of a previous study of patients with metastatic melanoma, in which patients receiving combined ipilimumab with IL-2 had a CR rate of 17%, compared with 7% with ipilimumab alone.18

Other novel agents are in clinical development for mRCC. AGS-003, a personalized immunotherapy comprising mature autologous dendritic cells that are coelectroporated with both synthetic RNA and the patient’s tumor RNA, has shown encouraging results in combination with sunitinib in a phase II study.19 A phase III study (NCT01582672) is currently ongoing. LY2510924 (X4P-001), a novel cyclic peptide that inhibits chemokine receptor type 4 (CXCR-4), is currently being investigated in a phase II study (NCT01391130), with results expected later this year.

The primary challenge of mRCC therapy is that CR to a single agent is rare. The latest findings of the PROCLAIM registry suggest that HD IL-2 is safe and effective before targeted therapy and immune checkpoint blockade. Continued analysis of data emerging from PROCLAIM will determine the optimal sequencing strategy of HD IL-2, targeted therapies and immunotherapies, with evidence to date supporting the use of HD IL-2 early in the treatment plan. The rapid growth of immune checkpoint inhibitor therapy is also likely to transform the management of mRCC; the result of trials involving combinations of these agents are eagerly awaited.

Support: Medical writing assistance was provided by Katrina Mountfort at Touch Medical Media. The publication of this article was supported by Prometheus.


1. NIH, Cancer Stat Facts: Kidney and Renal Pelvis Cancer, Accessed 2 October 2017.

2. American Cancer Society. Survival Rates for Kidney Cancer by Stage, https:// Accessed 2nd December 2017.

3. Proleukin, Package insert, Accessed 15 June 2017.

4. Dutcher J, Schwartzentruber, D.J., Kaufman, H.L. et al, High dose interleukin-2 (Aldesleukin) – expert consensus on best management practices-2014, Journal for ImmunoTherapy of Cancer, 2014;2:26.

5. Barata PC, Rini BI, Treatment of renal cell carcinoma: Current status and future directions, CA Cancer J Clin, 2017.

6. Motzer RJ, Jonasch E, Agarwal N, et al., Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology, J Natl Compr Canc Netw, 2017;15:804-34.

7. 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.

8. 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.

9. 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;JCO2016721985.

10. Escudier B, et al., Checkmate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain, 10 September 2017. Abstract LBA5.

11. Motzer RJ, Hutson TE, Cella D, et al., Pazopanib versus sunitinib in metastatic renal-cell carcinoma, N Engl J Med, 2013;369:722-31.

12. 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.

13. Pal SK, Vogelzang NJ, A “game of thrones” in metastatic renal cell carcinoma: vascular endothelial growth factor-tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors battling for position, Clin Genitourin Cancer, 2013;11:1-4.

14. Hanzly M, Aboumohamed A, Yarlagadda N, et al., High-dose interleukin-2 therapy for metastatic renal cell carcinoma: a contemporary experience, Urology, 2014;83:1129-34.

15. Payne R, Glenn L, Hoen H, et al., Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program, J Immunother Cancer, 2014;2:13.

16. Clark JI, Wong MK, Kaufman HL, et al., Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIMSM, Clin Genitourin Cancer, 2017;15:31-41 e4.

17. Wong MKK, Morse, M., McDermott, D.F. et al, Update on the overall survival of patients with metastatic melanoma treated with immune checkpoint blockade following initial treatment with HD IL-2., J Clin Oncol, 2016;34:suppl; abstr e21039.

18. Prieto PA, Yang JC, Sherry RM, et al., CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma, Clin Cancer Res, 2012;18:2039-47.

19. Amin A, Dudek AZ, Logan TF, et al., Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results, J Immunother Cancer, 2015;3:14.

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