Over the past decade, a number of new therapies have been approved for the treatment of renal cell carcinoma (RCC; Figure 1). Most treatments are driven by clear cell histology, which represents 70% to 75% of all RCCs. Eric Jonasch, MD, Professor, Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, and Vice Chair of the NCCN Guidelines Panel, reviewed the state of the art and new systemic therapies incorporated into the 2017 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer.
Adjuvant Therapy
Three trials have been conducted in the adjuvant setting, 2 of which (ASSURE and PROTECT) showed negative results for adjuvant sunitinib, sorafenib, and pazopanib. A third trial, S-TRAC, showed improved relapse-free (RFS) survival with adjuvant sunitinib versus placebo, but no improvement in overall survival (OS). Thus, the standard of care has not been altered for adjuvant treatment of kidney cancer, Dr. Jonasch stated.
ASSURE randomized 1,943 intermediate- and high-risk patients to receive adjuvant sunitinib, sorafenib, or placebo for 1 year. No difference in disease-free survival was seen among the 3 arms, and high rates of toxicity for the 2 active treatments led to dose reductions and treatment discontinuation.1
PROTECT randomized 1,500 patients to either adjuvant pazopanib or placebo for 1 year (ClinicalTrials.gov identifier: NCT01235962). Again, the study showed no difference in RFS between the arms.
S-TRAC randomized 720 high-risk patients to 1 year of either adjuvant sunitinib or placebo. This study showed improved RFS for sunitinib, with a median of 6.8 versus 5.6 years for placebo. No survival advantage was seen with adjuvant sunitinib.2
Two additional trials of adjuvant therapy are ongoing: SORCE, which is comparing 3 years of adjuvant sorafenib versus 1 year of sorafenib versus placebo in 1,656 patients; and EVEREST, comparing 1 year of everolimus versus 1 year of placebo in 1,218 patients. The primary end point of both trials is RFS.
“No VEGF [vascular endothelial growth factor] inhibitor in the adjuvant setting has improved OS. There are still no FDA-approved agents for adjuvant therapy, and no drug shows a benefit in high-risk patients. If ongoing follow-up of S-TRAC shows a survival benefit, the situation may change. There are ongoing trials in the adjuvant setting of immune checkpoint inhibitors, but we don't have that data yet. My fingers are crossed. Time will tell,” Dr. Jonasch said
Lines of treatment in advanced renal cell carcinoma. Abbreviations: HD, high dose; IFN, interferon; IL, interleukin; MSKCC, Memorial Sloan Kettering Cancer Center; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 5S; 10.6004/jnccn.2017.0078
Lines of treatment in advanced renal cell carcinoma. Abbreviations: HD, high dose; IFN, interferon; IL, interleukin; MSKCC, Memorial Sloan Kettering Cancer Center; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 5S; 10.6004/jnccn.2017.0078
Lines of treatment in advanced renal cell carcinoma. Abbreviations: HD, high dose; IFN, interferon; IL, interleukin; MSKCC, Memorial Sloan Kettering Cancer Center; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 5S; 10.6004/jnccn.2017.0078
First-Line Treatment for Advanced RCC
Sunitinib and pazopanib are the mainstays of therapy in the first-line setting and are considered “preferred” for good- or intermediate-risk patients in the 2017 NCCN Guidelines for Kidney Cancer (category 1 evidence). Bevacizumab plus interferon is also a category 1 recommendation for these risk groups.
Temsirolimus remains an option for patients at poor risk (category 1), but Dr. Jonasch said its use is declining. Temsirolimus is a category 2B recommendation for select patients in other risk groups. He noted that cabozantinib may turn out to be a good option for patients at intermediate or poor risk after data from an independent review of the CABOSUN trial become available.
Sunitinib was approved for the treatment of advanced RCC in 2006, based on a median progression-free survival (PFS) of 11 versus 5.1 months for interferon-alfa.3 OS was not significantly different between these 2 treatments.
“We are moving the bar up with antiangiogenic treatment, but we are not curing patients,” Dr. Jonasch said.
A phase III trial of pazopanib versus placebo in treatment-naïve or cytokine-pretreated patients with advanced kidney cancer showed improved PFS but not OS.4 A separate phase III trial, COMPARZ, met the primary end point showing noninferiority of pazopanib versus sunitinib. Survival did not differ between groups. Pazopanib had a more favorable adverse event profile compared with sunitinib.5
Temsirolimus was compared with interferon-alfa versus combination temsirolimus and interferon-alfa in a phase III study of 626 patients with advanced RCC and with poor- or intermediate-risk features.6 Temsirolimus improved OS compared with interferon-alfa or combination temsirolimus and interferon-alfa; median OS was 10.3, 7.3, and 8.4 months, respectively.
The phase II CABOSUN study of first-line cabozantinib versus sunitinib in 157 patients with untreated clear cell RCC and with intermediate- or poor-risk features found that cabozantinib significantly improved PFS (8.2 vs 5.6 months, respectively; P=.012) and achieved a 34% reduction in the median rate of progression. Rates of adverse events were similar between the arms.7
“Cabozantinib was approved in the second-line setting, and it may get frontline approval. Independent review of the study has not yet been performed,” Dr. Jonasch said. “The data need careful vetting to see if it will find a place in the frontline setting.”
Second-Line Treatment
In the 2017 NCCN Guidelines, nivolumab, cabozantinib, and lenvatinib plus everolimus are all listed as category 1 options for second-line treatment of advanced RCC after previous VEGF inhibitor therapy. These 3 treatments showed improved OS versus everolimus. Axitinib and everolimus are also second-line options.
Nivolumab was approved in November 2015 for patients in whom tyrosine kinase inhibitors (TKIs) failed. Approval was based on a study of 821 patients randomized to receive nivolumab versus everolimus with a primary end point of OS (25 vs 19 months, respectively; P=.002, for nivolumab).8
Objective response rates were 25% for nivolumab and 5% for everolimus. There was a dichotomization, with 35% in the nivolumab group having progressive disease as the best response versus 28% for those on everolimus.
“Responses to nivolumab can be deep and prolonged, and even look like a cure,” Dr. Jonasch said. “This is good for responders, but it leaves other patients high and dry. My personal practice [with nivolumab] is not to be lulled into a false sense of security. Be careful with [nonresponse]. If there is evidence of progression at 6 months, I switch therapy. Patients can develop brain metastasis or progressive bone lesions with little notice,” he emphasized.
Reviewing OS by subgroup showed that patients at poor risk responded best on nivolumab relative to everolimus. This group may have the highest level of programmed death ligand-1 (PD-L1) expression, he added.
Cabozantinib was approved in April 2016 for patients who experienced disease progression on TKIs. In a phase III study evaluating cabozantinib versus everolimus in 658 patients treated with at least one prior TKI, median PFS was 7.6 versus 3.8 months with everolimus, a highly statistically significant difference (P=.001). OS also favored cabozantinib, at a median of 21.4 versus 16.5 months, respectively (P=.0003).9
Lenvatinib plus everolimus is the most recent treatment to gain FDA approval in the second-line setting. Lenvatinib inhibits VEGF receptor (VEG-FR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), RET, and KIT. Approval was based on a phase II study of lenvatinib versus everolimus versus the combination of the 2 drugs in 153 patients with metastatic RCC. An independent review showed robust results for PFS favoring the combination arm—12.8 months versus 9 months for lenvatinib and 5.6 months for everolimus. OS was 25.5, 18.4, and 17.5 months, respectively.10
Axitinib was approved in 2012 in the second-line setting based on a study comparing the drug with sorafenib. Median PFS was 6.7 months for axitinib versus 4.6 with sorafenib. A subgroup analysis according to prior regimen showed a median PFS of 4.8 months with axitinib after sunitinib versus 3.4 months after sunitinib.
Everolimus was approved in 2009 as second-line treatment for patients previously treated with sunitinib, sorafenib, or both drugs. In the phase III RECORD-1 trial, median PFS was 4.9 months versus 1.9 months for placebo. OS was no different between everolimus and placebo.11
Key questions regarding second-line treatment are:
Can we predict which patients will benefit from these new agents?
Emerging data suggest that the degree of immune filtrate (“hot tumors”) may be associated with nivolumab response; is this correct?
Where does this leave mTOR monotherapy?
Dr. Jonasch has disclosed that he has received consulting fees and honoraria from Bristol-Myers Squibb Company, Eisai Inc., Exelixis Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., and Roche Laboratories, Inc., and grant/research support from Exelixis Inc., Novartis Pharmaceuticals Corporation, and Pfizer Inc.
References
- 1.↑
Hass NB, Manola J, Uzzo RG et al.. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomized, phase 3 trial. Lancet 2016;387:2008–2016.
- 2.↑
Ravaud A, Motzer RJ, Pandha HS et al.. Adjuvant sunitinib in high-risk renal cell carcinoma after nephrectomy. N Engl J Med 2016;375:2246–2254.
- 3.↑
Motzer RJ, Hutson TE, Tomczak P et al.. Sunitinib versus interferon alfa in metastatic renal cell carcinoma. N Engl J Med 2007;356:115–124.
- 4.↑
Sternberg C, Davis ID, Mardiak J et al.. Pazopanib in locally advanced metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–1068.
- 5.↑
Motzer RJ, Hutson TE, Cella D et al.. Pazopanib versus sunitinib in metastatic renal cell carcinoma. N Eng J Med 2013;369:722–731.
- 6.↑
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.
- 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;35:591–597.
- 8.↑
Motzer RJ, Escudier B, McDermott DF et al.. Nivolumab versus everolimus in advanced renal cell carcinoma. N Engl J Med 2015;373:1803–1813.
- 9.↑
Choueiri T, Powles T, Escudier BJ. Overall survival (OS) in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma [abstract]. J Clin Oncol 2016;34(Suppl):Abstract 4506.
- 10.↑
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:e4–5.
- 11.↑
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;372:449–456.
