ABSTRACT: The 21st century has seen an explosion in the development of agents for renal-cell carcinoma (RCC), a malignancy previously considered refractory to systemic therapy beyond cytokine therapy. At this time, there are six US Food and Drug Administration (FDA)-approved agents available. In addition, there was a recent favorable review by the FDA’s Oncologic Drugs Advisory Committee of a next-generation vascular endothelial growth factor receptor (VEGFR) inhibitor, axitinib (Inlyta); other agents are in advanced testing. Moreover, while VEGF- and mammalian target of rapamycin (mTOR)-targeted therapies have become the mainstay of RCC treatment, other new molecular targets and therapeutic approaches are being developed. The availability of active agents also brings opportunities for additional clinical maneuvers, such as neoadjuvant and adjuvant therapy, as well as a need for decisions on combinatorial therapeutics in the advanced disease setting. Together, these developments and the issues they raise pose important challenges for oncologists and cancer biologists, given the limited number of patients and resources available for studies and the urgent clinical needs of the patients and families affected by RCC.
Renal cell carcinoma (RCC) had historically been regarded as a disease that was refractory to therapy once surgical options had been exhausted. It is recognized that early intervention with nephrectomy results in excellent long-term survival. In 2005, the US Food and Drug Administration (FDA) approved the first small molecule therapy for kidney cancer, sorafenib(Drug information on sorafenib) (Nexavar). Five other approvals have followed. The introduction of these agents, which have inhibitory activity against the family of vascular endothelial growth factor receptors (VEGFRs) or the mammalian target of rapamycin (mTOR), has shifted treatment paradigms for advanced disease. Prior to this, only interferon (IFN)-alfa and interleukin (IL)-2 were used, both of which have always been viewed as highly toxic therapies with a small chance of long-term benefit. Despite the advances, however, none of the newer therapies have yielded a long-term solution for patients. Even today, the majority of patients present with locally advanced or metastatic disease, and the 5-year survival is on the order of 10% to 50%. More than 60,000 new cases of RCC were expected to be diagnosed in 2011, with more than 13,000 deaths expected in the same year.
This article will review the recent advances that form the current framework of therapy for RCC, as well as summarize key areas of progress and innovation in the evolving treatment paradigms for this disease.
Current Guidelines for Management of Advanced RCC
The current guidelines from the National Comprehensive Cancer Network (NCCN) continue to identify nephrectomy as an important initial consideration even in the setting of metastatic disease. The current recommendations call for removal of the kidney and/or oligometastatic sites of disease prior to initiation of systemic therapy when possible. For patients with clear-cell carcinoma, there are a number of approved agents, including sunitinib (Sutent), temsirolimus (Torisel), everolimus (Affinitor), bevacizumab(Drug information on bevacizumab) (Avastin; used with IFN-alfa), pazopanib (Votrient), high-dose IL-2 (Proleukin), and sorafenib (Nexavar). Despite the availability of these treatment options, clinical trials are an important consideration even in patients with untreated metastatic disease. All of the above agents have demonstrated some activity in the second-line setting. Most have shown activity in the first-line setting with the exception of everolimus, for which phase III clinical data are in the second-line setting (after progression on a tyrosine kinase inhibitor [TKI]). The questions that remain unanswered by the current guidelines are: (1) what the rationales are for selecting one agent over another in the first- and/or second-line setting; (2) what role signal transduction inhibitors play in the perioperative setting; (3) what role nephrectomy plays in metastatic disease; and (4) what combinations or sequences of these therapies are effective in patients.
Signal Transduction Inhibitors
Given the hypervascularity of RCC and the knowledge of the tumor’s biology we have gained from understanding Von Hippel–Lindau syndrome and its associated molecular pathways, VEGF- and mTOR-directed therapies have become a mainstay of RCC treatment (Table 1). The emergence of a number of active agents has created a new series of issues for oncologists. Before the introduction of signal transduction inhibitors (STIs), oncologists were faced with decisions about how to proceed in the face of cytokine therapy’s limited benefits. Now oncologists must select which of the approved treatments should be used as first-line therapy, and which should then be used subsequently. The Figure shows a flow chart that represents current practice guidelines for management of RCC.
Despite the growing number of therapies, significant gaps in our understanding of RCC treatment remain, and these gaps require investigation. Thus, enrollment in clinical trials needs to be supported by the community at large. At present, there are three treatments approved for first-line therapy: sunitinib, pazopanib, and bevacizumab with IFN-alfa. In the absence of head-to-head comparisons, it is difficult to determine with certainty which of these is best suited for a particular patient, given the current approach to RCC classifications. Some information may be gleaned from ongoing studies, but given the limited pool of patients and the number of active agents in use and in development, there is a need to bring to the population of RCC patients the most important and informative trials possible.
Additional and more potent agents are in active development—additional STIs as well as immunotherapies. These agents have the potential not only for sequential use but also combinatorial use. Table 2 summarizes phase II and phase III trials in RCC for therapies in advanced testing.
VEGFR Inhibitors: Axitinib (Inlyta), Tivozanib (AV-951, KRN-951), Cediranib (AZD2171)
Following the introduction of sorafenib, a series of VEGFR- targeted STIs has followed. Given the tremendous efficacy of these compounds, continued refinements have been made to drugs active on this signaling axis. These drugs share toxicities with other VEGF-/VEGFR-targeted agents, including hypertension, asthenia, and diarrhea.
Axitinib is an indazole derivative that is a highly effective inhibitor of the family of VEGF receptors (VEGFR-1, -2, and -3), and of platelet-derived growth factor receptor (PDGFR)-beta and c-Kit. It has demonstrated activity following sorafenib and cytokine therapy. Given emerging trends in RCC therapy, an international phase III study (AXIS) was initiated for patients with disease refractory to sunitinib, bevacizumab with IFN-alfa, temsirolimus, or other cytokine-based therapies. In the AXIS study, 723 patients were randomly assigned to receive axitinib (n = 361) or sorafenib (n = 362). Treatment with axitinib was associated with a progression-free survival (PFS) of 6.7 months, compared with 4.7 months for sorafenib (hazard ratio [HR], 0.665; P < .0001). These data were presented and reviewed favorably at an FDA advisory board meeting in December 2011.
Like axitinib, tivozanib is another orally available, ATP-competitive, small molecule inhibitor of VEGFR-1, -2, and -3, with inhibition in the picomolar range. In the nanomolar range, tivozanib inhibits phosphorylation of c-Kit and PDGFR-beta but has limited activity against other type III receptor tyrosine kinases (RTKs). A randomized discontinuation trial of tivozanib was conducted that included clear-cell and non–clear-cell RCC. Median PFS was 12.5 months for patients with clear-cell carcinoma. At the initial report of this study, median PFS had not been reached for patients with papillary RCC; median PFS for patients with other subtypes was 5.4 months. The overall response rate (ORR; complete response [CR] + partial response [PR]) and stable disease (SD) rate were 29% and 56%, respectively, for patients with clear-cell RCC; 18% and 82% for patients with papillary RCC; and 17% and 57% for patients with other non-clear subtypes. For patients with clear-cell RCC, median PFS was 14.8 months. The phase III study (TIVO-1) in which tivozanib was compared with sorafenib in patients who had not been exposed to STIs has been completed; the results are pending. As with sunitinib, hypothyroidism has been reported as an adverse event related to this drug.
Cediranib is a third pan-VEGFR inhibitor that has shown promising activity. In a preliminary report of a single-arm phase II study of cediranib in treatment-naive RCC, 12 of 32 evaluable patients (38%) had a PR, and 15 patients (47%) had SD, yielding a benefit rate of 85%. In a randomized, double-blind, phase II trial in the United Kingdom (UK), 71 patients with RCC were randomized 3:1 to cediranib or placebo. At 12 weeks, the investigators noted a highly significant difference in mean percentage change in tumor size between the study and control groups (-20% vs +19%, P < .0001). Of the 18 patients in the placebo arm, 14 crossed over to cediranib; of these 14 patients, 10 had tumor reduction. In the cediranib arm, 34% achieved a PR, and 47% had SD. Adverse events were typical for VEGFR inhibitor therapy, but 87% of patients required a dose reduction or pause at a median time of 29 days because of toxicities, including diarrhea (88%; 13% grade 3 or higher) and hypertension (61%; 19% grade 3 or higher). Given the level of availability of targeted agents in the UK at the time this study was designed and initiated, the use of a placebo arm was still considered acceptable. With a number of approved treatments now available globally, it is improbable that future randomized studies in metastatic RCC will include placebo arms, due to ethical concerns.
Non-TKI VEGF Inhibitors: Aflibercept (VEGF Trap, AVE 005), Ramucirumab (IMC112B)
Aflibercept is a soluble decoy receptor incorporating domains of both VEGFR-1 and -2 fused to the Fc region of human IgG1. Thus, aflibercept binds all isoforms of VEGF-A and placental growth factor (PlGF) with high affinity. Aflibercept has completed phase I testing and has moved to phase II testing in RCC.[13,14] The randomized phase II study tests two doses of aflibercept and is expected to complete accrual by 2016.
Ramucirumab is a fully human, high-affinity monoclonal antibody to the extracellular domain of VEGFR-2. Its binding prevents ligand binding. A phase II trial evaluating ramucirumab in TKI-refractory RCC completed accrual in 2011. The final report on this important study is not yet available.