Selecting Targeted Therapies for Patients With Renal Cell Carcinoma

Advanced renal cell carcinoma (RCC) is a heterogeneous disease with variable histology, biology, and response to treatment. In the past 5 years, 6 new agents have been approved for the treatment of RCC, and many more are in clinical development. With an ever-increasing number of treatment options, selecting among them for a particular patient can be a daunting task for clinicians. This article describes how treatment choice can be guided by the disease setting and histology, as well as patient characteristics, comorbidities, and preference within the context of available data. Results from clinical trials are combined with practical considerations to make recommendations for first-line and subsequent treatment of patients with clear cell and non-clear cell RCC. These recommendations should supplement the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of advanced RCC.

Abstract

Advanced renal cell carcinoma (RCC) is a heterogeneous disease with variable histology, biology, and response to treatment. In the past 5 years, 6 new agents have been approved for the treatment of RCC, and many more are in clinical development. With an ever-increasing number of treatment options, selecting among them for a particular patient can be a daunting task for clinicians. This article describes how treatment choice can be guided by the disease setting and histology, as well as patient characteristics, comorbidities, and preference within the context of available data. Results from clinical trials are combined with practical considerations to make recommendations for first-line and subsequent treatment of patients with clear cell and non-clear cell RCC. These recommendations should supplement the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of advanced RCC.

Medscape: Continuing Medical Education Online

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Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe currently available and new agents (approved in the past 5 years) for the treatment of RCC

  • Describe first-line therapy of metastatic clear cell RCC

  • Describe second-line management of patients with metastatic clear cell RCC

In the past 5 years, 6 new agents were approved for the treatment of renal cell carcinoma (RCC). These can be broadly categorized into 2 groups: vascular endothelial growth factor (VEGF)-directed therapies (sorafenib, sunitinib, pazopanib, and bevacizumab) and mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus). With such a large number of treatment options, selecting among them for a particular patient can be daunting for clinicians. This article describes how treatment choices can be guided by the disease setting, histology, patient characteristics and comorbidities, and patient preference.

Adjuvant or Neoadjuvant Therapy for Localized Disease

Adjuvant therapy has been shown to improve survival in patients with breast and colon cancer. With the advent of active targeted therapy for RCC, researchers have questioned whether treatment with targeted agents in the postnephrectomy setting can prevent recurrence. The first 2 adjuvant studies (ASSURE and S-TRAC) have closed to accrual; however, as is typical with adjuvant studies, results are expected to take years to report. In the meantime, several other adjuvant studies are open in both the United States and Europe. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer recommends adjuvant treatment be given in the context of a clinical trial (in this issue; to view the most recent version of these guidelines, visit the NCCN Web site atwww.NCCN.org).1 Adjuvant treatment outside a clinical trial is not recommended until it can be supported by prospective data.

In select cases of locally advanced disease, surgical resection with curative intent may be technically challenging because of tumor bulk or proximity to major vessels. Data from several small series suggest that targeted therapy can result in tumor shrinkage in the primary tumor, sometimes enough to make surgery feasible.2-5 The largest reported experience in this setting is with sunitinib, which has been shown to produce a mean of 10% to 20% shrinkage of the primary tumor, with approximately 90% of patients showing some degree of tumor reduction while on therapy.3,5 Another potential advantage of the neoadjuvant approach is the use of targeted therapy as a “litmus test” for patients with bulky local disease. If metastases appear during treatment with targeted therapy, a technically challenging resection may not be warranted because the goal of surgery would no longer be cure but rather cytoreduction.

Metastatic Clear Cell RCC: First-Line Treatment

Most patients with RCC for whom targeted therapy is considered have metastatic disease. Of these, clear cell histology is the most common, accounting for 80% of RCCs, and has the most data available. Cytoreductive nephrectomy should be considered for patients with clear cell histology and good performance status who are appropriate surgical candidates. This recommendation is based on 2 randomized trials conducted in the 1990s involving patients treated with interferon.6,7 This paradigm is being reevaluated in the era of targeted therapy, and studies are ongoing.8 In the NCCN Guidelines for Kidney Cancer, 6 options are given for first-line treatment of clear cell RCC, 4 of which are supported by category 1 data.1 Although all may be acceptable choices, certain considerations may weigh in the decision to choose one over another.

Stratifying Risk: Selecting Appropriate Treatment for Poor-Risk Patients

The Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria, first published in 1999 and revised in 2002, categorize RCC into 3 risk categories: good, intermediate, and poor based on 5 clinical characteristics: hemoglobin, serum calcium, lactate dehydrogenase, performance status, and length of disease-free interval (Table 1).9,10 The phase III clinical trials supporting the approval of sorafenib, sunitinib, bevacizumab plus interferon, and pazopanib included 10% or fewer patients with poor-risk disease. The only agent that has been studied specifically in the poor-risk population is temsirolimus. In the randomized 3-arm trial comparing temsirolimus with temsirolimus plus interferon or interferon alone in patients with poor-risk RCC, temsirolimus produced a 3.6-month improvement in median overall survival compared with interferon alone. Poor risk in this study was defined using the MSKCC criteria, but with the addition of more than one organ site of metastatic disease as a sixth risk factor (see Table 1). Based on these results, temsirolimus received FDA approval for first-line treatment of poor-risk patients with advanced RCC. Based on these data, temsirolimus is the only approved agent supported by level 1 evidence for the treatment of poor-risk RCC.

Table 1

Prognostic Models for Patients With Renal Cell Carcinoma

Table 1

Limited data support the use of VEGF-targeted therapies in poor-risk RCC. The pivotal trial comparing sunitinib with interferon alpha as first-line therapy for advanced RCC included 23 poor-risk patients who received sunitinib. The median progression-free survival for these poor-risk patients treated with sunitinib was 3.9 months compared with 1 month for interferon. Although the VEGF-targeted therapies have not been as well studied in the poor-risk population, data from the expanded access trial of sunitinib showed a response rate of 9% and a clinical benefit rate of 61% in patients with poor performance status.11 Taken together, these data support sunitinib as a reasonable alternative for poor-risk patients who have a contraindication to temsirolimus or a strong preference for oral therapy.12 No reported data support the use of everolimus, another mTOR inhibitor, in the first-line setting. Therefore, despite the similar mechanism of action, the authors do not recommend substituting everolimus for temsirolimus for poor-risk patients in the frontline setting.

Selecting Appropriate Candidates for First-Line Cytokine Therapy

High-dose interleukin-2 (HD IL-2) is the only single-agent cytokine therapy included in the NCCN Guidelines for Kidney Cancer, and remains an option for carefully selected patients (in this issue, and atwww.NCCN.org). Although markedly toxic, HD IL-2 is the only therapy shown to produce durable complete responses lasting beyond the duration of therapy, and in this sense has an advantage over targeted therapies, with which treatment is chronic and complete responses are extremely rare. Patients least likely to benefit according to the Survival After Nephrectomy and Immunotherapy (SANI) model are those with extensive lymph node involvement; metastasis in both bone and lung or in organs other than bone and lung; constitutional symptoms; and a thyroid-stimulating hormone level greater than 2.13 However, even with careful patient selection using the SANI model, the rate of durable response is only approximately 14%.14 This coupled with the high rates of severe toxicity (hypotension, arrhythmia, fluid retention, pulmonary congestion, neurologic dysfunction, purities, and renal insufficiency) make the decision regarding whether to proceed with HD IL-2 a personal one, even for patients with the best SANI characteristics. If HD IL-2 is to be considered, it should be used in the first-line setting. The limited experience with HD IL-2 as second-line treatment after VEGF-targeted therapies, as described retrospectively, indicates that when HD IL-2 is given after a VEGF inhibitor, efficacy is lower and the rate of life-threatening toxicities is higher than would be expected with HD IL-2 given as first-line therapy.15

Selecting a First-Line VEGF-Targeted Agent

Sorafenib, sunitinib, pazopanib, and bevacizumab with interferon are all options for first-line VEGF-targeted therapy. Of these, sorafenib is the only agent that did not show a superior progression-free survival compared with interferon in randomized comparison.16 Therefore, sorafenib is rarely used in the first-line setting. Among the remaining 3 agents, the choice will be based on other factors.

Sunitinib, an oral tyrosine kinase inhibitor (TKI), is the agent most familiar to clinicians because it has been in clinical use the longest. The “4 + 2” schedule of sunitinib (4 weeks on, 2 weeks off) at a starting dose of 50 mg daily is the approved regimen. A recently reported trial comparing the 4 + 2 schedule and 37.5 mg of sunitinib given on a continuous daily-dosing schedule showed that the overall toxicity was similar but quality of life was greater for the 4 +2 schedule, and the time to progression was superior for this schedule in multivariable analysis.17 Accordingly, the recommended schedule of sunitinib remains the approved 4 + 2 schedule. Sunitinib has the largest accumulation of experience in patients with impaired renal function (estimated glomerular filtration rate ≤ 30), and seems to be safe and effective in this population.18 Additionally, sunitinib is the only agent with published expanded access data showing efficacy in patients with brain metastases. Accordingly, sunitinib may be preferable in patients with central nervous system disease.11

Pazopanib is another oral TKI with a level 1 recommendation in the first-line setting. Based on available cross-study comparison data, pazopanib is hypothesized to have similar efficacy with a more favorable toxicity profile than sunitinib, with lower rates of hand-foot syndrome, fatigue, and neutropenia, but higher rates of hypertension and hepatic enzyme elevation.12,19 This hypothesis has been tested in a randomized study comparing efficacy and toxicity of pazopanib and sunitinib in the first-line setting. Accrual is complete and results are awaited (ClinicalTrials.gov identifier: NCT00678392). Differences in toxicity profiles among the various VEGF receptor (VEGFR) TKIs could be expected based on their differing patterns of kinase inhibition. For example, lower rates of neutropenia and thrombocytopenia associated with pazopanib compared with sunitinib are consistent with the lack of Flt-1 inhibition by pazopanib.19,20

Another consideration when choosing between sunitinib and pazopanib is the dosing schedule. As discussed, sunitinib is dosed using a 4 weeks on, 2 weeks off schedule, whereas pazopanib is given on a continuous daily-dosing schedule. Because of its continuous dosing, pazopanib may be preferable when important drug interactions could occur (e.g., with warfarin) or control of hypertension with antihypertensive medication is complicated by intermittent dosing of the TKI.

Bevacizumab is an intravenously administered humanized monoclonal antibody that binds to VEGF, preventing its interaction with the VEGFR and thus blocking VEGFR signaling. Two phase III studies compared the combination of bevacizumab plus interferon with interferon alone in the first-line treatment of patients with advanced clear cell RCC. The addition of bevacizumab to interferon produced response rates of 25.5% and 31% and progression-free survivals of 10.2 and 8.5 months, compared with response proportions of 13% and median progression-free survival of 5.2 and 5.4 months for patients receiving interferon as monotherapy in the AVOREN and CALGB 90209 trials, respectively.21,22 Because neither study included a single-agent bevacizumab arm, the contribution of interferon in the combination is unknown, as is whether it enhances the efficacy of bevacizumab or merely adds toxicity. To this point, a subset analysis in the AVOREN study showed similar progression-free survival in patients who received full-dose interferon and those who received a reduced dose.23 However, objective response proportions of 25.5% and 31% in the combination arms of the CALGB and AVOREN trials exceed those previously reported for either interferon (14%) or bevacizumab (13%) as single agents.24,25

Smaller studies have investigated bevacizumab alone in the first-line setting, with progression-free survivals ranging from 4.8 to 8.5 months.25,26 A recently completed randomized phase II trial by ECOG compares bevacizumab single-agent therapy given at 10 mg/kg every 2 weeks with three 2-drug combinations as first-line treatment for patients with predominantly clear cell RCC. Although this study does not directly address the role of interferon in the bevacizumab/interferon combination, it will clarify the relative efficacy of single-agent bevacizumab as first-line treatment of metastatic RCC.

Based on the available data and practical considerations, the authors believe that bevacizumab plus low-dose interferon (e.g., 3 MU subcutaneously 3 times weekly) is a reasonable first-line treatment that use of low dose interferon should increase tolerability of the combination therapy.23 Although bevacizumab as a single agent is generally considered to be well tolerated and may be appropriate in selected cases, level 1 evidence supporting its use in first-line therapy is lacking. Parenteral administration of bevacizumab with or without interferon makes it particularly suitable for patients with poor gastrointestinal absorption or difficulty taking pills. Conversely, for most patients with normal gastrointestinal function, the authors generally recommend one of the orally administered VEGFR TKIs for ease of administration and at least equivalent efficacy. Bevacizumab has a long half-life, can impair wound healing, and would not be a good choice for patients with wound issues or those for whom surgery is anticipated.

Metastatic Clear Cell RCC: Second-Line Treatment

In the second-line setting, the ideal sequence of agents is less clear. For the small proportion of patients who receive HD IL-2 and require second-line therapy, clinicians may select any of the first-line VEGF-targeted therapies discussed earlier. The data supporting this recommendation are provided by the phase III trials of sorafenib and pazopanib, which allowed prior cytokine therapy, and smaller studies evaluating bevacizumab and sunitinib after cytokine therapy.19,26-29 For patients who are still candidates for second-line therapy after temsirolimus, no data are available to guide the choice of agents. A clinical trial in this setting is preferred, but in the absence of this option, selection of any of the VEGF-targeted agents is reasonable.

Most patients for whom second-line therapy is considered will have already been treated with a VEGF-targeted therapy or temsirolimus in the first-line setting. For this group, patients who have progressed through a VEGF inhibitor are important to distinguish from those who were unable to tolerate it. In intolerant patients for whom VEGF-targeted therapy resulted in clinical benefit, switching to an alternate VEGF-directed therapy is a reasonable approach. The side effect profiles of sunitinib, pazopanib, and bevacizumab are similar but not identical (Table 2).

Table 2

Common Toxicities Associated With Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor Receptor, and Mammalian Target of Rapamycin Inhibitors

Table 2

For patients who experience true progression while on a VEGF-targeted agent, the choice of agents is less clear. Everolimus, an oral mTOR inhibitor, is the only currently approved treatment after one or more VEGF-targeted therapies. In the phase III registration trial, everolimus showed a 3-month improvement in progression-free survival over placebo (4.9 vs. 1.9 months) after first-line sunitinib, sorafenib, or both.30 Given the modest lengthening of progression-free survival with everolimus and no difference in overall survival, emphasis on clinical trial participation in the second-line setting is encouraged. Furthermore, everolimus may not be appropriate for all patients. Hyperglycemia, hypertriglyceridemia, and pneumonitis are all common side effects. Although each can be monitored and managed medically, everolimus may be a less-attractive option for patients with baseline advanced diabetes or underlying lung disease. For patients in whom everolimus is relatively contraindicated, bevacizumab or an alternate VEGF-directed TKI is also a reasonable option, particularly for patients who derived clinical benefit from their first-line VEGF-targeted therapy. Emerging clinical trial results suggest that a second VEGF-targeted therapy is effective after a variety of first-line therapies, including VEGFR TKIs.31 Preliminary reports show that axitinib, a VEGFR TKI currently in development, showed significant improvement in progression-free survival over sorafenib in patients previously treated with sunitinib (4.8 vs. 3.4 months; P = .011).32 Which class of agent—mTOR inhibitor or VEGF-directed therapy—is optimal after first-line VEGFR TKI therapy is currently unknown. A clinical trial comparing temsirolimus with sorafenib after disease progression on sunitinib may help address this question (ClinicalTrials.gov identifier: NCT00474786). Studies to identify clinical or molecular factors predictive of beneficial response to each class of agent would be of great value.

Metastatic Non-Clear Cell RCC

Although 80% of RCCs are of clear cell histology, the remaining 20% consist of a mix of histologies, each with a distinct biology. Because of the molecular rationale of the VEGF-targeted therapies, many of the clinical trials limited enrollment to patients with clear cell RCC, and therefore little has been reported regarding the efficacy of these agents in non-clear cell subtypes. Of the studies that included patients with non-clear cell RCC, the non-clear cell category was not further described and histologic subtype was not reported for many patients. Consequently, the true effect of these agents on particular non-clear cell subtypes is not well defined.11,12

The most common non-clear cell subtype is papillary RCC, which accounts for 12% of all RCCs. Biologically, at least a subset of papillary RCCs seem to be driven by dysregulation of c-Met signaling rather than by VEGF.33 Early reports show that VEGF inhibition does not have the robust antitumor effects in papillary RCC that it has in clear cell RCC. In a pooled analysis of 3 prospective trials in the United States and Europe investigating sunitinib in confirmed papillary RCC, one response was reported among a total of 53 patients.34-36 In the phase III registration trial for temsirolimus in poor-risk patients, patients with papillary RCC were specifically categorized and analyzed as a subset. In this analysis, progression-free and overall survivals were similar (∼ 6 and 11 months, respectively) for patients with papillary and clear cell RCC, prompting temsirolimus to be recommended for patients with-poor risk papillary RCC.37 An additional option for patients with papillary RCC is erlotinib, shown in a prospective multicenter study to produce a response rate of 11% and a disease control rate of 64%.38 Participation in a clinical trial, particularly one with a biologic rationale for papillary RCC, is the preferred treatment approach for this group of patients.

Sarcomatoid variant RCC has an aggressive biology and most commonly arises from underlying clear cell histology. Sarcomatoid histology is seen as a component of approximately 10% of RCCs, and is typically reported pathologically as an overall percent sarcomatoid differentiation, ranging from focal to pure sarcomatoid within the specimen. Sarcomatoid RCC has historically been treated with combination chemotherapy involving gemcitabine and doxorubicin.39,40 Although most responses with this regimen are of short duration at the expense of significant toxicity, a small subset (3%-11%) of patients experience durable complete remissions.41 Although the numbers are small, responses are reported in patients with more than 75% sarcomatoid differentiation.40 Two retrospective series suggest benefit with sunitinib in sarcomatoid RCC, with response rates ranging from 12% to 29% and a progression-free survival of approximately 5 months.42,43 Benefit seemed to be limited to patients with a less than 20% sarcomatoid component and underlying clear cell histology. Based on these data, it is reasonable to select a chemotherapeutic approach for fit patients willing to risk toxicity for the small chance at durable response, or for patients with a dominant (> 75%) sarcomatoid component. For other patients, sunitinib may be a more appropriate first choice.

Other non-clear cell subtypes include chromophobe, collecting duct, and renal medullary carcinoma. All are rare, making prospective and even retrospective study difficult. For collecting duct and renal medullary carcinoma, the available data and expert opinion support the use of cytotoxic chemotherapy with regimens typically used to treat urothelial carcinoma.44-49 Chromophobe RCC is typically indolent, and can often be observed off-therapy. For patients requiring treatment, anecdotal evidence supports the use of targeted therapies such as sunitinib or everolimus.50,51

Combination Therapies

Several clinical trials have investigated combination therapies in RCC (Table 3). Essentially all possible 2-drug combinations of the 6 currently available targeted therapies have been studied in a clinical trial.52 Several combinations, particularly those that are sunitinib-based, are notable for significant and severe toxicities.53-55 For the few combinations that are feasible, no signal of increased efficacy with combination therapy has emerged from early-phase study. One of the largest of these studies, the TORAVA study, showed increased toxicity and disappointing efficacy for the combination of 25 mg of temsirolimus weekly and 10 mg/kg of bevacizumab every 2 weeks compared with 50 mg of sunitinib on the 4 + 2 schedule and the combination of bevacizumab and interferon.56 A randomized, multicenter, 5-arm trial comparing 3 combinations (bevacizumab and temsirolimus, sorafenib and temsirolimus, and bevacizumab and sorafenib) with single-agent bevacizumab as the control arm has completed accrual and results are awaited. Because of the increased risk of severe toxicity without confirmed evidence of greater efficacy, the consensus expert opinion recommends combination therapy only in a clinical trial setting.

Table 3

Phase I/II Studies Using Various Combinations of Therapy

Table 3

Observation for Indolent Disease

Despite the armamentarium of targeted agents, none are considered curative; therefore, it is important to keep in mind the goal of care in the metastatic setting, which is to prolong survival while maintaining an acceptable quality of life. To this end, selected patients with indolent metastatic disease may be managed with observation. These patients may also be candidates for focused treatment of metastatic deposits using surgical or radiation therapy if technically feasible. Observation should be reserved for patients who are asymptomatic, with evidence of stable disease or minimal progression on serial imaging. This strategy may be used for treatment-naïve patients or those who show stable disease while on a break from prior systemic treatment.57

Conclusions and Future Directions

Although it would seem that we have an embarrassment of riches, with 6 targeted therapies and HD IL-2 available for the treatment of RCC, this is somewhat of an illusion. In reality, the many treatments rely on 1 of 3 mechanisms: immune modulation, VEGF pathway inhibition, or mTOR pathway inhibition. To improve on these treatments and seek methods of producing long-term durable remission, the search for new agents and strategies must be undertaken in earnest. Therefore, although a clinical trial is always preferred, the authors particularly recommend treatment on a clinical trial in the second-line setting and beyond. Except for patients who have received first-line cytokine therapy, no prospective clinical trial data support one treatment over another in the third-line setting.

Novel approaches currently in early development include c-Met inhibition, newer immunomodulators such as PD-1-targeted therapies, treatments targeting the Ang1/Ang2/Tie2 pathway, and PI3 kinase inhibitors (Table 4).58 In addition, several newer VEGF TKIs are currently in clinical trials, including axitinib, which is being studied in the second-line setting, and tivozanib, which recently completed a first-line phase III study and the results of which are awaited.31,59,60 Tivozanib seems to be active in non-clear cell RCC, particularly papillary, a finding that must be confirmed in a larger study.61

Table 4

Emerging Agents in Clinical Trials for Treatment of Renal Cell Carcinomas

Table 4

Although the past decade has been marked by new drug approvals for metastatic RCC at an unprecedented pace, the development of these many agents, most with similar mechanisms of action, has outpaced the ability to understand their optimal use. This article provides guidance based on available data, but further inquiry into sequence and timing of available agents is needed. In addition, the large number of available VEGF and mTOR-targeted agents should not hamper efforts to discover novel approaches for treatment of this still-incurable disease.

The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Elizabeth R. Plimack, MD, MS, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Disclosure: Elizabeth R. Plimack, MD, MS, has disclosed no relevant financial relationships.

Gary R. Hudes, MD, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Disclosure: Gary R. Hudes, MD, has disclosed no relevant financial relationships.

CME AUTHOR

Laurie Barclay, MD, Freelance writer and reviewer, Medscape, LLC

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

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Correspondence: Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497.E-mail: elizabeth.plimack@fccc.edu

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