Renal cell carcinoma (RCC) comprises 92% of all kidney cancers and has a poor prognosis, with approximately 10% of patients with metastatic disease surviving beyond 5 years.1 In 2006, the economic burden of metastatic RCC (mRCC) was estimated to be up to $1.6 billion worldwide and has since grown annually.2 A recent review reported that the economic burden of RCC in the United States ranges from $600 million to $5.19 billion, with annual per-patient medical costs of between $16,488 and $43,805.3 Furthermore, these costs will likely increase with the expanded use of targeted agents, based on a 2011 pharmacoeconomic analysis showing that the annual costs to treat patients with RCC receiving these agents are 3- to 4-fold greater than the costs to treat patients who are not receiving targeted therapies.4 In addition, the incidence and prevalence of RCC are rising, in part because of improved and earlier detection, and because of increases in related risk factors, such as hypertension, diabetes, and obesity.5-7
Clear-cell RCC, the most common histology, constitutes 75% of cases of RCC.8 The majority of patients with clear-cell RCC experience a loss of the functional von Hippel-Lindau gene, resulting in the accumulation of hypoxia-inducible factor-1α, an angiogenic factor whose protein synthesis is regulated by mammalian target of rapamycin (mTOR).9 The net effect is overproduction of downstream proteins that promote RCC progression by stimulating cell growth and proliferation, cellular metabolism, and angiogenesis (ie, vascular endothelial growth factor [VEGF], platelet-derived growth factor, and epidermal growth factor).9
Abnormal functioning of the mTOR pathway is therefore thought to play a role in the pathogenesis of RCC; inhibition of mTOR globally decreases protein production, suppresses VEGF synthesis, and induces cell cycle arrest.10 Knowledge of the critical role of VEGF and mTOR in RCC pathogenesis drove the development of targeted agents in the treatment of this disease. The US Food and Drug Administration (FDA) approval of axitinib in January 2012 brings the total of approved targeted agents for RCC to 7 in the past 7 years, making this one of the most prolific areas of cancer drug development (Table 1).11-25 The need for clarity regarding the optimal sequential use of these agents is stronger than ever, particularly given the high price of these agents.
The oral VEGF receptor tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib and pazopanib, the VEGF monoclonal antibody bevacizumab plus (subcutaneously injected) interferon-α, and the intravenous (IV) mTOR inhibitor temsirolimus are recommended by the National Comprehensive Cancer Network (NCCN) as first-line therapies for the treatment of mRCC (Table 2).26 The VEGFr-TKI sorafenib is recommended for select patients only. Despite efficacy in mRCC, agents targeted against VEGF only “inhibit” the disease, making resistance almost inevitable and universal, thereby necessitating second-line therapy after the failure of initial VEGF inhibition.18,19,22-24
Because curing metastatic disease with these agents is rare, most patients require lifelong therapy and are destined to cycle through the available treatment options. Guidelines on sequential therapy for the second-line treatment of mRCC and beyond are limited, indicating a lack of clinical trial–based comparative evidence and/or consensus in this area. In the NCCN guidelines, the oral agents everolimus and axitinib are category 1 recommendations for second-line therapy (Table 2).26 Despite their clinically proven benefit in extending progression-free survival (PFS), the cost of these agents and their lack of proven survival benefit have led to controversial government reimbursement decisions in some parts of the world (eg, by the National Institute for Health and Care Excellence in the United Kingdom27).
Given the lack of prospectively collected data sets assessing the optimal sequence of targeted therapies, as well as the high price of these agents, economic analyses provide important insights into the overall costs versus benefits of targeted therapies, thus helping to inform treatment decisions. In this review, we identify comparative economic evidence beyond the first-line treatment of mRCC and discuss the potential implications of the findings.
Literature Search of Comparative Economic Studies
Although we did not conduct a systematic review, we did conduct a broad, inclusive search of comparative economic evidence for targeted therapies used in the treatment of patients with mRCC after failure of initial therapy. Our search parameters were:
- The time frame was from January 1, 2005, to February 11, 2013 (lower boundary coincided with the introduction of sorafenib to the US market, marking the beginning of the targeted-therapy era in RCC)
- The databases that were searched included PubMed/MEDLINE and Ovid/EMBASE; abstracts and industry-sponsored articles were allowed
- The conference proceedings that were searched (to account for relevant data that were not published in the peer-reviewed literature) included the American Society of Clinical Oncology (ASCO), the Genitourinary Cancers Symposium, the International Society for Pharmacoeconomics and Outcomes Research, the Academy of Managed Care Pharmacy, the American Society of Health-System Pharmacists, the American Urological Association, and the International Society for Quality of Life Research
- The search was limited to studies in the English language and US-based studies (because national policy directly influences healthcare expenditures, and these agents entered the US pharmacopeia soon after FDA approval)
- The search terms included “metastatic renal-cell carcinoma or mRCC or advanced renal-cell carcinoma or aRCC or stage 4 RCC,” “second-line therapy,” “targeted therapy or everolimus or RAD001 or temsirolimus or sorafenib or sunitinib or axitinib or pazopanib or bevacizumab or mTOR inhibitor or tyrosine kinase inhibitor or TKI or vascular endothelial growth factor inhibitor or VEGF inhibitor,” and “health-related quality of life, or HRQOL, or health economics or health outcomes or cost-effective” or “cost-effectiveness” (see glossary).
All authors, who are experts in the health economics and outcomes research field, reviewed the search results. After this initial individual review, a group discussion was held to confirm which studies met our criteria and would be covered in this article. Studies of interest were those with a targeted agent—VEGF/VEGFr or mTOR inhibitor—in at least 1 study arm. Comparative outcomes of interest were health economics and outcomes research measures derived from any budget impact, cost minimization, cost-resource utilization comparison, or cost-effectiveness and cost utility analyses. Studies related to the economic burden (cost) of illness were excluded from this analysis.
Key Findings of Identified Studies
Because of the restrictive nature of our search, the overall number of results identified was low, and only 7 studies, which are summarized in Table 3, met our criteria of interest and were included here.28-35 Of these 7 studies, 3 compared one VEGF or VEGFr inhibitor with another and 4 compared one mTOR inhibitor with another or with a VEGF or VEGFr inhibitor. The studies were heterogeneous in design, with the incremental cost-effectiveness ratios (ICERs) or quality-adjusted life-years (QALYs) associated with various treatments (Glossary) the most common economic benchmarks utilized. Both clinical trial–based and observational-based studies were identified and included. No economic studies including pazopanib were identified using the search criteria. The key findings from each of the identified studies are presented below.
One cost-effectiveness analysis, which was presented at the 2006 ASCO annual meeting, evaluated sorafenib plus best supportive care versus best supportive care alone using a decision analytic Markov model to project lifetime survival and associated costs for patients with advanced RCC.28 Of note, this analysis was based on findings from the phase 3 TARGET trial, in which the majority of patients had received previous cytokine therapy.36 Findings showed lifetime per-patient costs to be $85,571 for sorafenib plus best supportive care and $36,634 for best supportive care alone.28 Treatment with sorafenib plus best supportive care resulted in an ICER of $75,354 per life-year gained.28 Because this ICER is within the societal willingness-to-pay threshold in the United States,37 the study authors concluded that sorafenib was a cost-effective treatment option for patients with advanced RCC.
The second study was a retrospective comparison of costs associated with 2 sequences of the oral VEGFr-TKIs sorafenib and sunitinib using claims in the MarketScan research database.29 This analysis, which was published in abstract form in conjunction with the 2010 ASCO annual meeting, showed that the univariate incremental total per-patient monthly medical cost for patients who first received sunitinib and then sorafenib was $1639 more than the per-patient monthly cost for the patients who first received sorafenib and then sunitinib (P = .003). This represented an annual cost-savings of $19,668 for patients treated with sorafenib initially, which was primarily attributable to outpatient costs.29
The third study that was identified (and was published in a peer-reviewed journal) reported the results of an indirect analysis designed to evaluate the cost-effectiveness of everolimus versus sorafenib for the treatment of sunitinib-refractory mRCC based on the RECORD-1 patient population.31 The drug costs for everolimus and sorafenib were based on dosages from the RECORD-1 trial21 and a phase 2 study of sorafenib.38 Using Markov modeling with deterministic and probabilistic sensitivity analyses, the superior cost-effectiveness of everolimus over sorafenib was demonstrated, with a difference of $81,643 in the total average per-patient cost of treatment with everolimus versus sorafenib; this difference was primarily driven by drug acquisition costs (80%).31 Compared with sorafenib treatment, patients treated with everolimus had an estimated gain in life-years of 1.273 and a gain in QALYs of 0.916, resulting in an ICER of $64,155 per life-year gained, or $89,160 per QALY.31 The estimated ICER in this pretreated population fell below the cost per QALY for many other oncology medications in widespread use. Compared with sorafenib, everolimus had a high probability of being considered cost-effective at a willingness-to-pay threshold of $100,000 per QALY in patients with advanced RCC who failed therapy with sunitinib.
An indirect model–based analysis comparing temsirolimus with everolimus after failure with sunitinib or with sorafenib over a 3-year time horizon was presented at the 2010 Genitourinary Cancers Symposium.32 The estimated average monthly cost of treatment was $5248 with everolimus and $5597 with temsirolimus, resulting in annual cost-savings of $4188 for treatment with everolimus.32 The cost difference was related to the route of administration for these 2 agents (oral for everolimus vs IV for temsirolimus, or outpatient vs in-clinic management) and the need for antihistamine premedication, which is often performed in a higher acuity setting, to prevent infusion reactions with IV temsirolimus therapy. In addition, a retrospective resource utilization study of the US Oncology Network’s iKnowMed electronic medical record (EMR) system that was published in a peer-reviewed journal suggests that everolimus is associated with a lower patient burden in terms of outpatient and laboratory visits compared with temsirolimus among patients with mRCC.34 Patients receiving everolimus had significantly fewer monthly outpatient visits and monthly laboratory frequency monitoring compared with those receiving temsirolimus (mean, 1.19 vs 1.60 and 1.25 vs 2.23, respectively; both P <.05).34
Finally, data from multiple regression analyses that were presented at the 2010 meeting of the European Society of Medical Oncology (ESMO) revealed that patients receiving temsirolimus had a 28% higher frequency of outpatient visits and a 58% increase in the utilization of laboratory procedures compared with patients receiving everolimus.35 Although not a direct economic evaluation, results from this analysis provide additional evidence for differences in economic burden between the agents.
An Excel-based economic model comparing 2 market scenarios that was published in a peer-reviewed journal found that introducing everolimus as a second- or third-line therapy after VEGFr-TKIs results in a minimal budget impact.33 In this hypothetical plan of 1 million covered lives, with a 0.023% prevalence of mRCC and 90% of patients receiving treatment for mRCC across first-, second-, and third-line treatments, the total cost of drugs, administration, and adverse event management (from April 2008 through March 2009) was $7,050,157 before the launch of everolimus. After the launch of everolimus, the total cost was $6,741,642 (from October 2009 through September 2010), resulting in a savings of $308,515.33 These trends remained consistent across scenario analyses in which everolimus replaced various combinations of comparators, as well as across sensitivity analyses. However, the sensitivity analysis that evaluated inclusion of the postapproval uptake lag period (April 2009-March 2010) and set the adverse event management costs to $0 yielded lower savings in comparison with the base-case analysis.33
Axitinib is a potent VEGFr-TKI and is the only drug other than everolimus that is included in the NCCN guidelines with category 1 evidence for use in patients with mRCC after initial failure with a VEGFr-TKI.26 This recommendation is predominantly based on data that were derived from the AXIS trial.25 An economic evaluation of sorafenib versus axitinib in the AXIS trial, which was presented at ESMO 2012, was based on a partitioned survival model with 3 health states—PFS, postprogression survival, and death—that was constructed to estimate the direct lifetime medical costs and clinical outcomes for patients starting second-line therapy.30 This model was populated with the Kaplan-Meier–derived overall survival and PFS data from the AXIS trial. The investigators estimated lifetime per-patient costs to be $123,171 for sorafenib and $152,013 for axitinib, with the $28,842 cost difference mainly attributable to the higher medication cost of axitinib.30 Although the AXIS trial showed that axitinib significantly prolonged PFS compared with sorafenib (median, 6.7 vs 4.7 months; hazard ratio, 0.665; 95% confidence interval, 0.544-0.812; one-sided P <.001),25 this partition model found similar benefit in terms of life-years and QALYs for both drugs but a lower total per-patient cost for sorafenib.30
Health economics research aimed at evaluating the comparative costs, cost-effectiveness, and budget impact of cancer therapies is an increasing area of focus, but large gaps remain,39 as evidenced by our comprehensive search returning only 7 studies. However, themes related to drug costs, IV versus oral therapies, oral mTOR salvage therapy, and the promising impact of molecular personalization of RCC therapy emerged from our analysis of the literature. Although drug price is a major driver of overall costs, there appears to be an advantage for oral therapies for the treatment of mRCC over those administered intravenously, presumably because of a lower economic impact on outpatient care.
Using data from a large US health insurance claims database, a retrospective analysis restricted to the period of first angiogenesis inhibitor use demonstrated that mean total cost per member per month for IV bevacizumab was approximately 2 times higher than for oral sorafenib and approximately 1.6 times higher than for oral sunitinib.40 The annualized total costs of therapy (adjusted to 2007 US dollars), including inpatient, outpatient, and drug costs, for patients with RCC who were treated with bevacizumab, sorafenib, and sunitinib were $160,212, $83,976, and $98,556 per patient, respectively.40 Therefore, the use of IV bevacizumab led to a cost increase of 56% to 71% more than the use of oral angiogenesis inhibitors.40
However, the clinical implications of this finding are not clear-cut. Although orally administered agents may result in lower outpatient costs, they may also be more likely to be associated with lower adherence and persistence rates, with a resultant negative impact on effectiveness. The data comparing adherence among oral and IV therapies are limited, and at least 1 retrospective claims database analysis suggests that schedule compliance with everolimus is higher than that with temsirolimus as second-line therapy for patients with mRCC (medication possession ratios of 0.93 vs 0.86, respectively; P <.001).41 The data on temsirolimus suggested the presence of higher toxicity than oral therapies (ie, infusion reactions), potentially generating higher monitoring demands and, as such, increasing costs.34
These hypotheses are congruent with data from other areas of medicine, but selection bias is one factor that may not be adequately captured in the reviewed literature. For example, the use of bevacizumab may be motivated by its more favorable toxicity profile, whereas the selection of temsirolimus may reflect the desire to use this drug in patients with poor performance status, as recommended in the current treatment guidelines.26
Although the data show that the oral mTOR inhibitor everolimus offers several economic options compared with other therapies in the second-line treatment setting of mRCC, a clear, economically favorable therapeutic path cannot be identified from the currently available data. This is a significant knowledge gap considering that the majority of patients receiving first-line anti-VEGF therapy will progress, at least 32.9% of patients receiving second-line therapy will experience treatment failure, and at least 16.6% of these patients will progress to receive third-line treatment.42 Although firm conclusions are not possible, our analysis is useful in that it raises several important testable hypotheses.
Of note, comparative economic analyses across treatments for mRCC are known to be problematic for numerous reasons, including the lack of available clinical comparative effectiveness data, as well as differing study designs, patient populations, clinical definitions, and instrumentation used for patient-reported outcomes. Such factors complicate the ability to compare economic data across multiple studies. In addition, interpretation of cost-effectiveness analyses differs depending on the determination of the willingness-to-pay threshold. Studies found in our literature search reported ICERs ranging from $64,155 to $89,160. These fit within the range of willingness-to-pay thresholds often cited in US sources ($50,000-$100,000 per QALY gained)37; however, the accepted threshold can vary drastically among decision makers.43,44
The pivotal trials summarized in Table 1 established the efficacy and safety of individual targeted therapies; nevertheless, there is a general lack of head-to-head comparisons relevant to everyday clinical practice. Specific to second-line therapy, there are no prospectively collected data comparing the efficacy and safety of everolimus with those of axitinib, the 2 agents that are recommended at a class 1 level in the NCCN guidelines.26 Coupled with the lack of head-to-head randomized trials in which the optimal sequence of treatments for mRCC is the primary outcome, comparisons of economic analyses are difficult.
Frequently, comparators are drawn from historical data sets. For example, in the recent phase 3 AXIS trial, a small subset of patients received axitinib after previous failure with sunitinib.25 The trial showed a favorable clinical response for axitinib based on median PFS25; however, during the formal discussion period that followed the initial presentation of the AXIS results at ASCO 2011, a number of discussants pointed out that the degree of benefit appears to approximate that of sorafenib historically. Indeed, the analysis by Ozer-Stillman and colleagues points to a similar benefit in terms of life-years and QALYs for sorafenib and axitinib, with the lower cost for sorafenib tipping the scale in its favor.30
It is hoped that current research that is underway involving several head-to-head and/or treatment sequencing trials will provide answers and will provide balanced prospective data that are sufficiently robust to draw meaningful conclusions, both on the usual clinical end points and on economic impact (Table 4).
The identification of specific biomarkers predictive of efficacy in patients with mRCC is a prolific area of research. This so-called personalized medicine has the potential to have a great impact on the existing therapeutic and, consequently, on economic paradigm. Theoretically, the successful identification of patient-specific sensitivity pathways would permit the exclusion of nonresponders before treatment is initiated, thereby favorably affecting cost versus benefit for that agent. Even with personalized medicine, it is likely that patients will require multiple lines of therapy, indicating that optimizing sequencing will remain critical. Unfortunately, the availability of mature data from biomarker and sequencing studies is likely many years away, and critical methodologic issues remain to be solved.45
As additional data flow from therapeutic clinical trials, one approach that may provide a more immediate answer to the appropriate second-line therapy is to leverage the current global adoption of EMRs. The proliferation of EMRs has allowed an unprecedented ability to access treatment data, which are, for the first time, robustly linked to resource utilization and costs through their built-in payer billing functionality. This will also allow a cross-sectional approach that can include both academic centers and community practices. The latter group is underrepresented in published studies but represents the majority of oncologic care in the United States.
This “real-world” approach of conducting chart reviews and/or evaluating EMR databases to address payer and provider issues for the armamentarium of treatment options for mRCC could provide a first approximation of the economic burden of various treatment sequences for mRCC in the current vacuum of head-to-head comparisons. Unfortunately, very little evidence is available to address whether outcomes research really affects drug policy or clinical practice.46 Further studies are warranted to improve clinical decision-making for the treatment of mRCC in the context of new targeted therapies and emerging research possibilities for biomarker identification.
Our review revealed that comparative economic evidence in the treatment of mRCC in patients who have failed initial therapy with targeted agents is very limited. Our extensive search of the published literature identified only 3 studies that were published in peer-reviewed journals. To account for relevant data that were not published in the peer-reviewed literature, abstracts of several major conferences and meetings were searched, yielding an additional 4 studies that met our inclusion criteria. The designs of these studies were also heterogeneous. This lack of publicly available data and the heterogeneous nature of the data that are available minimize the conclusions that can be drawn from these studies. Furthermore, the potential pitfalls of using observational studies (eg, selection bias) to make conclusive treatment decisions or recommendations for sequencing and the choice of second-line targeted therapies need to be recognized.
The 7 studies we reviewed analyze the economic impact of the care of patients with RCC using a diverse array of approaches, each with inherent strengths and weaknesses. For example, cost-effectiveness models present methodologic challenges from the standpoint of extrapolation of outcomes data beyond trial completion. Health economics and outcomes research measures, such as QALYs, express aggregate individual utility and are considered to be the most applicable to research- or population-based decision-making rather than day-to-day use. The aggregate nature of the QALY makes it useful for comparisons of outcomes across multiple studies. As such, economic analyses based on clinical trials may not directly reflect costs in the real-world clinical practice setting. With 7 potential choices at present, it is possible that lifestyle considerations, the adverse event profile, convenience, and hidden economic incentives may begin to play a role in drug selection.
Claims database analyses, budget impact analyses, and model-based cost comparisons present their own methodologic challenges. For example, claims database analyses generally use International Classification of Diseases, Ninth Revision codes that can potentially lead to the inclusion of false-positive cases, and only costs from the perspective of the payer are included.40 Budget impact analyses are primarily intended to inform healthcare decision makers; therefore, similar to cost-effectiveness analyses, the analyses do not include cost implications from the societal perspective.33 The limitations of model-based cost comparisons include a lack of generalizability of results to all patients with RCC, given that the probabilities are generally taken from clinical trials and are often based on a series of assumptions, which may underestimate or overestimate costs and benefits.31
The dearth of head-to-head comparator studies of RCC and consensus methodologies for economic analyses represents a major limitation and a key research opportunity in this field at the present time.
The limited number of economic studies related to targeted treatment options in the second-line setting and beyond in patients with mRCC does not allow firm conclusions to be drawn about the most cost-effective targeted treatment option in this setting. We hope that ongoing head-to-head therapeutic trials and biomarker studies will improve our ability to evaluate the economic efficiency of these expensive agents. Analysis of real-world utilization data may provide a more accurate understanding of the economic impact of these medications in the use of patients outside the controlled environment of clinical trials. However, this needs to be balanced against the potential pitfalls of using observational studies (eg, selection bias) to make conclusive treatment decisions or recommendations for the sequencing and the choice of second-line targeted therapies.
Dr Wong is Professor of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; Dr Wang is Director, Worldwide Health Outcomes, Value & Access, Novartis Pharmaceuticals, and Dr Liu is Director, Oncology US Health Economics & Outcomes Research, Novartis Pharmaceuticals, East Hanover, NJ; Mr Chulikavit is Associate Director, LA-SER Analytica International, New York, NY.
The authors would like to thank Denise Balog, PharmD, and Melanie Leiby, PhD, of ApotheCom, for their medical editorial assistance, and Novartis Pharmaceuticals for funding medical editorial assistance.
Novartis Pharmaceuticals provided funding for editorial support and for data acquisition and primary analysis by LA-SER Analytica International. All authors retained independent control of the manuscript.
Author Disclosure Statement
Dr Wong is on the advisory boards of Merck, Genentech, and Bristol-Myers Squibb. Drs Wang and Liu are employees and stockholders of Novartis Pharmaceuticals. Mr Chulikavit is an employee of LA-SER Analytica International and a consultant to Novartis Pharmaceuticals.
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