Renal cell carcinoma (RCC) is diagnosed in approximately

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1 At a Glance Budget Impact of Everolimus in Treating Metastatic Renal Cell Carcinoma Practical Implications p SP42 Author Information p SP47 Full text and PDF Web exclusive eappendices Original Research Maria Lopes, MD; Maruit Chulikavit, MPH; Rohan Parikh, MS; Lee Stern, MS; Zhimei Liu, PhD; and Jaqueline Rogerio, MD Renal cell carcinoma (RCC) is diagnosed in approximately 58,000 individuals each year in the United States 1 and accounts for more than 90% of all primary malignant renal tumors. 1,2 These statistics reflect the steady rise in the incidence rate of kidney cancers over the past 3 decades. 3 It has been estimated that 20% to 30% of patients with RCC present with metastatic disease. 4 Metastatic renal cell carcinoma (mrcc) is difficult to treat, with a 5-year survival rate of less than 10%. 5 Additionally, RCC is costly, with US-based studies suggesting the estimated annual cost of RCC to be as high as $4.4 billion. In those with metastatic disease, the estimate ranges from $107 to $556 million per year. 6,7 Several targeted chemotherapeutic agents have emerged over the past 4 years. Specifically, vascular endothelial growth factor tyrosine kinase inhibitors such as sunitinib and sorafenib have become the standard of care, replacing systemic therapies such as interferon-alfa. Despite the recent advances in treatment options, disease progression in RCC patients is typically only delayed; the disease is not cured. Trials investigating the efficacy of sunitinib and sorafenib demonstrated an increase in progression-free survival (PFS) ranging from 2.7 months to 6 months. 8,9 Bevacizumab, another drug option, has shown a benefit in PFS in a pivotal phase III trial in combination with interferon-alfa versus interferon-alfa alone; however, overall survival results have not yet been reported. 10 While there has been some improvement over prior therapies, the majority of patients will face inevitable disease progression. Therefore, there is a significant unmet need among RCC patients who experience treatment failure on these newer agents. Everolimus (Afinitor; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey) is a once-daily, orally administered agent with documented efficacy for the treatment of patients with advanced RCC after they fail to respond to or become intolerant to treatment with sunitinib or sorafenib. ABSTRACT Objectives: To examine the economic implications and annual budget impact of everolimus as a treatment for metastatic renal cell carcinoma (mrcc) based upon current therapy options from a US payer perspective. Study Design: An Excel-based cross-sectional budget impact model. Methods: Two market scenarios, one where everolimus was not a treatment option (April 2008 to March 2009) and one where everolimus was a treatment option (October 2009 to September 2010), were compared. Along with everolimus, systemic chemotherapeutic agents and targeted therapies were considered for the model. Costs included to estimate the budgetary impact were related to drug acquisition, drug administration (ie, intravenous infusions), and adverse event management (2010 US dollars). Market share data for all treatments were obtained from real-time drug utilization data from 36 states across the United States. Aggregate annual budget impacts per member per month (PMPM) and per member per year (PMPY) were evaluated. Results: In a hypothetical population of 1 million with an mrcc prevalence of % where 90% of patients receive treatment, the aggregated budget in the pre-everolimus launch market was found to be $7,050,157; for the post-everolimus launch market it was $6,741,642. This resulted in savings of $308,516 in the post-everolimus market; PMPM and PMPY savings across all plan members were $0.03 and $0.31, respectively. Conclusions: Introducing everolimus as second-line or third-line therapy to vascular endothelial growth factor tyrosine-kinase inhibitors resulted in minimal budget impact. Trends remained consistent across scenario analyses in which everolimus replaced different combinations of comparators. (Am J Pharm Benefi ts. 2012;4(Special Issue):SP41-SP48) Vol. 4, Special Issue The American Journal of Pharmacy Benefi ts SP41

2 Lopes Chulikavit Parikh Stern PRACTICAL IMPLICATIONS This model examines the budget impact of including everolimus as a treatment for metastatic renal cell carcinoma in a number of different treatment algorithm scenarios. Introducing everolimus as second-line or third-line therapy to vascular endothelial growth factor tyrosine-kinase inhibitors resulted in minimal budget impact. This research can help managed care decision makers appreciate the value of everolimus because it evaluated the most likely patterns of utilization, using real-world cost and market share data, and literature-based assumptions. Everolimus is an inhibitor of the mammalian target of rapamycin (mtor), a component of an intracellular signaling pathway that regulates cellular metabolism, growth, proliferation, and angiogenesis. 11 A pivotal, randomized, phase III trial of patients with mrcc whose disease had progressed on sunitinib, sorafenib, or both demonstrated a median PFS of 4.9 months for everolimus-treated patients compared with 1.9 months for those receiving best supportive care alone (hazard ratio 0.33, 95% confidence interval ; P <.001). 12 Although novel, targeted oncology treatments have resulted in incremental improvements in survival, they may be viewed as a potential source of substantial economic burden on the healthcare system, requiring payers and physicians to weigh costs and benefits when determining a treatment strategy. 13 In addition, payers can expect to incur relatively high costs during the last few months of life, during which time patients are receiving numerous expensive salvage therapies that ultimately may not affect their overall survival. Therefore, health plans will likely benefit from an examination of the incremental budget impact of a given treatment regimen upon its approval. The purpose of this study is to determine the impact that the introduction of everolimus may have on a health plan s budget by using a health economic model that considers the various treatments currently available to patients with mrcc within the bounds of explicit model assumptions. STUDY DESIGN AND METHODS A budget impact analysis was developed using Microsoft Excel (Microsoft Corporation, Redmond, Washington) to evaluate the current cost of therapy for RCC from April 2008 to March 2009 and October 2009 to September 2010 for a hypothetical health plan population of 1 million members. These time points were selected to account for markets before and after the approval of everolimus in mrcc (March 2009). Because there may be a delay associated with the uptake of everolimus immediately following approval, a 6-month period (April 2009 to September 2009) was considered as a lag period and was not included for base case post-everolimus launch market (see eappendix A, available at ). Population and Treatments Under Consideration Medication utilization data and prevalence rate for mrcc were applied to a hypothetical health plan of 1 million insured adults. The analysis considered only pharmacotherapeutic treatments for mrcc (ie, systemic chemotherapy and targeted treatments). The number of eligible patients was calculated based on mrcc epidemiology estimates (Table 1). Market share data for the different treatments were based on recent surveillance studies for RCC and real-world market share data (Novartis Pharmaceuticals Corporation, research market share data on file, proprietary and unpublished data, 2010). The Novartis data were obtained from patient-level drug utilization information, which was collected from 36 states electronically on a monthly basis. Treatment duration as well as the proportion of patients who moved from first-line to subsequent lines was based on a retrospective analysis of claims data performed by Intercontinental Marketing Services (IMS) Health, which has been used previously for other studies. 14 Information on treatment durations was available for both pre and post everolimus launch periods from IMS Health analysis. However, in order to keep the durations of each treatment consistent across both pre- and post-everolimus periods, treatment durations recorded during the pre-everolimus market were applied to the post-everolimus market. For drugs for which treatment duration data were not available in the pre-everolimus period (eg, everolimus, pazopanib), the treatment duration recorded in the post-everolimus period was applied. Cost Inputs To establish the total cost of treatment with a chemotherapeutic agent, the model considered the wholesale acquisition cost of each treatment, the recommended dose, administration costs, and the duration of treatment. Treatment schedule and dosing assumptions were based on the prescribing information for each product. 11,15-20 Treatment administration costs were added to every infused treatment, and were obtained from Current Procedural Terminology (CPT) codes. 21 The total administration cost for each regimen was estimated by multiplying unit SP42 The American Journal of Pharmacy Benefi ts Specialty Pharmacy 2012

3 Everolimus: Budget Impact in mrcc administrative costs by the mean treatment duration. Variable Details on the treatment schedules, unit costs, costs per dose, cost per week, and administration costs for the treatments considered are provided in Table 2. The model accounted for the differing safety profiles associated with each treatment. Treatment-related grade 3/4 adverse event incidence estimates were adopted from prescribing information or pivotal trials for each agent. 11,15-19,22 The costs of treating the adverse events were based on independent cost analyses Adverse events for which no cost literature was available had treatment costs estimated based on National Comprehensive Cancer Network guidelines 10,27-29 and unit costs from the Red Book 2010 CPT code book. 30,31 Details of specific calculations are available upon request. Costs calculated to treat adverse events were assumed for the entire course of chemotherapeutic treatment within a particular line of treatment. Costs for managing adverse events are shown in eappendix B, available at These costs along with incidence rates from prescribing information and pivotal trials were used to calculate the total cost of treating adverse events for treatments considered in the model (Table 2). 11,15-19,22 As underlying best supportive care was assumed to be the same across comparators, the cost of best supportive care was not included in this analysis. Analysis Total cost for each medication across the first, second, and third line of treatment was estimated by applying the drug acquisition, administration, and adverse event costs to the hypothetical mrcc population for the preeverolimus and post-everolimus scenarios. Across both the pre- and post-everolimus scenarios, mrcc incidence, treatment comparators, and costs (drug, administration, and adverse event management) were all assumed to remain the same; only the relative market share for each comparator varied. The eligible relative market share of patients treated with everolimus as second- or thirdline therapy in the postlaunch scenario was 11.63% and 27.73%, respectively. The analysis focused on evaluating budgetary differences between the pre and post everolimus launch Table 1. Metastatic Renal Cell Carcinoma Epidemiology Inputs Default Value Hypothetical MCO population size 1,000,000 Prevalence of mrcc % Proportion of patients with mrcc who receive treatment 90% Pre-everolimus launch period (2008, IMS Health data) Proportion of patients with mrcc who move from fi rst- to second-line therapy 28.2% Proportion of patients with mrcc who move from second- to third-line therapy 24.1% Post-everolimus launch period (2009, IMS Health data) Proportion of patients with mrcc who move from fi rst- to second-line therapy 21.8% Proportion of patients with mrcc who move from second- to third-line therapy 13.5% IMS indicates Intercontinental Marketing Services; MCO, managed care organization; mrcc, metastatic renal cell carcinoma. markets at 3 levels: (1) the aggregate level, (2) the aggregate budget impact stratified by treatment comparators, and (3) the budget impact per member per year (PMPY) and per member per month (PMPM). Sensitivity analyses were performed, where (1) the post-everolimus launch period was changed from October 2009 September 2010 to April 2009 March 2010 (which included the initial postapproval uptake lag period) and (2) the post everolimus launch period was changed to January 2010 December 2010 (which assumed a 9-month everolimus uptake lag period instead of 6 months) (see eappendix A). Additional sensitivity analyses were performed. They assumed that (3) administration costs were zero, (4) adverse event costs were zero, and (5) treatment duration for all comparators was the same as that for everolimus within each line of treatment. Market share of everolimus for second- and third-line treatment for the April 2009 March 2010 postlaunch period (sensitivity analysis 1) was 7.77% and 25.12%, respectively. For the January 2010 December 2010 postlaunch period (sensitivity analysis 2), market share was 12.80% and 27.82%, respectively. Sensitivity analyses 3, 4, and 5 were performed primarily to remove the effect of administration costs, adverse event costs, and treatment durations from the aggregate drug budgetary impact. Supplementary scenario analyses were conducted where market share of everolimus in the postlaunch period was exclusively captured from the market share of sorafenib (scenario 1) and sunitinib (scenario 2). Another scenario analysis, where everolimus market share was captured from temsirolimus (64.0%), bevacizumab (26.4%), and sorafenib (9.6%), was also performed. These analyses were conducted for both second and third lines of treatment. Market share data for the base case and all the scenarios are shown in Table 3. Costs are reported in 2010 US dollars. Vol. 4, Special Issue The American Journal of Pharmacy Benefi ts SP43

4 Lopes Chulikavit Parikh Stern Table 2. Drug and Administration Costs Treatment Bevacizumab Treatment Schedule 10 mg/kg administered intravenously once every other week until disease progression (assuming average body weight of 70 kg) 20 Unit Drug Cost 4-mL vial (25 mg/ml): $ mL vial (25 mg/ml): $ Administration Cost Drug Cost per Dose Drug Cost per Week Adverse Event Cost a $ $ $ $ Everolimus One 10-mg tablet taken orally once daily $ NA $ $ $ (total of 10 mg) until no more treatment effect 11 Interferon 9 miu administered subcutaneously $ $0.00 $ $ $ times per week on alternating days for a maximum of 52 weeks or until no more treatment effect 22 Interleukin Infusion of 18 mu per m2 of BSA once One 18-mU vial: $974 $0.00 $ $ $73.66 daily for 5 days, every 3 weeks (assuming 1.83 m 2 of BSA) 15 Pazopanib 800 mg orally once daily without food 19 $45.80 NA $ $ $ Sorafenib Sunitinib Temsirolimus Two 200-mg tablets taken orally twice daily (total of 400 mg) until no more treatment effect 18 One 50-mg tablet taken orally once daily; treatment cycle of 6 weeks (4 weeks on active treatment, 2 weeks off treatment) mg administered intravenously once a week with a 25- to 50-mg histamine H 1 blocker preinfusion until no more treatment effect 17 $55.51 NA $ $ $ $ NA $ $ $ mL vial (25 mg/ml): $ $ b $ $ $ BSA indicates body surface area; NA, not applicable. a Adverse events considered were anemia, anorexia/cachexia, diarrhea, dyspnea, fatigue, hand-foot syndrome, hemorrhage, hypertension, infection/infestation, leucopenia, nausea/ vomiting, neutropenia, pneumonitis, and thrombocytopenia. Costs for each adverse event were estimated for the entire course of treatment and are detailed in eappendix B. b Includes the cost of a histamine blocker preinfusion. RESULTS With an incidence rate of % and a hypothetical plan of 1 million covered individuals, a population of 203 mrcc patients was calculated, of whom 90% (182 patients) received first-line active treatment for mrcc. Longitudinal analysis of IMS Health data for patients in 2008 showed that 28.2% (52 patients) of patients who received first-line therapy moved to second-line therapy; 24.1% (12 patients) of these patients additionally received a third-line therapy. Similarly for 2009, 21.8% (40 patients) of patients receiving first-line therapy also received second-line therapy, while only 13.5% (5 patients) of these patients received third-line therapy (Table 1). In the pre everolimus launch market scenario, the total cost of drugs, administration, and adverse event management, across all lines of treatment, was found to be $7,050,157. In the market following the introduction of everolimus, the total cost decreased to $6,741,642, yielding a savings of $308,516. Table 4 reports the cost stratified by different therapies within each line of treatment. Based on the model calculations, with the availability of everolimus after October 2009, the budget impact PMPM cost was $0.03 and the budget impact PMPY cost was $0.31. Results for the sensitivity and additional scenario analyses are presented in Table 5. Sensitivity analyses that accounted for the extended postapproval lag period (January 2010 to December 2010) and the assumption that all comparators had the same treatment duration as that of everolimus (analyses 2 and 5, respectively) both resulted in additional savings of more than $70,000 (increased PMPY of >$0.07). However, the sensitivity analyses that examined the inclusion of the postapproval uptake lag period (April 2009 to March 2010) and set the adverse event management costs to zero dollars (analyses 1 and 4, respectively) resulted in less savings than the base case analysis. No substantial differences were found across all additional scenario analyses (scenarios 1, 2, and 3), where total savings ranged from $233,237 to $254,274. Both PMPY and PMPM costs for all the 3 additional scenarios appeared to be similar to those of the base case analysis. DISCUSSION This model estimated the annual budget impact of SP44 The American Journal of Pharmacy Benefi ts Specialty Pharmacy 2012

5 Everolimus: Budget Impact in mrcc Table 3. Market Share for Therapies Across Lines of Treatment in Different Scenarios Percentage Treatment Prelaunch Base Case Base Case Scenario 1 a Scenario 2 b Scenario 3 c First line Everolimus Bevacizumab Interferon Sorafenib Sunitinib Temsirolimus Pazopanib Interleukin Second line Everolimus Bevacizumab Interferon Sorafenib Sunitinib Temsirolimus Pazopanib Interleukin Third line Everolimus Bevacizumab Interferon Sorafenib Sunitinib Temsirolimus Pazopanib Interleukin Bold-faced entries are indicators of where the market share is captured from in the scenario analysis. a Scenario 1: market share for everolimus in postlaunch period exclusively captured from sorafenib. b Scenario 2: market share for everolimus in postlaunch period exclusively captured from sunitinib. c Scenario 3: market share for everolimus in postlaunch period captured from temsirolimus (64.0%), bevacizumab (26.4%), and sorafenib (9.6%). treating patients with mrcc in order to show the range of possible budget impacts in a market without everolimus compared with a market where everolimus was used in different amounts by different types of patients. The model results demonstrate the potentially favorable impact that the introduction of everolimus could have on a health plan s budget. Additional analyses were conducted to assess scenarios whereby the introduction of everolimus as a next-line therapy to sunitinib (scenario 1), sorafenib (scenario 2), or temsirolimus, bevacizumab, and sorafenib (scenario 3) resulted in a favorable aggregate budget impact compared with a treatment algorithm that excluded everolimus altogether. At the PMPM level, including everolimus in the treatment algorithm is cost neutral. The difference in total cost is mostly attributed to the difference in the cost of anticancer drugs. There are several limitations to this analysis. This model did not take into account or correct for differences in populations from study to study. Consequently, results might have been different if data had been extracted from a unified study. For instance, because adverse event rates were taken from a series of different studies, variation in the adverse event rates assigned to each drug might have Vol. 4, Special Issue The American Journal of Pharmacy Benefi ts SP45

6 Lopes Chulikavit Parikh Stern Table 4. Aggregate Budget Impact Stratified by Treatment Treatment Pre Everolimus Launch Post Everolimus Launch Difference a First line Everolimus $0.00 $0.00 $0.00 Bevacizumab $182, $145, ($37,122.25) Interferon $ $ ($ ) Sorafenib $475, $226, ($249,161.18) Sunitinib $3,238, $3,356, $117, Temsirolimus $1,792, $2,096, $303, Pazopanib $0.00 $11, $11, Interleukin $0.00 $0.00 $0.00 Total (fi rst line) $5,698, $5,840, $142, Second line Everolimus $0.00 $91, $91, Bevacizumab $ $11, $ Interferon $ $ ($ ) Sorafenib $390, $215, ($174,353.83) Sunitinib $479, $330, ($148,816.27) Temsirolimus $221, $126, ($95,005.78) Pazopanib $0.00 $10, $10, Interleukin $0.00 $0.00 $0.00 Total (second line) $1,102, $789, ($313,190.85) Third line Everolimus $0.00 $45, $45, Bevacizumab $15, $ ($11,156.11) Interferon $0.00 $0.00 $0.00 Sorafenib $74, $22, ($51,954.50) Sunitinib $126, $27, ($99,314.53) Temsirolimus $32, $10, ($22,130.65) Pazopanib $0.00 $ $ Interleukin $0.00 $0.00 $0.00 Total (third line) $249, $111, ($137,798.68) Total (all lines) $7,050, $6,741, ($308,515.64) PMPY $7.05 $6.74 ($0.31) PMPM $0.59 $0.56 ($0.03) PMPM indicates per member per month; PMPY, per member per year. a Values in parentheses indicate reduction in budget (savings) from pre-everolimus period to post-everolimus period. been more directly attributable to differences in patient populations. However, a sensitivity analysis was undertaken to assess the budget impact of everolimus when adverse event costs were excluded. The findings suggest an incremental PMPM budget impact of $0.02, which is in line with the base case results. Also, it was assumed that treatment durations recorded for comparator agents in the pre-everolimus market would be the same in the post-everolimus market. This assumption was made in order to prevent potential differences in treatment duration from biasing the model results. However, it should be acknowledged that this assumption could have led to either an overestimation or an underestimation of overall costs. To address this issue, a sensitivity analysis was performed, whereby all agents were assigned the duration of treatment recorded for everolimus. The results of this sensitivity analysis show that even with this adjustment, the budget impact results are similar to the base case $0.04 incremental PMPM for the sensitivity analysis versus $0.03 for the base case. Additionally, costs for best supportive care and palliative care were not taken into account in this model; therefore, the change in proportion of overall costs is likely overestimated in each scenario. Of note, the market share data were collected on a monthly basis only, and patients were not followed longitudinally. Therefore, the analysis was performed using patient-months to account for patient entry/dropout during the course of the data collection. To take into account the lag time involved in drug uptake immediately following approval and to avoid underestimating everolimus use in the current scenario, market share data 6 months following approval of everolimus were used for the base case analysis. However, sensitivity analyses that included the 6-month lag period and an extended lag period (9 months) resulted in findings comparable to those in the base case. Moreover, with increased market share of everolimus (relative to the base case) in the extended lag period analysis, the savings incurred were more than those observed in the base case. The analysis did not consider surgical options for 2 main reasons. Because the target population of this analysis was patients with mrcc, only a small proportion would have qualified for surgery. 27 Additionally, surgical procedures do not directly compete with everolimus therapy because the proportion of patients receiving surgery would remain the same before and after the introduction of everolimus to this disease landscape. If surgery were to be included as a comparator, the results would remain the same. Despite the potential generalization of some of the inputs given the only available data, it is important to SP46 The American Journal of Pharmacy Benefi ts Specialty Pharmacy 2012

7 Everolimus: Budget Impact in mrcc Table 5. Results From Sensitivity and Scenario Analyses Type of Analysis Sensitivity analysis Pre-Everolimus Launch Post-Everolimus Launch Difference a PMPY a PMPM a 1. Post-everolimus launch period changed to April 2009 to March 2010 $7,050, $6,770, ($279,302.14) ($0.28) ($0.02) 2. Post-everolimus launch period changed to January 2010 to December 2010 $7,050, $6,669, ($380,308.87) ($0.38) ($0.03) 3. No administration cost $6,510, $6,156, ($354,171.70) ($0.35) ($0.03) 4. No adverse event cost $6,706, $6,413, ($293,044.53) ($0.29) ($0.02) 5. Same duration of treatment as that of everolimus (within each line of treatment) $6,757, $6,318, ($438,678.84) ($0.44) ($0.04) Scenario analysis 1. Everolimus market share in postlaunch period captured from sorafenib $7,050, $6,809, ($240,776.30) ($0.24) ($0.02) 2. Everolimus market share in postlaunch period captured from sunitinib $7,050, $6,795, ($254,273.75) ($0.25) ($0.02) 3. Everolimus market share in postlaunch period captured from temsirolimus (64.0%), bevacizumab (26.4%), and sorafenib (9.6%) $7,050, $6,816, ($233,236.68) ($0.23) ($0.02) PMPM indicates per member per month; PMPY, per member per year. a Values in parenthesis indicate a reduction in budget (ie, savings) from the pre-everolimus period to the post-everolimus period. consider the relatively small overall impact that mrcc has on managed care budgets compared with other types of cancer or other chronic diseases. Even if the results of this study were underestimated or overestimated, the analysis shows that providing patients with additional treatment options such as everolimus would not result in a substantial increase in a health plan s overall budget. The future management of oncology therapy in mrcc may require quantification of value through evidencebased medicine, justifying the margin of benefit with each cycle. It is an opportunity to develop clinical pathways based on the efficacy, safety, and cost of second- or third-line treatment options. With new treatment options available in the future, it will become important to understand who can benefit with meaningful improvement in overall survival and to identify through biomarkers the sequence of therapies needed to maximize value. Acknowledgment Editorial assistance was provided by Jacob M. Willet, MPH, an employee of Analytica International. Author Affiliations: From AMC Health (ML), New York, NY; Analytica International (MC, RP, LS), New York, NY; and Novartis Pharmaceutical Corporation (ZL, JR), East Hanover, NJ. Funding Source: Funding for this research was provided by Novartis Pharmaceuticals Corporation, East Hanover, NJ. Author Disclosures: Mr Chulikavit, Mr Parikh, and Ms Stern report employment with Analytica which is a paid consultant to Novartis Pharmaceuticals Corporation. Drs Liu and Rogerio report employment with Novartis Pharmaceuticals Corporation and Dr Liu reports stock ownership in the company. The authors (ML) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. Authorship Information: Concept and design (ML, MC, RP, LS, ZL); acquisition of data (ML, ZL); analysis and interpretation of data (ML, MC, RP, ZL, JR); drafting of the manuscript (ML, MC, RP); critical revision of the manuscript for important intellectual content (ML, MC, RP, ZL, JR); obtaining funding (ZL, JR); and supervision (MC, LS, ZL, JR). Address correspondence to: Lee Stern, MS, Analytica International, 24 W 40th St, New York, NY lstern@analyticaintl.com. REFERENCES 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, CA Cancer J Clin. 2007;57(1): Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer. 2009;115(1): Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst. 2006;98(18): Ljungberg B, Hanbury DC, Kuczyk MA, et al; European Association of Urology Guideline Group for renal cell carcinoma. Renal cell carcinoma guideline. Eur Urol. 2007;51(6): Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335(12): Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mrcc): a literature review. Cancer Treat Rev. 2008;34(3): Lang K, Danchenko N, Gondek K, Schwartz B, Thompson D. The burden of illness associated with renal cell carcinoma in the United States. Urol Oncol. 2007;25(5): Escudier B, Eisen T, Stadler WM, et al; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma [published correction appears in N Engl J Med. 2007;357(2):203]. N Engl J Med. 2007;356(2): Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2): National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Palliative Care. Fort Washington, PA: NCCN; 2008: Afi nitor (everolimus) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March nitor.com/advanced-renal-cell-carcinoma/hcp/full-prescribing-information.jsp. Accessed May 27, Motzer RJ, Escudier B, Oudard S, et al; RECORD 1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma : fi nal results and analysis of prognostic factors. Cancer. 2010;116(18): Nadler E, Eckert B, Neumann PJ. Do oncologists believe new cancer drugs offer good value? Oncologist. 2006;11(2): Vol. 4, Special Issue The American Journal of Pharmacy Benefi ts SP47

8 Lopes Chulikavit Parikh Stern 14. Hess GP, Chen CC, Liu ZM, Hill JW, Gesme DH, Agarwala SS. Metastatic renal cell carcinoma: patient characteristics and recent treatment patterns in real-world practice. Paper presented at: AMCP s 23rd Annual Meeting & Showcase; April 27-29, 2011; Minneapolis, MN. 15. Proleukin (aldesleukin) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; revised December com/assets/proleukin.pdf. Accessed May 27, Sutent (sunitinib) [prescribing information]. New York, NY: Pfi zer Inc; revised April zer.com/fi les/products/uspi_sutent.pdf. Accessed May 27, Torisel (temsirolimus) [prescribing information]. Prescribing-Information.aspx. Philadelphia, PA: Wyeth Pharmaceuticals Inc; revised May Accessed May 27, Nexavar (sorafenib) [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Corporation; revised October Accessed May 27, Votrient (pazopanib) [prescribing information]. gskprm/en/us/adirect/gskprm?cmd=productdetailpage&product_id= &featureKey=601903#nlmhighlights. Research Triangle Park, NC: GlaxoSmithKline; revised April Accessed May 27, Avastin (bevacizumab) [prescribing information]. products/information/pdf/avastin-prescribing.pdf. South San Francisco, CA: Genentech Inc; revised April Accessed May 27, Physicians Fee and Coding Guide st ed. Atlanta, GA: MAG Mutual Healthcare Solutions; Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB J Clin Oncol. 2008;26(33): Dial E, Fournier A, Moyneur E, Neary MP, Duh MS, Oh WK. Frequency and cost of adverse events in renal cell carcinoma (RCC) patients receiving angiogenesis inhibitor therapies. Paper presented at: 2008 ASCO Annual Meeting; May 31- June 3, 2008; Chicago, IL. 24. Mickisch G, Escudier BJ, Gore ME, Walzer S, Sabaté E, Nuijten M. Cost of managing side effect in the treatment of fi rst-line metastatic renal cell carcinoma in Germany, France, and the UK: bevacizumab + interferon alpha-2a compared with sunitinib. Paper presented at: 2008 ASCO Annual Meeting; May 3-June 3, 2008; Chicago, IL. 25. Vanscoy GJ, Fortner B, Smith R, Weber R, Rihn TL. Preventing chemotherapyinduced nausea and vomiting: the economic implications of choosing antiemetics. Community Oncol. 2005;2(2): Weiner MG, Ross SJ, Mathew JI, et al. Estimating the costs of chemotherapyassociated adverse event clusters. Health Serv Outcomes Res Methodol. 2007; 7(1): National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Fort Washington, PA: NCCN; 2011: National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prevention and Treatment of Cancer-Related Infections. Fort Washington, PA: NCCN; 2008: National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain. Fort Washington, PA: NCCN; 2007: Beebe M, Dalton JA, Espronceda M. CPT 2009 Standard Edition. Chicago, IL: American Medical Association; Physicians Desk Reference. Red Book 2010: Pharmacy s Fundamental Reference. Vol 113. Montvale, NJ: Thomson Reuters; SP48 The American Journal of Pharmacy Benefi ts Specialty Pharmacy 2012

9 Everolimus: Budget Impact in mrcc eappendix A. Market Share Data Time Line (Base Case and Sensitivity Analysis) April 2009 (everolimus launch) October 2009 January 2010 September 2010 Lag Period March 2010 December 2010 Pre-everolimus launch period (base case) (sensitivity analysis including lag period) Post-everolimus launch (base case) (sensitivity analysis with extended lag period) eappendix B. Cost of Managing Adverse Events Adverse Event Unit Cost Anemia $ Anorexia/cachexia $ Diarrhea $ Dyspnea $ Fatigue $ Hand-foot syndrome $ Hemorrhage $ Hypertension $ Infection/infestation $ Leukopenia $ Lymphopenia $ Nausea/vomiting $ Neutropenia $ Pneumonitis $ Thrombocytopenia $ Vol. 4, Special Issue The American Journal of Pharmacy Benefi ts asp49