Pazopanib (VotrientTM) is a multi-target tyrosine kinase inhibitor approved by the FDA for the treatment of renal cell carcinoma. Renal cell carcinoma is the most common type of cancer that occurs within the kidneys. It is common for the patient to note abdominal pain, hematuria, and a palpable mass in either the abdomen or flank area. Diagnosis is confirmed via an abdominal CT scan and, according to the Washington Manual of Medicine, 20 to 30 percent of cases have already metastasized to other areas, often including the lungs, bone, liver and brain at diagnosis. Renal cell carcinoma results in about 64,770 new cases every year (40,250 in men, 24,520 in women) and 13,570 deaths (8,650 in men, 4,920 in women) annually, according to the American Cancer Society, making it one of the top ten most common cancers in both men and women. This cancer occurs generally in patients over the age of 45, with the average age of diagnosis being 65. The overall lifetime risk is about 1.5%, with the risk being 2-fold greater in men. Common risk factors include smoking, obesity, work place exposure to pesticides, cleaning agents or asbestos, uncontrolled hypertension, advanced kidney disease, long term use of high dose diuretics, and familial history. Genetic predisposition is a very common component because it has been documented that 40% of patients who are diagnosed with Von Hippel-Lindau disease, a condition resulting from a gene mutation on the third chromosome causing spontaneous growth of tumors, are diagnosed with renal cell carcinoma.
Pazopanib is an oral multikinase inhibitor of angiogenesis. Pazopanib inhibits vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-alpha and -beta, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-beta receptors. In patients with clear cell renal cell cancer (RCC), the most common histology of RCC, inactivation of the von-HippelLindau (VHL) gene, is present. Suppression of this gene leads to upregulation of a number of hypoxia-induced genes including VEGF and PDGF. VEGF induces a mitogenic response upon binding to one of the VEGF receptors (VEGFR-1 to -3) on endothelial cells. Transforming growth factor-alpha (TGF-alpha) is also regulated by the VHL gene; TGF-alpha acts as a ligand for EGF receptor and stimulates the growth of epithelial cells of the proximal renal tubule, where most RCCs appear to start.
According to the National Cancer Center Network, renal cell carcinomas that are staged as I-III use partial nephrectomy as first-line therapy for localized tumors and radical nephrectomy, including resection of the accompanying adrenal gland, if the tumor is seen to be very invasive. Both surgical options may or may not include palliative radiation. First line treatment for stage IV metastatic disease includes cytokine therapy with interleukin-2 and interferon alpha. Class I options for targeted therapy other than Pazopanib include sorafenib, sunitinib, bevacizumab, a monoclonal antibody against circulating VEGF-A, in combination with IL-2, and temsirolimus. Infusions of IL-2 and IFN-alpha result in response rates ranging from 5 to 27% with modest clinical benefits and are associated with high risks of systemic toxicity. The combination of bevacizumab and IL-2 resulted in an increase of PFS and OS that were not statistically significant and had a higher risk side-effect profile. Sorafenib is only a first line option for patients whose cancer is medically unresectable. Temsirolimus, an inhibitor of the M-Tor protein, is also a class 1 option for stage IV RCC, but comparatively to pazopanib or sunitinib, resulted in less of an increase in PFS and OS. When comparing efficacy data between pazopanib and sunitinib, the PFS data in treatment naïve patients (11.1 and 11 months for PFS respectively), while OS data has become recently available for sunitinib (26.1 months) and should become available for pazopanib along with comparative data between pazopanib and sunitinib.
Trial Design: Placebo controlled, randomized double blind, global, multicenter, Phase III studyBlinding: Patients were blinded based on placebo, but upon progression of disease, if they were on placebo had the option to join an open label trial of pazopanibRandomization: Stratified based on ECOG PS (1 vs. 0), prior nephrectomy ( y vs. n), prior systemic treatment (treatment naïve vs. systemic cytokine therapy), centrally randomly assigned 2:1 ratio, to receive pazopanib 800mg QD or placebo
Direct medical costs including: Routine follow-up of treated patients (first and second line) Managing treatment-related serious AEs Diagnosis and treatment of progression; and BSC in the terminally ill Indirect costs (eg, lost productivity or premature death) were not included;costs are re-ported in 2006 US dollarsDrug treatment costs were based on the following schedulesIFN-alpha (first cycle): three injections/wk with 3 MU/injection in the first week, 6 MU/ injection in the second week, and 9 MU/injection, thereafter.6 IFN-alpha (subsequent cycles): three injections/wk with 9 MU/injectionSunitinib (full dose): 50 mg/d for 4 weeks followed by 2 weeks off treatment Sunitinib (reduced dose): 37.5 mg/d for 4 weeks followed by 2 weeks off treatment. IL-2: infusion of 18 MU/m2 body-surface area (BSA)/d for 5 days, once every 3 weeks (assuming 1.9 m2 of BSA) Sorafenib (second-line treatment): 400 mg twice per day.Expected follow-up for patients receiving active treatment, health care resources required for BSC of terminally ill patients, resource use associated with treatment-related SAEs and the expected hospital stay were obtained from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) Database
In the base-case analysis for both countries in this model, sunitinib was more effective than bevacizumab plus IFN-α (Table 5). In the US and Swedish settings, sunitinib was dominant (i.e. both more effective and less costly) compared with bevacizumab plus IFN- α with cost savings per patient over 10 years of $67 798 and $47 264, respectively (Table 5). Among patients in the US, sunitinib was associated with gains of 0.52 PFLYs, 0.16 LYs and 0.17 QALYs compared with sorafenib. Sunitinib was dominant with a total cost over 10 years of $13 576 less per patient. The total cost of treatment over a 10-year period is higher for bevacizumab plus IFN-α compared with sunitinib in both the US and Sweden. However, the cost- effectiveness results were similar as clinical gain was equal in both countries and the relative (non-absolute) costs were similar. DETERMINISTIC SENSITIVITY ANALYSIS In the one-way sensitivity analyses, individual variables were set to ±20% of the base case one by one, in order to see their independent effects on the cost-effectiveness results. The most influential variables were the HRs for survival, BSC costs, the drug prices and utilities associated with treatments (see Supporting Information, Figs. S1–S3). PFS directly comparing sunitinib with sorafenib (0.58, 95% CI 0.38–0.86) and with bevacizumab plus IFN-α (0.75, 95% CI 0.60–0.93) from the indirect comparison in a recent traditional meta-analysis by Mills et al. , published after completion of the present analysis, further increased the PFS differences between sunitinib and the other two comparators, favouringsunitinib. In addition, using data from the phase III CALGB 90206 trial , estimates for bevacizumab plus IFN-α produced essentially the same results as our base case (data not shown).
Direct medical costs included were: routine follow-up of treated patients (first and second line); managing treatment-related serious AEs (SAEs); diag- nosis and treatment of progression; and BSC in the terminally ill. Indirect costs (eg, lost productivity or premature death) were not included; costs are re- ported in 2006 US dollars.
The reference case results (Table 4) indicate a difference of $7,534 in the total average per-patient lifetime cost of treatment with sunitinib versus IFN-, and cost savings of $3,441 versus IL-2. The acquisition cost of sunitinib largely explains its higher cost. The probabilistic analysis showed that the incremental cost per progression-free year gained for sunitinib versus IFN- was $18,611, and the ICER and ICUR of sunitinib versus IFN- were $67,215 per LY gained and $52,593 per QALY gained, respectively. At a 3% discount, the ratios were $18,113, $65,246, and $51,130, respectively. Using full hospital charges re- sulted in ratios for sunitinib versus IFN- of $1,278, $4,082, and $3,434, respectively. At thresholds of $50,000/QALY and $100,000/QALY, the probabilistic analyses indicated that sunitinib had 45.9% and 64.9% probability, respectively, of being cost-effective compared with IFN-, and was the optimal treatment above a $55,000/QALY threshold (Fig 2). Sunitinib has a more than 50% probability of being cost effective compared with IFN- at any threshold above the ICUR calculated from the probabilistic analysis ($57,619/ QALY), and has a 65% probability of being cost effective at the $100,000/QALY threshold. The tornado analysis indicated that the most sensitive parameters were utility values, and costs of sunitinib and BSC (Fig A2). ICURs obtained from varying the most sensitive parameters ranged from $1,470 using higher costs for BSC to $136,783 using lower utility values for sunitinib during treatment (online-only Table A2). Reducing the time horizon from 10 years to 1 year increased the ICUR to $120,304/QALY, while with a 2-year analy- sis, the ICUR fell to $67,507/QALY.
Pazopanib: A Formulary Dossier
PazopanibFormulary DossierBy Joseph Feliciano
Renal Cell Carcinoma• Occurs most commonly in patients over the age of 45, with the average age of diagnosis being 65 • overall lifetime risk is 1.5%, with the risk being 2-fold greater in men • 64,770 new cases every year • 40,250 in men, 24,520 in women13,570 deaths (8,650 in men, 4,920 in women)• Patients present with : • abdominal pain • hematuria and a palpable mass in either the abdomen or flank area • Diagnosis is confirmed via an abdominal CT scan • 20 to 30% of cases have already metastasized to other areas, often including the lungs, bone, liver and brain at diagnosis • Risk Factors • Smoking • Advanced kidney disease • Obesity • long term use of high dose • Exposure to diuretics pesticides, cleaning • familial history/Genetic agents or asbestos
PRODUCT INFORMATION• Pazopanib (VotrientTM) • FDA Labeled Indication • Approved by the FDA on • Renal cell carcinoma October 19, 2009 • Off Label Uses • Therapeutic Class and AHFS Classification • Nasopharyngeal Carcinoma • Oral Tyrosine Kinase • Hepatocellular Carcinoma Inhibitor/ Anti-neoplastic • Thyroid Cancer agent • Metastatic Breast Cancer • AWP and WAC: $7408.16 and • Recurrent Glioblastoma $ 6173.47 • Ovarian Cancer • AWP per Unit Cost: $61.73
Place Of Product In Therapy• National Cancer Center Network Recommendations Regarding RCC – Stages I-III • Partial nephrectomy as first-line therapy for localized tumors • Radical nephrectomy, including resection of the accompanying adrenal gland – Both surgical options may or may not include palliative radiation – Stage IV metastatic disease – First Line Therapy • Cytokine therapy – Interleukin-2 and interferon alpha • Targeted therapy – Pazopanib – Sunitinib – Bevacizumab
Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial• Research Goal • To evaluate safety and efficacy of pazopanib in treatment naïve patients and those who previously received systemic cytokine therapy • Trial Design • Placebo controlled, randomized double blind, global, multicenter, Phase III study • Randomization • Based on: • ECOG PS (1 vs. 0) • prior nephrectomy ( y vs. n) • prior systemic treatment
Pazopanib in Locally Advanced or Metastatic Renal CellCarcinoma: Results of a Randomized Phase III Trial (continued)• Inclusion criteria – Documented RCC, treatment naïve or received systemic cytokine therapy, measurable disease per Response Criteria in Solid Tumors, age >/18, ECOG PS </ 1, adequate hepatic, renal and hematologic function.• Exclusion criteria – CNS metastases, leptomeningeal lesions, or any of the following within 6 months of screening: • uncontrolled HTN, QTc prolongation >/470ms, history of class III/IV CHF, MI or unstable angina, angioplasty or stenting, or CVA• Participant Demographics – Treatment naïve patients or patients who have received systemic therapy – 435 total patients, median age for treatment or placebo was 60, – 68% of treatment group and 75% of placebo group were men, – 87% of TG and 84% of P were white – Median time to initial diagnosis was 15.7 and 13.8 months
Pazopanib in Locally Advanced or Metastatic Renal CellCarcinoma: Results of a Randomized Phase III Trial (continued)• Outcomes Measure – Primary endpoint: progression free survival • Secondary endpoints: Overall survival, complete response, partial response, duration of response, and health related quality of life• Results – PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001) • The treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001) • The cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001) – The objective response rate was 30% with pazopanib compared with 3% with placebo (P <.001) – The median duration of response was longer than 1 year – The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting
Pazopanib: An Oral Multi-targeted Tyrosine Kinase Inhibitor for Use in Renal Cell Carcinoma• Research Goal – To evaluate the available clinical data available on pazopanib, as well as review the merit and adverse events of using pazopanib in RCC• Trial Design – Systematic primary literature search• Inclusion/Exclusion Criteria – All available English-language articles and trials that described the pharmacokinetics, pharmacology, pharmacodynamics, clinical activity, or adverse effects of pazopanib were reviewed• Participant Demographics – Phase 2 trial: 225 patients that either received prior systemic treatment with cytokines alone, cytokines with Avastin, or treatment naïve – Phase 3 trial: Previously covered – Toxicity study: 977 patients that were taking pazopanib for a median time of 7.5 months
Pazopanib: An Oral Multi-targeted Tyrosine Kinase Inhibitor for Use in Renal Cell Carcinoma (continued)• Outcomes Measured – Progression free survival – Overall survival – Rates of toxicity and adverse events (all grades)• Results – Reported Results from phase III trial – Reported incidences of toxicities and their associate adverse events • Determined how safe it is use to pazopanib in the treatment of mRCC
Economic evaluation of new targeted therapies for the first- line treatment of patients with metastatic renal cell carcinoma• Research Goal – To assess the cost effectiveness and cost utility of sunitinib malate as a first-line treatment in metastatic renal cell carcinoma (mRCC) compared with IFN-alpha and interleukin-2• Perspective – Presented from a U.S. and Swedish third party payor perspective• Study Design – A Markov model simulated disease progression, adverse events and survival with sunitinib vs sorafenib in the US and bevacizumab plus interferon- alpha and to analyze the associated costs.
Economic evaluation of new targeted therapies for the first-line treatment of patients with metastatic renal cell carcinoma (Continued)• Cost
Economic evaluation of new targeted therapies for the first-line treatment of patients with metastatic renal cell carcinoma (Continued) • Results
Economic evaluation of sunitinib malate for the first-line treatment of metastatic renal cell carcinoma• Research Goal – To compare cost-effectiveness of three new targeted therapies in mRCC head-to-head • Based on indirect comparison of clinical efficacy• Perspective – U.S. societal perspective• Study Design – A Markov model was developed to simulate disease progression and to determine progression- free survival, total life-years (LYs), and quality-adjusted life- years (QALYs) gained.
Economic evaluation of sunitinib malate for the first-line treatment of metastatic renal cell carcinoma (continued)• Costs
Economic evaluation of sunitinib malate for the first-line treatment of metastatic renal cell carcinoma (continued)• Results
Conclusions• Clinical Benefit – As a First Line Option • Can be used in newly diagnosed or previously treated patients, safely – Noted to cause hepatotoxicity, hypertension, and gastrointestinal discomfort • Difficult to differentiate between pazopanib and sunitinib – Matter of preference for the physician• Economic Benefit – Difficult to assess due to the lack of data • Used a comparable drug in efficacy, adverse events, and associated costs• Recommendations – Non-preferred agent • Used only as step up treatment or due to a complete contraindication – Reevaluate when: • the head to head study between pazopanib and sunitinib in mRCC is complete • More economic data on pazopanib is released
ReferencesBenedict, Agnes. "Economic Evaluation of New Targeted Therapies for theFirst-line Treatment of Patients with Metastatic Renal Cell Carcinoma."British Journal of Urology International (2011). Web.Biocarta. Web. <http://www.biocarta.com/pathfiles/h_vegfpathway.asp>.LaPlant, K. D., and P. D. Louzon. "Pazopanib: An Oral Multitargeted Tyrosine Kinase Inhibitor for Use in Renal Cell Carcinoma." Annals of Pharmacotherapy 44.6 (2010): 1054-060. Print.Remak, E., C. Charbonneau, S. Negrier, S. T. Kim, and R. J. Motzer. "Economic Evaluation of Sunitinib Malate for the First-Line Treatment of MetastaticRenal Cell Carcinoma." Journal of Clinical Oncology 26.24 (2008): 3995-4000. Web.Sternberg, Cora Anne. "Journal of Clinical Oncology." Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. Web. 01 Apr. 2012.<http://jco.ascopubs.org/content/28/6/1061>.