Committee Approval Date: November 13, 2014 Next Review Date: November 2015

Transcription

1 Medication Policy Manual Policy No: dru128 Topic: Sutent, sunitinib Date of Origin: April 7, 2009 Committee Approval Date: November 13, 2014 Next Review Date: November 2015 Effective Date: December 1, 2014 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Sunitinib (Sutent) is an oral medication used to treat kidney, gastrointestinal, and pancreatic cancers. It blocks the growth of cancer cells by inhibiting multiple tyrosine kinases. dru Page 1 of 11

2 Policy/Criteria I. Most contracts require prior authorization approval of sunitinib (Sutent) prior to coverage. Sunitinib (Sutent) may be considered medically necessary in patients when both criteria A and B below are met. A. Documentation of one of the following diagnoses: 1. Gastrointestinal stromal tumor. OR 2. Renal cell carcinoma. OR 3. Pancreatic neuroendocrine tumors. AND B. Sunitinib (Sutent) is dispensed from a pharmacy that has demonstrated the ability to provide the clinical support services outlined in Appendix 1. II. III. Administration, Quantity Limitations, and Authorization Period A. RegenceRx considers sunitinib (Sutent) to be a self-administered medication. B. When prior authorization is approved, sunitinib (Sutent) may be authorized in quantities of up to 50 mg per day. Doses of up to 87.5 mg per day may be authorized when sunitinib (Sutent) is administered concomitantly with medications that decrease sunitinib (Sutent) plasma concentrations. (See Appendix 2) C. Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. Sunitinib (Sutent) is considered investigational when used for all other conditions, including but not limited to: A. Angiosarcoma B. Breast cancer C. Chordoma D. Colorectal cancer E. Gastric cancer F. Glioma G. Non-small cell lung cancer H. Neuroendocrine tumors other than pancreatic in origin I. Non-gastrointestinal stromal tumor sarcoma J. Thyroid carcinoma dru Page 2 of 11

3 Position Statement Sunitinib (Sutent), an orally administered tyrosine kinase inhibitor, may be covered for certain cancers where it has been shown to be safe and effective including gastrointestinal stromal tumor, renal cell carcinoma, and pancreatic neuroendocrine tumors. Although there is no useful evidence that any one agent is more effective than another, when the use of a tyrosine-kinase inhibitor is indicated, sunitinib (Sutent) is the best value for patients with advanced or metastatic renal cell carcinoma. Sunitinib (Sutent) improved progression-free survival, an endpoint that uses x- rays to measure the size of tumors, relative to interferon-alfa. It is unclear if sunitinib (Sutent) improves overall survival relative to interferonalfa due to problems with the way the clinical trials were designed and analyzed. Sunitinib (Sutent) improved the time it took tumors to progress in patients with gastrointestinal stromal tumor relative to no treatment. It is unknown whether this effect will result in improved survival. Sunitinib (Sutent) improved the time it took tumors to progress in patients with pancreatic neuroendocrine tumors relative to no treatment. There was a trend towards improved survival. Sunitinib (Sutent) may be covered at the doses at which it has been shown to be effective (up to 87.5 mg per day). Clinical Efficacy GASTROINTESTINAL STROMAL TUMOR Sunitinib (Sutent) was studied in 312 patients with gastrointestinal stromal tumor who were unresponsive or intolerant to imatinib (Gleevec). [1,2] * The time to tumor progression (primary endpoint) was delayed in patients receiving sunitinib (Sutent) compared to patients receiving placebo (27.3 weeks vs 6.4 weeks; p < ). * Progression free survival was improved in patients receiving sunitinib (Sutent) compared to patients receiving placebo (24.1 weeks vs 6.0 weeks; p < ). * More patients receiving sunitinib (Sutent) achieved an objective response rate (6.8%) compared to patients receiving placebo (0%; p < 0.006). * Treatment crossover was allowed due to positive results of an interim analysis (103 of 118 in the placebo group crossed over); therefore, the final median overall survival data was confounded. It is uncertain whether the surrogate endpoint of time to tumor progression correlates with the more meaningful endpoint of overall survival. dru Page 3 of 11

4 The National Comprehensive Cancer Network (NCCN) guidelines list sunitinib (Sutent) as a potential second-line therapy for patients with metastatic or recurrent gastrointestinal stromal tumor after surgical resection and imatinib. [3] METASTATIC RENAL CELL CARCINOMA Sunitinib (Sutent) was compared to interferon alfa in an open-label, randomized clinical trial in 750 patients with previously untreated, metastatic renal-cell carcinoma. Patients were randomized to sunitinib (Sutent) 50 mg daily for 4 weeks, followed by 2 weeks off, or interferon-alfa 9 million units subcutaneously three times weekly. [4,5] * This trial suffered design flaws which make the results uncertain. In addition to using a surrogate endpoint (progression-free survival) as the primary endpoint of the trial, the estimation of overall survival was biased due to patient crossover to other therapies after progression had occurred. * The median duration of treatment for sunitinib (Sutent) was 11 months (range, < 1 to 41 months) in the sunitinib (Sutent) group and 4 months (range, < 1 to 40 months) in the interferon-alfa group. * The median progression-free survival was 11 months in patients receiving sunitinib (Sutent) and 5 months for patients receiving interferon alfa (hazard ratio 0.539; 95% CI: to 0.643; p < 0.001). * Median overall survival time was numerically greater in the sunitinib (Sutent) group (26.4 months; 95% CI: 23.0 to 32.9) than in the interferon-alfa group (21.8 months; 95% CI: 17.9 to 26.9), but this difference did not reach statistical significance (hazard ratio 0.821; 95% CI: to 1.001; p = 0.051). Sunitinib (Sutent) was compared to pazopanib (Votrient) in an open-label, randomized clinical trial in 1,110 patients who had not received prior systemic therapy. Patients were randomized to sunitinib (Sutent) 50 mg daily for 4 weeks, followed by 2 weeks off, or pazopanib (Votrient) 800 mg daily. * Pazopanib (Votrient) was non-inferior to sunitinib (Sutent) with respect to progression-free survival. [6] * Final results for the secondary endpoint, overall survival support the primary analysis of progression-free survival. Overall survival in the pazopanib (Votrient) group was 28.3 months compared to 29.1 months for patients treated with sunitinib (Sutent). [7] NCCN guidelines list sunitinib (Sutent) as a potential first or second-line therapy for patients with stage IV or relapsing stage I-III kidney cancer. [8] PANCREATIC NEUROENDOCRINE TUMORS - Sunitinib (Sutent) was compared to placebo in 171 patient with pathologically confirmed, well-differentiated pancreatic tumors that were advanced, metastatic, or both. Patients dru Page 4 of 11

5 were randomized to sunitinib (Sutent) 37.5 mg orally each day, or matching placebo, with a median duration of 4.6 months and 3.7 months, respectively. [9] Median progression-free survival was 11.4 months with sunitinib (Sutent) compared with 5.5 months with patients receiving placebo. The hazard ratio for progression or death was 0.42; 95%CI: 0.26 to 0.66; p < Nine deaths (10%) were reported in the sunitinib (Sutent) group and 21 deaths (25%) were reported in the placebo group (hazard ratio 0.41; 95%CI: 0.19 to 0.89; p = 0.002). At the time of analysis, the data were not mature enough to allow an estimation of median overall survival. - While preliminary data is promising, there is no high quality evidence supporting the efficacy of sunitinib (Sutent) in neuroendocrine tumors that are not pancreatic in origin. [10] - NCCN guidelines list sunitinib (Sutent) as a treatment option for both pancreatic and lung neuroendocrine tumors (category 2A). [11] OTHER CANCERS Sunitinib (Sutent) is also being studied in several other conditions; however, due to lack of positive data, or lack of data from large, high quality randomized controlled trials, these conditions are considered investigational. Sunitinib (Sutent) has not shown a clinical benefit in advanced breast cancer. * A phase III trial evaluating patients with HER-2 negative advanced breast cancer who had progressed after an anthracycline and a taxane, was stopped early due to lack of statistical evidence that sunitinib (Sutent) improved progression-free survival (primary endpoint) relative to capecitabine. [12] * A second phase III study evaluating either sunitinib (Sutent) or bevacizumab (Avastin) in combination with paclitaxel in patients with HER-2 negative advanced breast cancer who had been disease free for at least 12 months following treatment with a taxane was also stopped early because progressionfree survival was shorter in the sunitinib (Sutent) group. [13] * A third phase III study evaluating sunitinib (Sutent) plus docetaxel vs docetaxel alone as first-line therapy in HER-2 negative advanced breast cancer, improved objective response rate, but did not prolong either progression-free or overall survival. [14] Progression-free survival was not improved with the addition of sunitinib (Sutent) to a standard therapy regimen in patients with metastatic colorectal cancer. [15] Sunitinib (Sutent) failed to prolong time to progression when combined with docetaxel vs docetaxel alone in patients with metastatic gastric cancer. [16] dru Page 5 of 11

6 In a small study evaluating sunitinib (Sutent) as monotherapy in 21 patients with highgrade glioma, no patients achieved an objective response. [17] One patient achieved a partial response in a study evaluating sunitinib (Sutent) in 48 patients with non-gastrointestinal stroma tumor sarcoma. [18] Due to durable disease control in subsets of patients in this trial (e.g. those with desmoplastic round cell tumor, solitary fibrous tumor, and giant cell tumor of bone), sunitinib (Sutent) is listed as a treatment option in the NCCN guidelines for chordoma (category 2A) and angiosarcoma (category 2A). [19] Sunitinib (Sutent) failed to improve overall survival when combined with erlotinib (Tarceva) vs erlotinib (Tarceva) alone in patients with non-small cell lung cancer. [20] Current NCCN guidelines list sunitinib (Sutent) among potential treatment options for thyroid carcinoma when a clinical trial is not available; however, evidence for sunitinib (Sutent) in this condition is poor (no control group, small number of patients, subjective endpoint, case studies). [20] RegenceRx performs independent analyses of oncology medications. The RegenceRx analysis and coverage policy may differ from NCCN guidelines. Safety [21] Serious adverse events (warnings) with the use of sunitinib (Sutent) include: * Pregnancy Category D * Left ventricular dysfunction In the presence of clinical manifestations of congestive heart failure, discontinuation of sunitinib (Sutent) is recommended. In a retrospective subset analysis of patients exposed to sunitinib (Sutent) during phase I/phase II clinical trials, 11% of patients exhibited a cardiovascular adverse event, which could include cardiac death, myocardial infarction or congestive heart failure. [22] * QT Interval Prolongation and Torsade de Pointes * Hypertension Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. * Hemorrhagic events * Hypothyroidism * Adrenal toxicity Dosing [21] The recommended dose of sunitinib (Sutent) for gastrointestinal stromal tumor and renal cell carcinoma is one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off. dru Page 6 of 11

7 * A dose reduction to a minimum of 37.5 mg daily should be considered if sunitinib (Sutent) must be co-administered with a strong CYP3A4 inhibitor. * A dose increase to a maximum of 87.5 mg daily should be considered if sunitinib (Sutent) must be co-administered with a CYP3A4 inducer. The recommended dose of sunitinib (Sutent) used in the clinical trial for pancreatic neuroendocrine tumors is 37.5 mg orally per day. A dose reduction to 25 mg per day can be considered to manage adverse events. Pharmacy Support Services - The treatment of cancers with targeted oncology medications is unique and complex. The increased level of care provided by clinical pharmacists and experienced nurses may improve the chances of treatment success and lower overall treatment costs. * Oral cancer medications are often associated with troublesome side effects that may affect adherence to treatment regimens and decrease clinical success. Clinical pharmacists and nurses can provide patient education to help patients recognize and manage adverse effects. * Oral cancer medications are often discontinued because of disease progression or adverse effects. The ability of pharmacies to dispense smaller quantities of medication can reduce waste and patient out-of-pocket costs. * Clinical oncology pharmacy support services may also: o Provide patient education concerning treatment frequency and duration. o Proactively provide regular patient contact to monitor for and encourage adherence. o Notify providers when patients receive medications. o Work with prescribing physicians to identify tolerability issues which may require discontinuation of therapy. o Identify and recommend the need for additional clinical interventions (e.g. dosage adjustments due to side effects or drug-drug interactions). o Identify and assist in managing other cancer-related medical problems (e.g. control of pain or nausea). dru Page 7 of 11

8 Appendix 1: Clinical Pharmacy Support Services Necessary for Dispensing Sunitinib to RegenceRx Members Implement a cycle management program that supports split-fill dosing of self-administered oral oncology medications. These medications are considered Specialty medications and are used to treat complex medical conditions requiring the additional education and support of a healthcare professional. Provide and manage split-fills of oral oncology medications to reduce the potential for waste while ensuring therapy is not unnecessarily interrupted. A member s first fill is for a 16-day supply, followed by a 14-day supply as approved. Demonstrate the ability in systems for both tracking and billing prorated copayments/coinsurance. Instruct patients at the time of each dispensing that their therapy is to continue as instructed by their physician and that regular refills of their medication will be necessary to prevent therapy interruption. Provide urgent dispensing for members to ensure that therapy is not unnecessarily interrupted. Contact members between days 10 to 12 of each month and again on day 20 of each month to monitor patients for adverse events and adherence with the goal of improving quality of care by minimizing the impact of side effects, improving outcomes, and reducing hospital admissions. Provide a comprehensive Patient Adherence Report 20 days after the start of oral chemotherapy that details dose changes, side effects, and interventions. Coordinate communication between patients and providers regarding ongoing tolerability and adherence issues with oral chemotherapy through the use of regularly scheduled follow up telephone consultations and the use of a systematic screening tool to identify and assist patients in the management of adverse effects. Provide a dedicated team of clinical pharmacists for RegenceRx membership. Provide 24 hours per day, 7 days per week availability of clinical support staff for members. Provide documentation of current ACHC and URAC accreditation. Provide reporting to RegenceRx at least quarterly to describe the following metrics: - Number of patients enrolled in oral oncology medication cycle management program. - Adherence data on patients enrolled. Note: RegenceRx reserves the right to establish whether the above conditions have been met and may revoke pharmacy approval status at any time. dru Page 8 of 11

9 Appendix 2: Sunitinib Drug Interactions. Medications that may DECREASE sunitinib plasma concentrations (CYP 3A4 Inducers)* carbamazepine dexamethasone hypericum perforatum (st. john s wort) phenobarbital phenytoin rifabutin rifampin rifapentine Medications that may INCREASE sunitinib plasma concentrations (CYP 3A4 inhibitors)* aprepitant clarithromycin erythromycin atazanavir nefazodone ritonavir itraconazole ketoconazole voriconazole indinavir nelfinavir saquinavir telithromycin *This is not an exhaustive list. Please consult a pharmacist or appropriate references if unsure. Cross References Afinitor, everolimus, RegenceRx Medication Policy Manual, Policy No. dru178 Avastin, bevacizumab, RegenceRx Medication Policy Manual, Policy No. dru215 Gleevec, imatinib mesylate, RegenceRx Medication Policy Manual, Policy No. dru043 Inlyta, axitinib, RegenceRx Medication Policy Manual, Policy No. dru273 Nexavar, sorafenib, RegenceRx Medication Policy Manual, Policy No. dru134 Votrient, pazopanib, RegenceRx Medication Policy Manual, Policy No. dru199 dru Page 9 of 11

10 Codes Number Description HCPCS C9399 Unclassified drugs or biologicals HCPCS J8999 Prescription drug, oral, chemotherapeutic, Not Otherwise Specified. (Refer to manual for billing instructions.) ICD Malignant neoplasm of other specified sites of connective and other soft tissue ICD Malignant neoplasm of connective and other soft tissue site unspecified ICD Neoplasm of uncertain behavior of connective and other soft tissue ICD Malignant neoplasm of the kidney except pelvis ICD Malignant neoplasm of the renal pelvis ICD Malignant neoplasm of islets of langerhans ICD Secondary malignant neoplasm of the lung ICD Malignant neoplasm of the liver, secondary ICD Secondary malignant neoplasm of bone and bone marrow References 1. Demetri, GD, van Oosterom, AT, Garrett, CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. England, p Demetri, GD, Garrett, CR, Schoffski, P, et al. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. United States, p NCCN Clinical Practice Guidelines in Oncology TM. Soft Tissue Sarcoma V [cited 10/24/2014]; Available from: 4. Motzer, RJ, Hutson, TE, Tomczak, P, et al. Sunitinib versus interferon alfa in metastatic renalcell carcinoma. United States, p Motzer, RJ, Hutson, TE, Tomczak, P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. United States, p Motzer, RJ, Hutson, TE, Cella, D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. The New England journal of medicine Aug 22;369(8): PMID: Motzer, RJ, Hutson, TE, McCann, L, Deen, K, Choueiri, TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. The New England journal of medicine May 1;370(18): PMID: NCCN Clinical Practice Guideline in Oncology TM. Kidney Cancer v [cited 10/21/2014]; Available from: dru Page 10 of 11

11 9. Raymond, E, Dahan, L, Raoul, JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. The New England journal of medicine Feb 10;364(6): PMID: Strosberg, JR, Weber, JM, Choi, J, et al. A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors. England, p NCCN Clinical Practice Guidelines in Oncology TM. Neuroendocrine Tumors v [cited 10/29/14]; Available from: Barrios, CH, Liu, MC, Lee, SC, et al. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast cancer research and treatment May;121(1): PMID: Robert, NJ, Saleh, MN, Paul, D, et al. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. United States, p Bergh, J, Bondarenko, IM, Lichinitser, MR, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. United States, p Carrato, A, Swieboda-Sadlej, A, Staszewska-Skurczynska, M, et al. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. United States, p Yi, JH, Lee, J, Park, SH, et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. England, p Neyns, B, Sadones, J, Chaskis, C, et al. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. Journal of neuro-oncology Jul;103(3): PMID: George, S, Merriam, P, Maki, RG, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. United States, p NCCN Clinical Practice Guidelines in Oncology TM. Bone Cancer v [cited 10/24/2014]; Available from: NCCN Clinical Practice Guidelines in Oncology TM. Thyroid Carcinoma v [cited 10/24/2014]; Available from: Sutent [package insert]. New York, NY: Pfizer, Inc; 6/ Chu, TF, Rupnick, MA, Kerkela, R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. England, p dru Page 11 of 11