First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus

Transcription

1 Practice Guideline: Systemic Therapy Summary First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus (GENU Temsirolimus) Genitourinary Disease Site Group Effective: January 2009 Updated: May 2015

2 Systemic Therapy Summary 2 ACKNOWLEDGEMENT AND SPONSORSHIP DISCLAIMERS There are no relevant conflicts of interest to disclose. CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 2

3 Systemic Therapy Summary 3 Preface This document has been prepared by the Winnipeg Regional Health Authority/CancerCare Manitoba (WRHA/CCMB) Oncology Pharmacotherapeutic (P&T) Subcommittee s Systemic Therapy Summaries Working Group, as a means of disseminating drug information and formulary decisions made by the Subcommittee. The CCMB Provincial Pharmacy Program, Provincial Oncology Drug Program (PODP) and Clinical Practice Guidelines Initiative (CPGI) have contributed to the development of this summary. Systemic Therapy Summaries (STS) are being developed for drugs/or indications where the P&T Subcommittee, based on scientific data, has accepted clinical benefit. The P&T Subcommittee Chair and the CPGI Lead/Advisory Panel Chair approve all STS documents. The content of this STS was in large part adapted from the Formulary Addition Request submitted to the P&T Subcommittee by the CCMB Genitourinary (GENU) Disease Site Group (DSG), January This document will be reviewed, and updated as necessary, once in every twelve-month period; unless emerging evidence from scientific research dictates otherwise. Purpose This document is intended as a guide to facilitate the safe and effective clinical use of temsirolimus in the first-line treatment of advanced renal cell carcinoma. For this purpose, it may be used by qualified and licensed healthcare practitioners involved with the care of oncology patients, which may include (but is not limited to): physicians, nurses, and pharmacists at CancerCare Manitoba, Community Cancer Programs Network (CCPN) sites and WRHA Community Oncology Program sites. Disclaimer Use of this document should not preclude the practitioner s independent clinical judgment, nor should it replace consultation with the oncologist. It is the responsibility of the practitioner to develop an individualized treatment plan for each patient under his/her care, and ideally this should take place within the context of a multidisciplinary team. The unique needs and preferences of the patient and the family should always be reflected in the plan of care. This document is not a comprehensive drug monograph. Practitioners must refer to other sources for complete drug information. CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 3

4 Systemic Therapy Summary 4 First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus Protocol Code: GENU Temsirolimus Developed by: Genitourinary Disease Site Group Date of Presentation to P&T Subcommittee: January 20, 2009 Treatment Recommendation The Genitourinary DSG recommends temsirolimus as an option for the first-line treatment of advanced renal cell carcinoma for patients who meet the inclusion criteria (see below). Treatment Intent Non-curative Prolongation of overall survival (OS) and progression-free survival (PFS) Rationale Most cases of metastatic renal cell carcinoma cannot be cured. Standard first-line oral tyrosine kinase inhibitors have not been specifically tested in patients with extensive tumour burden and adverse prognostic factors. Temsirolimus, a mammalian target of rapamycin (mtor) inhibitor, has demonstrated a survival advantage in this high-risk patient population. Clinical Benefit (Level Ib Evidence see Appendix I) Support for the use of temsirolimus in newly diagnosed advanced renal cell carcinoma comes from the phase III Global Advanced Renal Cell Carcinoma (ARCC) trial. 1 The trial compared three treatment arms in a patient population with poor disease prognosis (n= 626): temsirolimus alone, temsirolimus and IF-α, and IF-α alone. Eligibility criteria were restricted to patients with at least three of the following six predictors of short survival: a corrected serum calcium level > 2.5 mmol/l; a time from initial diagnosis to randomization < 1 year; a Karnofsky performance status score of 60 or 70; metastases in multiple organs; a serum lactate dehydrogenase (LDH) level of more than 1.5 times the upper limit of the normal (ULN) range; a hemoglobin level below the lower limit of the normal (LLN) range. The primary endpoint of the study was OS. Patients who received temsirolimus alone had a longer median OS than IF-α alone (10.9 months versus 7.3 months; hazard ratio [HR] for death, 0.73; 95% confidence interval [CI] 0.58 to 0.92; p = 0.008). PFS was also longer in the temsirolimus alone arm (p < 0.001). The study results demonstrated that the combination of temsirolimus and IF-α did not improve survival. CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 4

5 Systemic Therapy Summary 5 Patient Population and Selection Criteria Inclusion criteria Advanced or metastatic renal cell carcinoma (both clear cell and non-clear cell histology) with poor prognosis defined as having at least 3 of the following 6 criteria: An Eastern Cooperative Oncology Group (ECOG) performance status score of 2 (see Appendix II) A serum LDH greater than 1.5 x upper limit of normal (ULN) range A corrected serum calcium level above the ULN range (greater than 2.6 mmol/l) A time from initial diagnosis of renal-cell carcinoma to treatment of less than 1 year Metastases in multiple organs A hemoglobin level below the lower limit of normal (LLN) range Exclusion criteria Major surgery within the last 4 weeks; OR Active brain metastases; OR A fasting cholesterol level greater than 9.1 mmol/l; OR A fasting triglyceride level greater than 4.5 mmol/l; OR An ECOG performance status greater than or equal 3 CCMB Formulary Status 1. Formulary definition Restricted* *Approved and funded by CCMB, provided that criteria for use are met and request is adjudicated by DSG chair or Designate. 2. Adjudication process Complete Restricted Drug Form GU DSG (J:\Pharmacy\FORMS) Approval granted by: Genitourinary DSG Chair or Designate 3. Restrictions Prescribing of temsirolimus is restricted to the Genitourinary DSG (exclusively oncologists at the St. Boniface and MacCharles sites). CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 5

6 Systemic Therapy Summary 6 Implementation and Safety Considerations Notify physician before administering full doses of chemotherapy if platelets less than 100 x 10 9 /L or absolute neutrophil count (ANC) less than 1.5 x 10 9 /L Establish IV of NaCl 0.9% 500 ml for medication administration and any hypersensitivity reaction Administer within 6 hours of mixing Treatment Regimen GENU Temsirolimus 1 cycle = 4 weeks (planned treatment 6 cycles) Drug Dose CCMB Administrative Guideline Temsirolimus 25 mg once weekly IV in 250mL normal saline (NS) (non-pvc bag) over 30 to 60 minutes Use non-pvc tubing with in-line filter Pre-Medication and Supportive Care Drug Dose CCMB Administrative Guideline Diphenhydramine 50 mg once weekly, pre-chemotherapy IV in 50 ml NS over 15 minutes, administered 30 minutes prior to start of each temsirolimus infusion CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 6

7 Systemic Therapy Summary 7 Clinical Monitoring and Follow-Up Recommendations Hematology, chemistry and required tests At baseline and prior to each 4 week cycle: o Complete blood count (CBC) with differential, electrolytes, creatinine, blood urea nitrogen (BUN), serum glucose, phosphorous, AST, lactate dehydrogenase (LDH), total bilirubin, alkaline phosphatase, fasting total cholesterol and triglycerides Before each dose: o CBC with differential Clinical toxicity assessment (see Appendix III) Prior to each cycle: assess patient for signs and symptoms of hyperglycemia, bleeding, fluid retention, skin toxicity, infections, nausea and vomiting, mucositis, diarrhea Assessment of treatment response Clinical follow-up with diagnostic imaging every 2 months. Treatment should continue until the patient is no longer benefiting clinically from therapy or unacceptable toxicity occurs CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 7

8 Systemic Therapy Summary 8 Common or Clinically Important Adverse Events* 2-4 (Refer to individual drug monographs for full details of adverse events) Hyperglycemia Hyperglycemia was reported on at least one occasion in over 82% of patients receiving temsirolimus. Approximately 16% of patients reported on one occasion a serum glucose level greater than 13.9mmol/L Hyperglycemia may necessitate dose modification and treatment with insulin Hyperlipidemia Hypercholesterolemia and/or hypertriglyceridemia (total cholesterol greater than mmol/l and/or triglycerides greater than 5 x ULN) were present in approximately 45% of patients Hematological toxicity Grade 3 or 4 anemia was reported in 20% of patients receiving temsirolimus weekly. Grade 3 or 4 leukopenia, neutropenia and thrombocytopenia occurred in 1%, 5% and 1% of patients, respectively Bleeding Bleeding events were observed in 25% of patients who received temsirolimus. The most common bleeding event was epistaxis (12% of patients). Most bleeding events were Grade 1 or 2 (3% were Grade 3 or 4) Other adverse effects Edema/peripheral (28%, severe 3%) Hematuria (31%, severe 1%) Proteinuria (36%, severe < 1%) *See Appendix III CTCAE v.4.0 CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 8

9 Systemic Therapy Summary 9 Precautions 2-4 Respiratory Cases of interstitial lung disease have occurred in patients who received temsirolimus. Patients should be followed closely for clinical respiratory symptoms. Caution is advised for the use of this drug in patients with significant lung dysfunction. Hypersensitivity reactions Hypersensitivity reactions, including anaphylactic reactions, have occurred with the administration of temsirolimus. Most reactions have occurred with initial dosing. Infections Temsirolimus may be immunosuppressive. Patients should be observed for signs and symptoms of infection. CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 9

10 Systemic Therapy Summary 10 Dose Modifications 2-4 Hepatic dysfunction Temsirolimus is mainly metabolized and excreted through the liver. Caution should be exercised and dose modifications considered in patients with moderate to severe hepatic impairment. Renal dysfunction A very small percentage of temsirolimus and its metabolites are excreted by the kidney. No data exist for temsirolimus in patients with moderate to severe kidney failure. Hematological toxicity Day 1 Blood Counts ANC greater than or equal to 1.0 x 10 9 /L and Platelets greater than or equal to 75 x 10 9 /L Dose 100% ANC less than 1.0 x 10 9 /L or Platelets less than 75 x 10 9 /L Hold until ANC greater than or equal to 1.0 x 10 9 /L and Platelets greater than or equal to 75 x 10 9 /L Reduce by 5 mg/week Non- Hematological toxicity Grade Dose Adjustments % Intolerable Grade 2 Reduce by 5 mg/week Hold until recovered to grade 2 or lower 3 or 4 and reduce by 5 mg/week CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 10

11 Systemic Therapy Summary 11 Drug Interactions 3,4 Drug-drug interactions Cytochrome P450 34A temsirolimus is metabolized primarily by cytochrome P450 3A4. Potential drug interactions with inducers or inhibitors must be considered. CYP 3A4 inducers inducers may decrease exposure of temsirolimus and its metabolite, sirolimus. CYP 3A4 inhibitors inhibitors may increase blood concentrations of temsirolimus and sirolimus. Sunitinib, gemcitabine or fluoruracil temsirolimus in combination with sunitinib, gemcitabine or fluoruracil has been associated with serious adverse drug reactions. Fatal events have been seen when temsirolimus was combined with fluoruracil. CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 11

12 Systemic Therapy Summary 12 References 1. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007:356(22): Pfizer Canada Inc. Pr Torisel TM (Temsirolimus) product monograph. Updated January [Accessed 16 April 2015]. 3. British Columbia Cancer Agency. BCCA Protocol Summary for Therapy for Advanced Renal Cancer Using Temsirolimus. Updated August [Accessed 16 April 2015]. 4. CancerCare Ontario. CCO Regimen Code: Temsirolimus and CCO Drug Monograph for Temirolimus. Updated June [Accessed 16 April 2015]. CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 12

13 Systemic Therapy Summary 13 CCMB Contributors Dr. Piotr Czaykowski, Medical Oncologist, Genitourinary Systemic Therapy Lead (2015) Dr. Piotr Czaykowski, Medical Oncologist, Genitourinary Systemic Therapy Group Mr. Marc Geirnaert, BSc (Pharm), Genitourinary Systemic Therapy Group Ms. Kimberly Watkinson, BSc (Pharm), Provincial Oncology Drug Program Ms. Kristi Hofer, BSc (Pharm), Community Cancer Programs Network Contact Physician Dr. Piotr Czaykowski, Medical Oncologist, Genitourinary Systemic Therapy Group Approved By Dr. Ralph PW Wong, Medical Oncologist Chair, WRHA/CCMB Oncology Pharmacotherapeutic Subcommittee Dr. Vallerie Gordon, Medical Oncologist Lead and Advisory Panel Chair, CCMB Clinical Practice Guidelines Initiative We gratefully acknowledge the support of CancerCare Manitoba, the CancerCare Manitoba Foundation and the Provincial Oncology Clinical Practice Guidelines Initiative CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 13

14 Systemic Therapy Summary 14 Appendix I Levels of Evidence Ia Evidence obtained from meta-analysis of randomised controlled trials Ib Evidence obtained from at least one randomised controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomisation IIb Evidence obtained from at least one other type of well-designed, quasi- experimental study III Evidence obtained from well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities British Committee for Standards in Haematology CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 14

15 Systemic Therapy Summary 15 Appendix II ECOG Performance Status Scale 0 Fully active, able to carry on all pre-disease activities without restriction (Karnofsky ) 1 Restricted in physical strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework or office work (Karnofsky 70-80) 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about greater than or equal to 50% of waking hours (Karnofsky 50-60) 3 Capable of only limited self-care, confined to bed or chair greater than or equal to 50% of waking hours (Karnofsky 30-40) 4 Completely disabled, cannot carry on any self-care, totally confined to bed or chair (Karnofsky 10-20) Oken MM, Creech RH, et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5: , Eastern Cooperative Oncology Group Robert Comis M.D., Group Chair CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 15

16 Systemic Therapy Summary 16 Appendix III Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Publish Date: 18 May 2009 Grades Grade refers to the severity of the AE. The CTCAE displays grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. A semi-colon indicates or within the description of the grade. A single dash (-) indicates a grade is not available. Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for grade selection. Grade 5: Grade 5 (Death) is not appropriate for some AEs and therefore is not an option Activities of Daily Living (ADL): * Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. ** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. CTCAE document available at: Accessed 10 September 2010 CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 16

17 Systemic Therapy Summary 17 CancerCare Manitoba 675 McDermot Avenue Winnipeg, Manitoba, Canada R3E 0V9 CCMB STS: GENU Temsirolimus January 2009 Effective: January 2009 Updated: May 2015 CancerCare Manitoba, January All rights reserved. This material may be freely reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organization, or for commercial purposes is allowed without written permission of CancerCare Manitoba. CCMB, STS: First-Line Treatment of Advanced Renal Cell Carcinoma with Temsirolimus p. 17