Practice Guideline: Systemic Therapy Summary First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab (BREAST Trastuzumab) Breast Disease Site Group Effective: May 2009 Updated: November 2015
Systemic Therapy Summary 2 ACKNOWLEDGEMENT AND SPONSORSHIP DISCLAIMERS There are no relevant conflicts of interest to disclose. CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 2
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 Medical Director/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 Breast Disease Site Group (DSG), May 2009. 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 trastuzumab in the first-line treatment of human epidermal growth factor receptor 2 (HER2)/neu positive metastatic breast cancer. 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 Program Network (CCPN) sites and WRHA Community Oncology Program sites. Disclaimer Use of this document should not preclude use of 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 HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 3
Systemic Therapy Summary 4 First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab Protocol Code: BREAST Trastuzumab Developed by: Breast Disease Site Group Date of Presentation to P&T Subcommittee: May 19, 2009 Treatment Recommendation The Breast DSG recommends the use of trastuzumab as a single-agent or in combination therapy as a first-line treatment in the management of HER2/neu positive metastatic breast cancer patients who meet the inclusion criteria (see below). Treatment Intent Non-curative Prolongation of progression-free survival (PFS) and overall survival (OS) Rationale In HER2 overexpressing metastatic breast cancer, it is standard practice to offer first-line treatment with a combination regimen of trastuzumab plus a taxane chemotherapeutic. This is based on the publication of two large randomized controlled trials in the first-line setting (one phase III and one phase II) that documented the superior efficacy of trastuzumab plus taxane chemotherapy compared to taxane alone, in terms of OS, response rate, response duration, time to progression and minimal toxicity. 1,2 In the pivotal phase III trial, 72% of the patients initially randomized to chemotherapy alone subsequently received trastuzumab at the time of disease progression. 1 Despite this crossover, patients receiving upfront trastuzumab plus chemotherapy had longer OS rates suggesting that front-line treatment should include a taxane plus trastuzumab. Further, several phase II studies have confirmed the safety and efficacy of trastuzumab combined with vinorelbine, permitting this combination to be considered as a treatment option if there are contraindications to taxanes or taxane intolerance/resistance. Single-agent trastuzumab is an active drug with tumour response rates of greater than 30% and may be selected for patients with poor performance status or of advanced age who may not be able to tolerate the toxicities of chemotherapy. 3 CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 4
Systemic Therapy Summary 5 Clinical Benefit (Level Ib Evidence see Appendix I) The efficacy and safety of trastuzumab in the treatment of HER2 positive patients with metastatic breast cancer was evaluated in a phase III randomized controlled trial. 1 This trial compared standard chemotherapy alone versus standard chemotherapy plus trastuzumab. 1 Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in a select group of patients) and cyclophosphamide with or without trastuzumab. Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone or paclitaxel with trastuzumab. The trastuzumab and chemotherapy group had a longer time to disease progression (median, 7.4 versus 4.6 months; p < 0.001), a higher rate of objective response (50% versus 32%; p < 0.001), a longer duration of response (median, 9.1 versus 6.1 months; p < 0.001), a lower rate of death at 1 year (22% versus 33%; p = 0.008), longer survival (median survival, 25.1 versus 20.3 months; p = 0.046) and a 20% reduction in the risk of death. Patient Population and Selection Criteria Inclusion criteria Histologically confirmed metastatic breast cancer; AND HER2 positive overexpression (defined as a 3+ score on immunohistochemistry or 2+ score and a positive fluorescence in situ hybridization [FISH] test); AND An Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2; AND Normal left ventricular ejection fraction (LVEF) (i.e., greater than or equal to 50%) CCMB Formulary Status 1. Formulary definition Restricted 2. Adjudication process Complete Restricted Drug Form BREAST DSG (J:\Pharmacy\FORMS), and provide the supporting documentation: o o Documentation required for initial request: Proof of HER2 overexpression; baseline LVEF (i.e., multiple-gated acquisition (MUGA) scan or echocardiogram (ECHO) report) Documentation required for renewal requests: Most recent imaging tests documenting treatment response or stable disease; most recent LVEF (i.e., MUGA or ECHO report) Approval granted by: Breast DSG Chair or Designate CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 5
Systemic Therapy Summary 6 Implementation and Safety Considerations Treatment Regimen BREAST Trastuzumab* Treatment can be administered on a q3 weekly or q weekly schedule depending on patient tolerability and physician discretion (until disease progression, unacceptable toxicity or withdrawal of consent). Drug Dose CCMB Administration Guideline Trastuzumab q3 weekly schedule: 8 mg/kg loading dose, followed by 6 mg/kg maintenance doses q weekly schedule: 4 mg/kg loading dose, followed by 2 mg/kg maintenance doses Doses administered in 250 ml NaCl 0.9% Loading dose administered over 90 min; if well tolerated, maintenance doses can be administered over 30 min Observation period of 60 min post-infusion for loading dose, then 30 min post-infusion for maintenance doses. If there is no reaction for 3 consecutive maintenance treatments, observation is not required for further doses *If combined with chemotherapy, trastuzumab should be used preferentially with a taxane (docetaxel or paclitaxel), but may be combined with vinorelbine if the patient has a taxane contraindication, is unable to tolerate taxanes or has taxane-resistant disease. CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 6
Systemic Therapy Summary 7 Clinical Monitoring and Follow-Up Recommendations Assessment of treatment response Treatment with trastuzumab can be continued until disease progression or unacceptable toxicity Treatment with trastuzumab should be discontinued if there is systematic disease progression while on treatment Patients with progression or new metastases in the central nervous system (CNS) only can consider trastuzumab continuation if performance status ECOG less than or equal to 2 and CNS metastases controlled by local therapy Common or Clinically Important Adverse Events* 5-7 (Refer to individual drug monographs for full details of adverse events) Infusion-related reactions During the first infusion of trastuzumab, chills and/or fever are a common occurrence (up to 40% of patients). Other infusion reactions include nausea, vomiting, pain, rigors, headache, cough, dizziness, rash, asthenia and hypertension. These symptoms are usually mild-moderate and do not occur frequently with subsequent infusions. Other adverse effects Incidence 5-10%: arthralgia, fatigue, nasopharyngitis, diarrhea, back pain, peripheral edema. *See Appendix III CTCAE v.4.0 CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 7
Systemic Therapy Summary 8 Precautions 5-7 Cardiotoxicity Treatment with trastuzumab can result in the development of congestive heart failure and ventricular dysfunction. In patients receiving trastuzumab in the metastatic setting, the incidence and severity of cardiac dysfunction is particularly high in those who receive trastuzumab along with anthracyclines and cyclophosphamide. LVEF should be evaluated in all patients prior to and during treatment with trastuzumab. Infusion reactions; pulmonary toxicity Serious infusion reactions and pulmonary toxicity can occur with trastuzumab administration. Fatal infusion reactions have been reported. In most cases, symptoms occurred during the infusion or within 24 hours thereafter. If a patient experiences dyspnea or clinically significant hypotension during trastuzumab infusion, the infusion should be interrupted. The patient should be monitored until complete resolution of signs and symptoms. Trastuzumab should be discontinued in patients who experience infusion-related anaphylaxis, angioedema, interstitial pneumonitis or acute respiratory distress syndrome. Pulmonary events have been reported to occur within 24 hours of treatment initiation, and beyond 30 days after the start of treatment. Embryo-fetal toxicity Exposure to trastuzumab during pregnancy can lead to impaired renal growth in the fetus and/or impaired renal function. CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 8
Systemic Therapy Summary 9 Dose Modifications ( adapted from Herceptin product monograph and the Canadian Consensus Guidelines) 5,8 No reductions in the dose of trastuzumab were made during the clinical trials; however, doses were held for decreases in LVEF see table below. Recommendations for Continuation or Withdrawal of Trastuzumab Therapy in Asymptomatic Patients Based on Serial Measurements of LVEF a Relationship of LVEF to LLN Asymptomatic Decrease in LVEF from Baseline Less than or equal to 10 percentage points 10-15 percentage points Greater than or equal to 15 percentage points Within radiology facility s normal limits Continue trastuzumab Continue trastuzumab Hold trastuzumab and repeat MUGA or ECHO after 4 weeks 1-5 percentage points Hold trastuzumab and below LLN Continue trastuzumab b repeat MUGA or ECHO after 4 weeks b,c Hold trastuzumab and repeat MUGA or ECHO after 4 weeks c,d Greater than or equal to 6 percentage points below LLN Hold trastuzumab and repeat MUGA or ECHO after 4 weeks d Hold trastuzumab and repeat MUGA or ECHO after 4 weeks c,d Hold trastuzumab and repeat MUGA or ECHO after 4 weeks c,d a Based on NSABP B-31 trial protocol. Modified to include recommendations for cardiology consultation or treatment of cardiac dysfunction (or both) when appropriate, as indicated in the subsequent footnotes b Consider cardiac assessment and initiation of angiotensin converting-enzyme inhibitor therapy c After two holds, consider permanent discontinuation of trastuzumab d Initiate angiotensin converting-enzyme inhibitor therapy and refer to cardiologist Abbreviations: LLN, lower limit of normal; MUGA, multiple-gated acquisition scan; ECHO, echocardiography Drug Interactions Strong evidence for clinically significant interactions with concomitant medications used in clinical studies has not been observed. 5 CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 9
Systemic Therapy Summary 10 References 1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11):783-92. 2. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005;23(19):4265-74. 3. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20(3):719-26. 4. Bontenbal M, Seynaeve C, Stouthard J, et al. Randomized study comparing efficacy/toxicity of monotherapy trastuzumab followed by monotherapy docetaxel at progression, and combination trastuzumab/docetaxel as first-line chemotherapy in HER2-neu positive, metastatic breast cancer (MBC)(HERTAX study). J Clin Oncol 2008;26(15S):1014. 5. Hoffmann-La Roche Ltd. Drug monograph: Trastuzumab. Updated April 2015. http://www.rochecanada.com [Accessed 20 April 2015]. 6. British Columbia Cancer Agency. Drug Monograph: Trastuzumab. Updated October 2014. http://www.bccancer.bc.ca [Accessed 02 November 2014]. 7. CancerCare Ontario. Drug Monograph: Trastuzumab. Updated July 2014. http://www.cancercare.on.ca [Accessed 02 November 2014]. 8. Mackey JR, Clemons M, Côté MA, et al. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol 2008;15(1):24-35. CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 10
Systemic Therapy Summary 11 CCMB Contributors Mrs. Lindsay Livingston, BSc (Pharm), Breast Disease Site Group Mrs. Danica Lister, BSc (Pharm) Mrs. Kristi Hofer, BSc (Pharm), Senior Pharmacist, Operations Contact Physician Dr. Debjani Grenier, Medical Oncologist, Breast Disease Site Group Approved By Dr. Ralph PW Wong, Medical Oncologist Chair, WRHA/CCMB Oncology Pharmacotherapeutic Subcommittee Dr. Vallerie Gordon, Medical Oncologist Medical Director 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 HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 11
Systemic Therapy Summary 12 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 2007 http://www.bcshguidelines.com CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 12
Systemic Therapy Summary 13 Appendix II ECOG Performance Status Scale 0 Fully active, able to carry on all pre-disease activities without restriction (Karnofsky 90-100) 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 5:649-655, 1982. Eastern Cooperative Oncology Group Robert Comis M.D., Group Chair CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 13
Systemic Therapy Summary 14 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: http://ctep.cancer.gov Accessed 10 September 2010 CCMB, STS: First-Line Treatment of HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 14
Systemic Therapy Summary 15 CancerCare Manitoba 675 McDermot Avenue Winnipeg, Manitoba, Canada R3E 0V9 www.cancercare.mb.ca CCMB STS: BREAST Trastuzumab Effective: May 2009 Updated: November 2015 CancerCare Manitoba, May 2009. 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 HER2/neu Positive Metastatic Breast Cancer with Trastuzumab p. 15