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Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for HER2 Positive Metastatic Breast Cancer
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Pertuzumab for HER2 Positive Metastatic Breast Cancer

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Pertuzumab for HER2 Positive Metastatic Breast Cancer

Pertuzumab for HER2 Positive Metastatic Breast Cancer

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  • National Comprehensive Cancer Network – breast cancer guidelines
  • Transcript

    • 1. Pertuzumab for the Treatment of HER2 Positive Metastatic Breast Cancer Rod Bugawan April 17, 2014 Lipscomb College of Pharmacy
    • 2. Objectives • Describe the mechanism of action (MoA) of pertuzumab • Recall the loading dosing, maintenance dose, and route of administration for pertuzumab • Explain why breast cancer studies should include more patients that are advanced in age • Explain the results of the CLEOPATRA trial • Recall the black box warning for pertuzumab
    • 3. Breast Cancer Background • 1 out of every 8 women in their lifetime (approx 12.3% lifetime risk) • Highest risk in age 70+ • 2nd most common type of cancer • In 2013, estimated 232,340 (14.1%) new cases and 39,620 deaths • 5 year overall survival is 89.2% • Breast cancer rates highest 55-64 years http://seer.cancer.gov/statfacts/html/breast.html
    • 4. Relative Risk > 4 • 65+ years of age • Biopsy confirmed atypical hyperplasia • Genetic mutations (BRCA1 and BRCA2) • Lobular carcinoma • Mammographically dense breast • Early onset < 40 years of age • Two or more 1st degree relatives diagnosed at an early age http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-040951.pdf
    • 5. Modifiable Factors – Increased Risk • Higher risk associated with longer use of hormone therapy, estrogen and progestin (26%) • Overweight (1.5x) and obese women (2x) • Consuming an alcoholic beverage/day (7-12%) and tobacco (12%) http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-040951.pdf
    • 6. Modifiable Factors – Decreased Risk • Estrogen use in women with a hysterectomy • Physical activity (10-20%) • Early pregnancy <35 years of age (50%) • Breast feeding (4.3% every 12 months, additional 7% for each birth) http://www.cancer.gov/cancertopics/pdq/prevention/breast/HealthProfessional#Section_366
    • 7. Symptoms • Typically no symptoms for small tumors • Swelling of all or part of the breast • Skin irritation or dimpling • Breast pain • Nipple pain or the nipple turning inward • Redness, scaliness, or thickening of the nipple or breast skin • A nipple discharge other than breast milk • A lump in the underarm area http://www.breastcancer.org/symptoms/understand_bc/symptoms
    • 8. Diagnosing • Sentinel lymph node biopsy – Use of dye in tumor to sentinel lymph • Chest X-ray • CT scan • Bone scan – To check if cancer spread to bones • PET scan – Radioactive glucose to find cancer cells in body http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page2
    • 9. Staging http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page2#Keypoint12 Stage 0 Noninvasive – Ductal carcinoma in situ (DCIS) – Lobular carcinoma in situ (LCIS) – Paget disease, nipple only Stage I Cancer formed
    • 10. Staging continued Stage II Lymph nodes Stage III Locally advanced Stage IV Metastasized – Most often to the bones, lungs, liver, or brain http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page2#Keypoint12
    • 11. 5 year Overall Survival by Stage Stage 5- year overall survival Classification 0 100% In situ I 100% Cancer formed II 93% Lymph nodes III 72% Locally advanced IV 22% Metastatic http://www.cancer.org/cancer/%20breastcancer/detailedguide/breast-cancer-survival-by-stage
    • 12. Treatment Options • Surgery • Radiation therapy • Hormone therapy for ER+, PR+ – 2 of every 3 breast cancers – Selective Estrogen Receptor Modifiers, anti-estrogens, aromatase inhibitors, GnRH • Chemotherapy – Docetaxel • Targeted therapy for HER2 positive (HER2+) – Trastuzumab, pertuzumab http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-treating-general-info
    • 13. Chemotherapy – Docetaxel • Taxane, interferes with microtubules • Pregnancy category D • CYP 3A4 inducers, inhibitors, or substrates • Blackbox warning: toxic deaths, hepatotoxicity, neutropenia, hypersensitivity reactions, and fluid retention • Adverse reactions: cardiovascular, cutaneous, gastrointestinal, hematological, hypersensitivity, hepatic, neurologic, ophthalmologic, hearing, respiratory, renal, metabolism and nutrition disorders http://products.sanofi.us/Taxotere/taxotere.html
    • 14. HER2 Positive (HER2+) MBC • Human epidermal growth factor receptor (HER2), a tyrosine kinase transmembrane receptor • Approximately 15-20% of all BC • Aggressive phenotype and poorer prognosis Baselga J et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med m 2012 (366)2
    • 15. HER2+ MBC Dimerization • Pairing of HER2:HER3 activates key pathways that regulate cell survival and growth http://www.perjeta.com/hcp/moa
    • 16. Objectives • Describe the mechanism of action (MoA) of pertuzumab • Recall the loading dosing, maintenance dose, and route of administration for pertuzumab • Explain why breast cancer studies should include more patients that are advanced in age • Explain the results of the CLEOPATRA trial • Recall the black box warning for pertuzumab
    • 17. Pertuzumab (Perjeta®) - MoA 1. Perjeta binds to subdomain II and prevents dimerization http://www.perjeta.com/hcp/moa
    • 18. Pertuzumab (Perjeta®) - MoA 2. Perjata also mediates antibody dependent cell mediated cytotoxicity (ADCC) http://www.perjeta.com/hcp/moa
    • 19. Trastuzumab (Herceptin®) - MoA 3. Trastuzumab (Herceptin®) binds to subdomain IV prevents dimerization; ADCC http://www.perjeta.com/hcp/moa
    • 20. Pertuzumab (Perjeta®) - MoA 4. Pertuzumab and trastuzumab combination provides a more comprehensive block http://www.perjeta.com/hcp/moa
    • 21. Targeted therapy – Trastuzumab (Herceptin®) • Was the first FDA approved targeted therapy for HER2+ MBC (Sept 1998) • Herceptin in combination with paclitaxel • Median overall survival: 25.1 months with Herceptin vs 20.3 months with chemotherapy alone; HR 0.8; P = 0.046 http://www.gene.com/media/product-information/herceptin-breast
    • 22. Study #1 - CLEOPATRA
    • 23. Baselga J et al. Objective • The CLinical Evaluation Of Pertuzumab And TRAstuzmab (CLEOPATRA) • Will pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) increase progression free survival compared to placebo plus trastuzumab plus docetaxel (control group) in patients with HER2+ MBC?
    • 24. Trial Design • Phase 3, multicenter, randomized, parallel, double- blind, placebo-controlled trial • Patients with HER2+ MBC, 204 sites from 25 countries – Inclusion criteria • Age 18+, HER2 positive MBC • Left Ventricular Ejection Fraction (LVEF) > 50% • Eastern Cooperative Oncology Group (ECOG) of 0 or 1 – Exclusion • > 1 Hormonal treatment, chemotherapy within 12 months of randomization • LVEF < 50% • Central Nervous Systems metastases • Cumulative doses of doxorubicin > 360mg/m² Baselga J et al.
    • 25. Trial Design Baselga J et al. • Control Arm = placebo + trastuzumab + docetaxel • Pertuzumab Arm = pertuzumab + trastuzumab + docetaxel
    • 26. Objectives • Describe the mechanism of action (MoA) of pertuzumab • Recall the loading dosing, maintenance dose, and route of administration for pertuzumab • Explain why breast cancer studies should include more patients that are advanced in age • Recall the black box warning for pertuzumab • Explain the results of the CLEOPATRA trial
    • 27. Interventions • Trastuzumab – Loading dose (LD) 8 mg/kg – Maintenance dose (MD) 6 mg/kg every 3 weeks until disease progression • Docetaxel 75 mg/m² every 3 weeks, reduce by 25% (55 mg/m²) if toxic effects; minimum at least 6 cycles of chemotherapy • Pertuzumab or Placebo – LD 840 mg – MD 420 mg every 3 weeks until disease progression or toxicities not effectively managed Baselga J et al.
    • 28. Outcomes • Primary endpoint was independently assessed progression free surival (PFS) using Response Evaluation Criteria In Solid Tumors (RECIST) • Secondary endpoints – Overall survival (OS) – Median PFS by investigator – Objective response rate (ORR) – Safety Baselga J et al.
    • 29. Assessments • Every 3 weeks – Laboratory tests – ECOG of 0 or 1 • Every 9 weeks – Independent review for tumors based on RECIST – LVEF must be > 50%, then every 6 months in the 1st year after discontinuation, then annually thereafter for up to 3 years • Adverse events continuously monitored Baselga J et al.
    • 30. Sample Size • 800 patients • Primary analysis of PFS after 381 events of disease progression or death – 80% power to detect a 33% improvement in Pertuzumab group (Hazard Ratio 0.75) at a 2-sided significance level of 5% • Interim analysis of OS at time of primary analysis • A Lan-DeMets alpha spending function with the O’Brien-Fleming stopping boundary was applied to interim analysis Baselga J et al.
    • 31. Randomization and Blinding • Interactive Voice Response System (IVRS) will be utilized to collect patient screening information and to randomize eligible patients in a 1:1 ratio to one of two treatment arms • Block randomization was applied to achieve balanced treatment assignment with each strata (prior treatment status and region) Baselga J et al.
    • 32. Statistical Methods • Based on Intent-to-Treat (ITT) population • Primary endpoint of PFS based on Independent Review Facility (IRF) – Log-rank test – Kaplan-Meier approach • Secondary Outcomes – Overall survival (OS) – Median PFS by investigator – Objective response rate (ORR) by Mantel-Haenszel test – Safety Baselga J et al.
    • 33. Primary Endpoint Median PFS by IRF – 406 patients randomized to placebo – 402 pertuzumab arm • Prolonged median PFS by 6.1 months • From 12.4 months in control group to 18.5 months to pertuzumab group – HR 0.62, 95% CI 0.51-0.75; P < 0.001 Baselga J et al.
    • 34. Progression Free Surival Baselga J et al.
    • 35. Secondary Endpoints Fixed sequence testing hierarchy: PFS > OS > ORR – Median PFS by investigator • Prolonged 6.1 months • From 12.4 months in control group to 18.5 months in pertuzumab group • HR 0.65, 95% CI 0.54 to 0.78; P < 0.001 – Interim analysis of OS after 165 events (43% of prespecified total number for final analysis) • Deaths in control group 96 (23.6%) • Deaths in pertuzumab group 69 (17.2%) • HR 0.64 (95% CI, 0.47 to 0.88; P = 0.005) • Not significant because did not meet O’Brien-Fleming stopping boundary (HR < 0.603; P < 0.0012) Baselga J et al.
    • 36. Secondary Endpoints Fixed sequence testing hierarchy: PFS by IRF > OS > ORR – Objective response rate (ORR) • Control group 69.3% • Pertuzumab group 80.2% • 95% CI, 4.2 to 17.5; P = 0.001 Baselga J et al.
    • 37. Side Effects • Pertuzumab group – AEs incidence of any grade of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported at least 5% points – Incidence of grade 3 or higher febrile neutropenia and diarrhea by at least 2% points • Placebo group – Increased left ventricular systolic dysfunction (9.3% vs 4.4%) – Decrease in LVEF of < 50% (6.6% control vs 3.8%) • Death due to disease progression 81 (20.4%) control, 57 (14.0%) pertuzumab • Infection were most common cause of death due to AE and were similar in both groups Baselga J et al.
    • 38. Baselga J et al.
    • 39. CLEOPATRA – Baseline Characteristics Baselga J et al. Median age 54 Whites, Asians ECOG = 0
    • 40. CLEOPATRA – Baseline Characteristics Baselga J et al. Visceral Disease HER2 positive
    • 41. CLEOPATRA – Baseline Characteristics Baselga J et al. Prior chemo ~ no prior chemo
    • 42. Results • First line treatment of HER2+ MBC with pertuzumab and trastuzumab with docetaxel prolonged PFS by 6.1 months • There is a strong trend toward OS but results are exploratory since it did not cross O’Brien- Flemming stopping boundary • There was an increase of AEs when using the combination pertuzumab therapy but no increase in the rates of cardiac dysfunction
    • 43. Study #2 – Subgroup Analyses
    • 44. Subgroup Analyses – Objective • Is the treatment pertuzumab plus trastuzumab plus docetaxel in patients with HER2+ MBC limited by age? • Reporting the efficacy and safety of pertuzumab in older patients age > 65 compared to patients < 65 years of age Miles D et al.
    • 45. Objectives • Describe the mechanism of action (MoA) of pertuzumab • Recall the loading dosing, maintenance dose, and route of administration for pertuzumab • Explain why breast cancer studies should include more patients that are advanced in age • Recall the black box warning for pertuzumab • Explain the results of the CLEOPATRA trial
    • 46. • Incidence of cancer increases with age and older patients are under-represented in trials – In the US women age 65+, estimated proportion with breast cancer is 49% – Representing only 9% in trials • Increased complexity in older patients – More comorbidities and related medications Hutchins LF et al: Underrepresntation of patients 65 years of age or oler in cancer treatment trials. N Engl J Med 1999 (341) 2061-2067 Miles D et al: Treatment of older patients with HER2-positive metastaic breast cancer with pertuzumab, trastuzumab, and docetaxel: subgroup analyses from CLEOPATRA . Breast Cancer Res Treatment 2013 (142) 89-99 Background
    • 47. Methods • Subgroup analysis, CLEOPATRA protocol – Primary endpoint = PFS by IRF – Secondary endpoint • OS • PFS by investigator • ORR • Safety – Study methods – Inclusion/exclusion – Statistical Analysis Miles D et al.
    • 48. Intent to Treat Population < 65 age 681 (84%) > 65 age 127 (16%) Miles D et al
    • 49. Baseline Characteristics Miles D et al
    • 50. Miles D et al
    • 51. Primary Endpoint Primary endpoint • Independently assessed median PFS by age group < 65 years 12.5 months in placebo arm 17.2 months pertuzumab arm (HR: 0.65, 95% CI 0.53-0.80) > 65 years 10.4 months in placebo arm 21.6 months pertuzumab arm (HR: 0.52, 95% CI 0.31-0.86) • Whole ITT population of median PFS of 12.4 months for placebo arm vs 18.5 months in trastuzumab arm (HR: 0.62; 95% CI 0.51-0.75; P < 0.001) Miles D et al
    • 52. Progession Free Surival Miles D et al
    • 53. Secondary Endpoint ORR favored pertuzumab arm Difference between control arm and treatment arm: 10.8% in the ITT population 11.5% in patients < 65 years of age 8.1% in patients > 65 years of age Miles D et al
    • 54. Results • Age > 65 reported more frequently diarrhea, fatigue, asthenia, decreased appetite, vomiting dysgeusia. – Pertuzumab arm reported higher incidence of grade > 3 diarrhea, therefore monitor • Age < 65 reported more leukopenia, neutropenia grade > 3, and febrile neutropenia • No statistically significant association LVSD – Univariate Cox regression analysis for LVSD of > 65 vs < 65; HR: 1.25; 95% CI 0.61-2.56; P = 0.5502 – However monitor cardiac function because the elderly are already at risk for congestive heart failure Miles D et al
    • 55. Objectives • Describe the mechanism of action (MoA) of pertuzumab • Recall the loading dosing, maintenance dose, and route of administration for pertuzumab • Explain why breast cancer studies should include more patients that are advanced in age • Explain the results of the CLEOPATRA trial • Recall the black box warning for pertuzumab
    • 56. Summary of Results Patients with HER2+ MBC treat with pertuzumab, trastuzumab and docetaxel • Statistically significant PFS in the ITT population, increased median PFS by 6.1 months Age > 65, increased median PFS by 11.2 months Age < 65, increased median PFS by 4.7 months • Increase AEs, but no increase in cardiac dysfunction • Elderly treatment: consider life expectancy, co- morbidities, monitoring cardiac function
    • 57. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 1st line treatment for HER2+ MBC
    • 58. Objectives • Describe the mechanism of action (MoA) of pertuzumab • Recall the loading dosing, maintenance dose, and route of administration for pertuzumab • Explain why breast cancer studies should include more patients that are advanced in age • Explain the results of the CLEOPATRA trial • Recall the black box warning for pertuzumab
    • 59. Pertuzumab (Perjeta®) • Dosage – Initial dose 840 mg as a 60 minute intravenous (IV) infusion, followed every 3 weeks by a dose of 420 mg administered as an IV over 30 to 60 minutes – With Perjeta, initial dose of trastuzumab 8 mg/kg administered, 90 minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV infusion over 30 to 90 minutes – Administer sequentially with docetaxel administered last • BBW – Cardiomyopathy and embryo-fetal toxicity, – Pregnancy category D • AEs – Left ventricular dysfunction, infusion related reactions, hypersensitivity reactions/anaphylaxis • Storage – refrigerate, do not freeze, do not shake • Patient counseling – advise females of reproductive potential to use effective contraception http://www.gene.com/download/pdf/perjeta_prescribing.pdf
    • 60. Discussion Limitations – OS is still exploratory because it is a new drug and the required number of deaths have yet to be reached – HER2 positive nonmetastatic breast cancer – Elderly > 75 years of age – Approximate cost of drug treatments/month Over $15,000 (pertuzumab $9800 + trastuzumab $4500) http://www.medscape.com/viewarticle/780107
    • 61. Role of the Pharmacist • Encourage BC screening • Encourage elderly with MBC to participate in trials • Manage chemotherapy side effects • Recommend treatment options, dosing regimens, particularly chemotherapy and targeted therapies
    • 62. Other HER2+ BC Trials with Pertuzumab • NEOSPHERE – Treatment naive, improved pathological complete response rate • TRYPHANENA – Confirmed Pertuzumab as neoadjuvant treatment Ongoing trials • PHEREXA – Disease progressed during/following trastuzumab • MARIANNE –Trastuzumab-emtansine • APHINITY – Non-metastatic BC Hubalek et al. Role of pertuzumab in the treatment of HER2-postive breast cancer. Breast Cancer: Targets and Thearpy 2012 (4) 65-73
    • 63. CLEOPATRA – Information • ClinTrials.gov Identifier NCT00567190 • Protocol WO20698 • Hoffman-La Roche http://www.roche-trials.com/studyResultGet.action?studyResultNumber=WO20698

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