Pertuzumab for HER2 Positive Metastatic Breast Cancer
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Transcript of Pertuzumab for HER2 Positive Metastatic Breast Cancer
Pertuzumab for the Treatment of HER2 Positive Metastatic Breast Cancer
Rod BugawanApril 17, 2014
Lipscomb College of Pharmacy
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
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
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
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
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
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
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
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
Staging continued
Stage II Lymph nodesStage III Locally advancedStage IV Metastasized– Most often to the bones,
lungs, liver, or brain
http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page2#Keypoint12
5 year Overall Survival by Stage
Stage 5- year overall survival
Classification
0 100% In situI 100% Cancer formedII 93% Lymph nodesIII 72% Locally
advancedIV 22% Metastatic
http://www.cancer.org/cancer/%20breastcancer/detailedguide/breast-cancer-survival-by-stage
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
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
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
HER2+ MBC Dimerization
• Pairing of HER2:HER3 activates key pathways that regulate cell survival and growth
http://www.perjeta.com/hcp/moa
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
Pertuzumab (Perjeta®) - MoA
1. Perjeta binds to subdomain II and prevents dimerization
http://www.perjeta.com/hcp/moa
Pertuzumab (Perjeta®) - MoA
2. Perjata also mediates antibody dependent cell mediated cytotoxicity (ADCC)
http://www.perjeta.com/hcp/moa
Trastuzumab (Herceptin®) - MoA
3. Trastuzumab (Herceptin®) binds to subdomain IV prevents dimerization; ADCC
http://www.perjeta.com/hcp/moa
Pertuzumab (Perjeta®) - MoA
4. Pertuzumab and trastuzumab combination provides a more comprehensive block
http://www.perjeta.com/hcp/moa
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
Study #1 - CLEOPATRA
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?
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.
Trial Design
Baselga J et al.
• Control Arm = placebo + trastuzumab + docetaxel• Pertuzumab Arm = pertuzumab + trastuzumab + docetaxel
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
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 managedBaselga J et al.
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.
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 monitoredBaselga J et al.
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.
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.
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.
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.
Progression Free Surival
Baselga J et al.
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.
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.
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 progression81 (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.
Baselga J et al.
CLEOPATRA – Baseline Characteristics
Baselga J et al.
Median age 54
Whites, Asians
ECOG = 0
CLEOPATRA – Baseline Characteristics
Baselga J et al.
Visceral Disease
HER2 positive
CLEOPATRA – Baseline Characteristics
Baselga J et al.
Prior chemo ~ no prior chemo
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
Study #2 – Subgroup Analyses
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.
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
• 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) 2061-2067Miles 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
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.
Intent to Treat Population
< 65 age681 (84%)
> 65 age127 (16%)
Miles D et al
Baseline Characteristics
Miles D et al
Miles D et al
Primary EndpointPrimary endpoint• Independently assessed median PFS by age group
< 65 years12.5 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
Progession Free Surival
Miles D et al
Secondary Endpoint
ORR favored pertuzumab armDifference between control arm and treatment arm:
10.8% in the ITT population11.5% in patients < 65 years of age8.1% in patients > 65 years of age
Miles D et al
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
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
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 monthsAge > 65, increased median PFS by 11.2 monthsAge < 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
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
1st line treatment for HER2+ MBC
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
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
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
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
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
CLEOPATRA – Information
• ClinTrials.gov Identifier NCT00567190• Protocol WO20698• Hoffman-La Roche
http://www.roche-trials.com/studyResultGet.action?studyResultNumber=WO20698