Pertuzumab for HER2 Positive Metastatic Breast Cancer

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