Research To Practice

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2
Challenging Cases in Breast CancerOncologist
and Nurse Investigators Consult on Actual
Patients from the Practices of the Invited
FacultyThursday, May 1, 2014600 AM 730 AM
Faculty
Joan M Armstrong, MSN, APRN-BC Emily Olson, RN,
CNP
Adam M Brufsky, MD Denise A Yardley, MD
ModeratorNeil Love, MD
3
Oncology 6-Part Case Series Key Themes

• Mechanisms of action of novel agents and tissue
  assays to predict response
• Side effects and toxicities of novel agents dose
  adjustments
• Assessment and management of adherence
• Specific goals of therapy and likely outcomes
  sequencing of agents in advanced disease
• Local and systemic complications of cancer
  Fatigue, pain, CNS involvement
• Care of older, frail patients and those with
  comorbidities

4
Oncology 6-Part Case Series Key Themes

• Clinical trials as a means to access new
  treatments earlier
• Management of anxiety and depression
• Key determinants of patient satisfaction What do
  people with cancer want and need?
• Quality, value and cost Investing resources
  optimally
• End-of-life care and planning
• Impact of the cancer experience on family and
  loved ones, including minor children
• Impact of the oncology experience on oncology
  health professionals

5
Agenda

• A Patient with a Recent Myocardial Infarction and
  Locally Advanced ER/PR-Negative, HER2-Positive
  Breast Cancer
• 53 yo unemployed single mother of 4 children with
  inflammatory breast cancer and a complicated
  history (Ms Olson)
• A Patient with Widespread Triple-Negative
  Metastatic Breast Cancer (mBC) and Bone Marrow
  Involvement
• 67 yo with mBC and persistent low blood counts
  (Ms Olson)

6
Agenda

• Two Patients with HER2-Positive mBC
• 62 yo with bone and liver metastases who
  subsequently develops brain metastases (Ms
  Armstrong)
• 55 yo with bilateral pulmonary metastases (Ms
  Olson)
• Two patients with ER/PR-positive, HER2-negative
  mBC
• 84 yo with bilateral pleural effusions requiring
  several thoracenteses (Ms Armstrong)
• 61 yo with mBC who speaks no English (Ms
  Armstrong)

7
Case 1 (from the practice of Ms Olson)

• A 53-year-old unemployed single mother of 4
  children experienced a myocardial infarction 4
  months before presenting with a 6.7-cm,
  inflammatory, ER/PR-negative, HER2-positive
  breast cancer
• After a cardiology consultation she received TCH
  (docetaxel, carboplatin and trastuzumab) and
  experienced a complete clinical response
• Mastectomy revealed a pathologic complete
  response in the breast, but 1 lymph node
  contained residual disease
• She received trastuzumab to complete 1 year of
  treatment (February 2014)
• Her history includes treatment for depression and
  extensive alcohol and tobacco use for which she
  is seeking treatment

8
Pretreatment
9
Post-docetaxel/carboplatin/trastuzumab
10
Discussion Point

• Long-term outcomes for patients with inflammatory
  breast cancer

11
Discussion Point

• First-ever FDA approval of a neoadjuvant therapy
  of breast cancer (pertuzumab/trastuzumab/chemother
  apy)

12
Pertuzumab and Trastuzumab Mechanisms of Action
Pertuzumab
HER2
HER1/3/4
Trastuzumab
Dimerization domain
Subdomain IV

• Trastuzumab
• Inhibits ligand-independent HER2 signaling
• Activates ADCC
• Prevents HER2 ECD shedding

• Pertuzumab
• Inhibits ligand-dependent HER2 dimerization and
  signaling
• Activates ADCC

ADCC antibody-dependent cell-mediated
cytotoxicity ECD extracellular domain
13
FDA News ReleaseSeptember 30, 2013

• The US Food and Drug Administration today granted
  accelerated approval to pertuzumab as part of a
  complete treatment regimen for patients with
  early stage breast cancer before surgery
  (neoadjuvant setting). Pertuzumab is the first
  FDA-approved drug for the neoadjuvant treatment
  of breast cancer.

www.fda.gov/newsevents/newsroom/pressannouncements
/ucm370393.htm
14
NeoSphere Study Design
TH (n 107) Docetaxel Trastuzumab
FEC q3wk x 3 Trastuzumab q3wk, cycles 5-17
SURGERY
Patients with operable or locally
advanced/ inflammatory HER2-positive breast cancer
THP (n 107) Docetaxel Trastuzumab Pertuzumab
FEC q3wk x 3 Trastuzumab q3wk, cycles 5-17
HP (n 107) Trastuzumab Pertuzumab
Docetaxel q3wk x 4 ? FEC q3wk x 3 Trastuzumab
q3wk, cycles 5-17
Chemonaive and primary tumors gt2 cm (N 417)
TP (n 96) Docetaxel Pertuzumab
FEC q3wk x 3 Trastuzumab q3wk, cycles 5-21
Study dosing q3wk x 3
FEC 5-fluorouracil, epirubicin and
cyclophosphamideLocally advanced T2-3, N2-3,
M0 or T4a-C, any N, M0 operable T2-3, N0-1,
M0 inflammatory T4d, any N, M0 Gianni L et
al. Lancet Oncol 201213(1)25-32.
15
NeoSphere pCR and Hormone Receptor Status
pCR ( 95 CI)
pCR pathologic complete response H
trastuzumab P pertuzumab T docetaxel Gianni
L et al. Lancet Oncol 201213(1)25-32.
16
APHINITY A Phase III Adjuvant Study Design
Target accrual 4,806
Chemotherapy Trastuzumab x 1 yr Pertuzumab x 1 yr
Resected HER2 BC Node (except T0) Baseline LVEG
55
Chemotherapy Trastuzumab x 1 yr Placebo x 1 yr
Primary endpoint Invasive disease-free survival
www.clinicaltrials.gov www.ibcsg.org
ClinicalTrials.gov Identifer NCT01358877
17
NCCN Breast Cancer Clinical Practice Guidelines
v3.2014

• A pertuzumab-containing regimen can be
  administered to patients with T2 or N1,
  HER2-positive, early-stage breast cancer.
• Patients who have not received a neoadjuvant
  pertuzumab-containing regimen can receive
  adjuvant pertuzumab.

18
Discussion Point

• Adjuvant therapy for node-negative,
  HER2-positive disease Clinical trial findings
  with trastuzumab/paclitaxel

19
Adjuvant Paclitaxel and Trastuzumab for
Node-Negative HER2 Breast Cancer
Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B,
Marcom PK, Albain KS, Rugo H, Ellis M, Shapira I,
Wolff AC, Carey LA, Overmoyer BA, Partridge AH,
Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP
SABCS 2013Abstract S1-04.
20
Phase II Study Design(APT Trial)
HER2 ER or ER- Node negative lt3 cm
Enroll
PACLITAXEL 80 mg/m2 TRASTUZUMAB 2 mg/kg x 12
Planned N 400
T
T
T
T
T
T
T
T
T
T
T
T
T
FOLLOWED BY 13 EVERY 3-WEEK DOSES OF TRASTUZUMAB
(6 mg/kg)
Dosing could alternatively be 2 mg/kg IV weekly
for 40 weeks Radiation and hormonal therapy were
initiated after completion of paclitaxel Tolaney
SM et al. SABCS 2013Abstract S1-04.
21
APT Results (N 406)
3-year DFS 98.7 3-year DFS 98.7 3-year DFS 98.7
Adverse Events Adverse Events Adverse Events
Type of AE Grade 3 Total
Fatigue 2 22
Diarrhea 1 13
Neuropathy 3 13
Neutropenia 5 11
Hyperglycemia 2 10
Leukopenia 2 9
Allergic reaction 2 9
Elevated ALT 2 7
Anemia lt1 7
Tolaney SM et al. SABCS 2013Abstract S1-04.
22
ATEMPT Trial Schema
Trastuzumab emtansine (T-DM1)every 3 weeks for
17 weeks
Stage I HER2 ER or ER- PS 0-1 Adequate organ fx
3
N 375
Paclitaxel trastuzumab once weekly for 12
weeks ?trastuzumab every 3 weeks beginning from
week 13
1
N 500
N 125
HER2-positive defined as IHC 3 or FISH 2.0
will be confirmed by central HER2 testing prior
to study enrollment
Adjuvant endocrine therapy can be initiated after
completion of 12 weeks of therapy Adjuvant
radiation therapy can be administered
concurrently with study treatment
www.clinicaltrials.gov ClinicalTrials.gov
Identifier NCT01853748
PI Sara Tolaney, MD, MPH
23
Discussion Point

• Impact of clinical depression and extensive
  alcohol and tobacco use on patients who are
  undergoing treatment for cancer

24
Case 2 (from the practice of Ms Olson)

• A 67-year-old physical therapist was diagnosed in
  2011 with locally advanced ER/PR/HER2-negative
  breast cancer
• She received neoadjuvant dose-dense AC ? T
  followed by mastectomy and radiation therapy
• Eleven months later she developed a biopsy-proven
  supraclavicular lymph node recurrence
• Workup revealed liver metastases
• She received capecitabine as first-line treatment
  and eribulin in the second line
• She experienced persistent problems with low
  blood counts, and a bone marrow biopsy revealed
  tumor infiltration

25
Liver metastasis
26
Liver metastasis after 9 months of capecitabine
27
Liver metastasis after 6 cycles of eribulin
28
Leptomeningeal disease April 2014
29
Discussion Point

• Neoadjuvant treatment for triple-negative breast
  cancer (TNBC) Available data with platinum agents

30
CALGB-40603 Randomized Phase II Study Schema
Paclitaxel 80 mg/m2 wkly x 12
ddAC x 4
ddAC x 4
Paclitaxel 80 mg/m2 wkly x 12
Surgery XRT No Adjuvant Systemic Treatment
Planned
Bevacizumab 10 mg/kg q2wk x 9
2 X 2 Randomization
Paclitaxel 80 mg/m2 wkly x 12
ddAC x 4
Carboplatin AUC 6 q3wk x 4
ddAC x 4
Paclitaxel 80 mg/m2 wkly x 12
Paclitaxel 80mg/m2 weekly x 12
Carboplatin AUC 6 q3wk x 4
Research biopsies if residual tumor MD
discretion
Bevacizumab 10 mg/kg q2wk x 9
Research biopsies- frozen and fixed
Sikov WM et al. SABCS 2013Abstract S5-01.
31
pCR Breast (ypT0/is N any) Carboplatin
60 (54-66)
46 (40-53)
Odds ratio 1.76 p 0.0018
N 212
N 221
Sikov WM et al. SABCS 2013Abstract S5-01.
32
Mechanism of Action of Eribulin
Eribulin, which is derived from a sea sponge,
works by inhibiting microtubules the
scaffolding of cancer cells.
Eribulin suppresses microtubule growth
Eribulin
Growing microtubule
Eribulin sequesters tubulin into nonfunctional
aggregates
Spindle Pole
Eribulin
Eribulin
Shortening microtubule
Eribulin doesn't affect microtubule shortening
Nonfunctional tubulin aggregate
Adapted from Jordan MA et al. Mol Cancer Ther
200541086-95.
33
Neoadjuvant Phase II trial with carboplatin and
eribulin in triple negative breast cancer patients
Giordano SB, Jeruss JS, Bethke KP, Hansen NM,
Khan S, Von Roenn J, Rosen S, Gradishar WL,
Siziopikou KP, Meservey C, Kaklamani V.
Northwestern University, Chicago, IL
SABCS 2013Abstract P3-14-14.
Clinical response rate (PR CR) 82.8
34
A Phase III Study of Eribulin Mesylate versus
Capecitabine in Patients with Locally Advanced or
MBC Previously Treated with Anthracyclines and
Taxanes
Population Median overall survival Median overall survival Hazard ratio
Population Eribulin Capecitabine Hazard ratio
HER2-positive 14.3 mo 17.1 mo 0.965
ER-positive 18.2 mo 16.8 mo 0.897
Triple-negative 14.4 mo 9.4 mo 0.702
Kaufman PA et al. SABCS 2012Abstract S6-6.
35
Consider the last patient in your practice who
died of triple-negative metastatic breast
cancer How long did the patient live?
lt12 months
5
19
12-24 months
2
gt24 months
Median 17 months
Research To Practice Survey of Clinical
Investigators (N 26) December 2013.
36
Most common systemic agents administered
Eribulin
21
21
Platinum
19
Capecitabine
18
Gemcitabine
17
Taxane
37
Discussion Point

• Consideration of toxicity profiles and methods of
  administration in the selection and sequencing of
  systemic therapies

38
Two Patients with HER2-Positive mBC

• 62 yo with bone and liver metastases who
  subsequently develops brain metastases (Ms
  Armstrong)
• 55 yo with bilateral pulmonary metastases (Ms
  Olson)

39
Case 3 (from the practice of Ms Armstrong)

• A 62-year-old woman presented with
  ER/PR-negative, HER2-positive breast cancer
• Workup revealed metastatic disease to liver and
  bone
• Paclitaxel, trastuzumab and pertuzumab were
  administered, resulting in a partial response,
  but paclitaxel was stopped after 6 months because
  of fatigue
• She continued on dual-antibody therapy until
  disease progression, at which time she was
  switched to trastuzumab emtansine (T-DM1)
• After 6 months she developed brain metastases and
  received whole brain radiation therapy followed
  by capecitabine and lapatinib

40
Discussion Point

• Rationale for and available data with the
  addition of pertuzumab to trastuzumab/taxane

41
CLEOPATRA Study

• Centrally confirmed HER2 locally recurrent,
  unresectable or metastatic BC (MBC)
• 1 hormonal regimen for MBC
• Prior (neo)adjuvant systemic rx, incl
  trastuzumab and/or taxane allowed if followed by
  DFS 12 mo
• Baseline LVEF 50 no CHF or LVEF lt 50 during
  or after prior trastuzumab

N 406
Docetaxel Trastuzumab Placebo
11
Docetaxel Trastuzumab Pertuzumab
N 402
Baselga J et al. N Engl J Med 2012366(2)109-19.
Swain S et al. SABCS 2012Abstract P5-18-26.
42
CLEOPATRA Response and Survival Analyses
Endpoint Ptz T D Pla T D
3-yrs OS 66 50
Median PFS 19 mo 12 mo
ORR 80 69
Baselga J et al. N Engl J Med 2012366(2)109-19.
Swain SM et al. Lancet Oncol 201314(6)461-71.
43
CLEOPATRA Safety Analysis

• Safety profile similar between groups
• No increase in left ventricular systolic
  dysfunction with the addition of pertuzumab
• Increased incidence of Grade 3 AEs with
  pertuzumab
• Diarrhea 8 vs 5
• Febrile neutropenia 14 vs 8
• All grade rash 34 vs 24

Baselga J et al. N Engl J Med 2012366(2)109-19.
44
Trastuzumab Emtansine (T-DM1) Mechanisms of
Action
Immuneeffector cell
HER2
T-DM1
HER2
T-DM1
Inhibition of HER2 shedding
Fc? receptor
Emtansine release
Internalization
Antibody-dependentcellular cytotoxicity(ADCC)
Inhibition of HER2 signaling
Inhibition of microtubule polymerization
Lysosome
PI3K
MAPK
Nucleus
Adapted from LoRusso PM et al. Clin Cancer Res
2011.
45
Phase III EMILIA Study

• HER2-positive LABC or MBC (N 991)
• Prior taxane and trastuzumab
• Progression on metastatic treatment or within 6
  months of adjuvant treatment

T-DM1 3.6 mg/kg q3w IV
PD
11
Capecitabine 1,000 mg/m2 PO BID, days 114,
q3w Lapatinib 1,250 mg/day PO qd
PD
Median OS 30.9 vs 25.1 mo Median PFS 9.6 vs 6.4
mo
Verma S et al. N Engl J Med 2012367(19)1783-91.
46
T-DM1-Associated Side Effects
Lapatinib Capecitabine (N 488) Lapatinib Capecitabine (N 488) T-DM1 (N 490) T-DM1 (N 490)
Adverse Event Any Grade Grade 3 or 4 Any Grade Grade 3 or 4
Thrombocytopenia 2.5 0.2 28.0 12.9

• 1st occurrence of Grade 3 or 4 thrombocytopenia
  typically occurs during the first 2 cycles of
  T-DM1 treatment
• Majority able to continue treatment with dose
  modifications
• 2 of patients discontinued T-DM1 due to
  thrombocytopenia
• 7.2 of patients experienced Grade 3 liver
  function abnormalities

Verma S et al. N Engl J Med 2012367(19)1783-91.
47
Phase III MARIANNE Study Design
Target Accrual 1,095 (Active, not recruiting)
T-DM1

• HER2, locally recurrent or metastatic BC
• No prior treatment for metastatic BC

T-DM1 pertuzumab
Taxane trastuzumab
www.clinicaltrials.gov, April 2013
ClinicalTrials.gov Identifier NCT01120184
48
Case 4 (from the practice of Ms Olson)

• A 55-year-old secretary received treatment for
  breast cancer in 2000 and fared well until 2012,
  when a routine chest x-ray revealed multiple
  bilateral pulmonary nodules that on biopsy proved
  to be ER-positive, HER2-positive mBC
• She received docetaxel/pertuzumab/trastuzumab x
  6 cycles followed by pertuzumab/trastuzumab
• While receiving chemotherapy, she developed
  peripheral neuropathy and alopecia, both of which
  resolved on the double-antibody treatment.

49
Pulmonary metastases at diagnosis
50
After 6 cycles of docetaxel/pertuzumab/trastuzumab
51
ER, HER2 mBCAge 45, premenopausalMinimally
symptomatic, liver mets
24
Trastuzumab pertuzumab taxane
2
Other
ET trastuzumab trastuzumab pertuzumab ET
Research To Practice Survey of Clinical
Investigators (N 26) December 2013.
52
ER, HER2 mBCAge 45, premenopausalAsymptomatic
Low disease burden bone mets
ET Tras
10
5
ET
7
Tras/Pert/Taxane
4
Other
Trastuzumab/pertuzumab/ET x 2 trastuzumab
taxaneET lapatinib trastuzumab
Research To Practice Survey of Clinical
Investigators (N 26) December 2013.
53
Two patients with ER/PR-positive, HER2-negative
mBC

• 84 yo with bilateral pleural effusions requiring
  several thoracenteses (Ms Armstrong)
• 61 yo with mBC who speaks no English (Ms
  Armstrong)

54
Case 5 (from the practice of Ms Armstrong)

• An 84-year-old woman initially presented with
  Stage II ER/PR-positive, HER2-negative breast
  cancer and received an adjuvant aromatase
  inhibitor (AI), which she discontinued due to
  extensive myalgia and arthralgia
• Two years later she was diagnosed with metastatic
  disease and was noted to have bilateral pleural
  effusions requiring several thoracenteses

55
Key Endocrine Therapy Options for Breast Cancer
Treatment Administration and Dose
Ovarian ablation Oophorectomy
Ovarian suppression IM injection
Tamoxifen 20-mg tablet/day
Aromatase inhibitors (AIs) Anastrozole Letrozole Exemestane 1-mg tablet/day 2.5-mg tablet/day 25-mg tablet/day
Fulvestrant IM injection 250 mg or 500 mg
AI fulvestrant Variable doses of AI 250 or 500-mg fulvestrant (IM injection)
Everolimus exemestane 10-mg tablet/day 25-mg tablet/day
56
Everolimus-Associated Stomatitis
Grade 1 Grade 2 Grade 3 Grade 4
Clinical Exam Erythema of the mucosa Patchy ulcerations or pseudomembranes Confluent ulcerations or pseudomembranes, bleeding with minor trauma Tissue necrosis, significant spontaneous bleeding
Functional Symptoms Minimal symptoms, normal diet Symptomatic but can eat and swallow modified diet Symptomatic and unable to adequately aliment or hydrate orally Symptoms associated with life-threatening consequences
De Oliveira et al. Oral Oncol 2011 Ferte C et
al. Eur J Cancer 2011 Cawley M et al. Clin J
Oncol Nurs 2005
57
STOPP Phase II Trial of Alcohol-Free,
Steroid-Based Mouthwash for Prevention of
Mucositis

• Postmenopausal women
• Locally advanced or metastatic HR-positive,
  HER2-negative BC
• Everolimus exemestane treatment begun on day 1
  of trial

Dexamethasone-basedmouthwash 10 ml (0.5 mg/5 ml
dex oral solution) 4x per day

• Primary outcome Incidence of Grade 2 stomatitis
  at 2 months

Rugo HS et al. SABCS 2013Abstract OT2-6-14.
58
ER, HER2-neg mBCAge 65, postmenopausalAsymptoma
ticLow disease burden bone metsAfter 4 years
adjuvant anastrozole
Fulvestrant
14
8
Exemestane/everolimus
4
Other
Tamoxifen x 3 fulvestrant AI
Research To Practice Survey of Clinical
Investigators (N 26) December 2013.
59
Discussion Point

• Use of fulvestrant in patients receiving
  anticoagulation

60
Use of Fulvestrant in Patients Receiving Warfarin

• Because fulvestrant is administered
  intramuscularly, it should be used with caution
  in patients with bleeding diatheses,
  thrombocytopenia, or in patients receiving
  anticoagulants

Fulvestrant package insert
61
Final Overall Survival Fulvestrant 500mg vs 250
mg in the Randomized CONFIRM Trial
Di Leo A, Jerusalem G, Lubos P, Torres R,
Bondarenko IN, Khasanov R, Verhoeven D, Pedrini
JL, Smirnova I, Lichinitser, MR, Pendergrass K,
Malorni L, Garnett S, Rukazenkov Y, Martin M
J Natl Cancer Inst 20141006(1)djt337.
In patients with locally advanced or metastatic
estrogen receptor-positive breast cancer,
fulvestrant 500 mg is associated with a 19
reduction in risk of death and a 4.1-month
difference in median OS compared with
fulvestrant 250 mg.
62
Discussion Points

• Extending adjuvant endocrine therapy beyond 5
  years
• Use of bisphosphonates as adjuvant treatment