Despite remarkable progress in the treatment of HER2+ breast cancer, management of this patient population continues to remain a challenge, both in the adjuvant and metastatic settings. An enhanced understanding of the treatment options available for HER2+ breast cancer patients in different settings is imperative to improving patient survival and quality of life. This activity consisting of didactic presentations and case illustrations will address treatment choices for HER2+ patients after trastuzumab progression; proposed mechanisms of resistance; combination treatment approaches; the role of anthracyclines and HER2-targeted agents in this population; and novel targeted agents under investigation, including mTOR inhibitors, antiangiogenic inhibitors, and HER2-targeted therapies. More information: http://imeronline.com/867dsd Review a downloadable slide deck by Kathy D. Miller, MD, covering the most clinically relevant new data reported from Future Directions in the Treatment of Patients With HER2+ Breast Cancer: What Community Oncologists Need to Know. Target Audience This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care. Slide Deck Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of September 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details. More information: http://imeronline.com/867dsd

2. DISCLAIMER
This slide deck in its original and unaltered format is for educational purposes and is
current as of September 2012. All materials contained herein reflect the views of the
faculty, and not those of IMER, the CME provider, or the commercial supporter. These
materials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readers
should not rely on this information as a substitute for professional medical advice,
diagnosis, or treatment. The use of any information provided is solely at your own risk,
and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be
used for personal, non-commercial presentations only if the content and references
remain unchanged. No part of this slide deck may be published in print or
electronically as a promotional or certified educational activity without prior written
permission from IMER. Additional terms may apply. See Terms of Service on
IMERonline.com for details.

3. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patient’s conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This educational activity may contain discussion of published and/or investigational
uses of agents that are not indicated by the FDA. Albert Einstein College of
Medicine and IMER do not recommend the use of any agent outside of the labeled
indications. The opinions expressed in the educational activity are those of the
faculty and do not necessarily represent the views of Albert Einstein College of
Medicine and IMER. Please refer to the official prescribing information for each
product for discussion of approved indications, contraindications, and warnings.

4. Disclosure of Conflicts of Interest
Kathy D. Miller, MD
Reported a financial interest/relationship or affiliation in
the form of: Contracted Research, Clovis Oncology, Inc.,
Geron Corporation, Merrimack Pharmaceuticals, Roche
Pharmaceuticals, Inc.; Consultant, Clovis Oncology, Inc.,
Necktar Therapeutics, Roche Pharmaceuticals, Inc.

5. Future Directions in the Treatment
of Patients With HER2-Positive Breast
Cancer: What Community Oncologists
Need to Know

6. Learning Objectives
Upon completion of this activity,
participants should be better able to:
 Identify treatment options for patients with HER2+ breast cancer
that have failed trastuzumab
 Describe the significance of HER2 status in making clinical
decisions
 Assess the optimal combinations of HER2-targeted therapy for
treating patients with HER2+ breast cancer
 Identify proposed mechanisms of resistance to HER2-targeted
therapies for treating HER2+ patients
 Cite new data from clinical trials on novel and emerging agents for
treating HER2+ breast cancer including mTOR inhibitors,
antiangiogenic inhibitors, and HER2-targeted therapies

7. Activity Agenda
 Activity Overview (5 mins)
 Anthracyclines or No Anthracyclines: Are Adjuvant Anthracyclines
Necessary for the Treatment of HER2+ Breast Cancer? (10 mins)
 Trastuzumab Progression: Which Treatment Options Provide the
Best Outcomes for Patients With HER2+ Breast Cancer After
Progression on Trastuzumab? (20 mins)
 Combination Approaches: What Combination Approaches Are
Options for Treating Patients With HER2+ Breast Cancer? (20 mins)
 Questions & Answers (5 mins)

8. HER2/neu Overview
General Features of HER2/neu Characteristics of HER2 + Disease
 Located on chromosome17q  Increased tumor size
 Amplified in approximately 20% of  Positive nodal status
primary breast cancers  Decreased ER and PR expression
 Encodes for tyrosine kinase  Ductal rather than lobular histology
transmembrane growth factor
– High S-phase fraction
receptor
– High nuclear grade
 Both a prognostic and predictive
factor in early stage and advanced
 Higher risk of recurrence
breast cancer  More advanced stage at
 HER2 overexpression seen in presentation
DCIS but not in earlier
premalignant lesions
DCIS = ductal carcinoma in situ; ER = estrogen receptor; PR = progesterone receptor.
Gutierrez et al, 2011.

9. Anthracyclines or No Anthracyclines:
Are Adjuvant Anthracyclines Necessary
for the Treatment of HER2+ Breast Cancer?

10. Topics for Discussion
 Anthracyclines
or nonanythracyclines
combined with trastuzumab: Efficacy vs.
risk factors?
 What risk factors and preexisting conditions
define which regimen to use?

11. Adjuvant Trastuzumab Trial Designs
Tripathy, 2011.

12. Trastuzumab Adjuvant
Trial DFS Benefits
Study FU (yrs) N HR
1 3,387 0.54
HERA
2 3,401 0.64
NSABP B-31/ 2 3,351 0.48
NCCTG 9831 4 3,968 0.48
BCIRG 006 3 3,222 0.61
FinHer 3 231 0.42
PACS 04 4 528 0.86
0 1 2
In favor of T In favor of Obs.
DFS = disease-free survival; FU = follow-up; HR = hazard ratio.
Metcalfe, 2007.

13. BCIRG 006 – Final Analysis
CI = confidence interval.
Slamon et al, 2009.

14. Therapeutic Index for Critical
Clinical Events
Clinical Event Number of Events
AC-T AC-T plus TCH
Trastuzumab
Total Events 201 146 149
Distant breast-cancer recurrence 188 124 144
Grade 3 or 4 congestive heart 7 21 4
failure
Acute Leukemia 6 1 1
 This is a compilation of the distant breast-cancer recurrences, cases
of CHF, and cases of acute leukemia.
CI = confidence interval, AC-T = doxorubicin and cyclophosphamide followed by
docetaxel, TCH = docetaxel, carboplatin, and trastuzumab..
Slamon et al, 2011.

15. Clinical Cardiomyopathy in
Trastuzumab Adjuvant Trials
H = trastuzumab; A = doxorubicin; C = cyclophosphamide; P = paclitaxel; T = docetaxel;
LVEF = left ventricular ejection fraction; CHF = congestive heart failure.
Smith et al, 2007; Perez et al, 2008; Slamon et al, 2011; Rastogi et al, 2007.

16. N9831: Schema and Cardiac Testing
Arm A: AC Paclitaxel
(q3wks x 4) (qwk x 12)
R Arm B: AC
(q3wks x 4)
Paclitaxel
(qwk x 12)
H
(qwk x 52)
Arm C: AC Paclitaxel + H H
(q3wks x 4) (qwk x 12) (qwk x 40)
RT/Hormone as Indicated
Time (mos)
0 3 6 9 18–21
LVEF Measurement
Pre-AC Post-AC Post T or TH
RT = radiation therapy.
Perez et al, 2008.

17. Asymptomatic Patients
Rules for Trastuzumab Continuation Based on
Serial LVEF Used in Trials
Relationship of Absolute Absolute Decrease Absolute Decrease
Decrease
LVEF to LLN of 10%–15% ≥ 16%
< 10%
WNL Continue Continue *Hold
1%–5% below LLN Continue *Hold *Hold
≥ 6% below LLN *Continue *Hold *Hold
* Repeat LVEF assessment after 4 wks
– If criteria for continuation met – resume trastuzumab
– If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab
WNL = within normal limits; LLM = lower limit of normal.

18. Post-AC LVEF Results for
2,999 Patients
Arm A
Arm B Arm C Total
(n = 1,012;
%) (n = 1,065; %) (n = 922; %) (N = 2,999; %)
LVEF decrease ≥
15% 3.8 1.7 2.3 2.6
LVEF decrease ≤
15% to below LLN 3.1 2.5 1.6 2.4
Prohibited from
receiving 6.9 4.2 3.9 5.0
trastuzumab (5.3–8.6) (3.1–5.6) (2.8–5.4) (4.3–5.8)
Perez et al, 2005.

19. Cumulative Incidence Rate of
Cardiac Events (Arms B and C)*
Arm B Arm C
n 1 yr 2 yrs n 1 yr 2 yrs
Post-AC LVEF ≤ 55%
Age ≤ 60 yrs 62 1.6% 3.6% 60 1.7% 1.7%
Age ≥ 60 yrs 13 0% 0% 6 1.7% 1.7%
Post-AC LVEF ≥ 55%
Age ≤ 60 yrs 541 1.5% 2.1% 414 2.4% 2.4%
Age ≥ 60 yrs 94 2.2% 4.5% 94 8.5% 8.5%
*Among patients who enrolled prior to April 25, 2004 and had a satisfactory
post-AC cardiac evaluation.
Perez et al, 2005.

20. Most Recent LVEF Levels for Patients
Who Experienced CHF in Arms B and C
Arm B (n = 16) Arm C (n = 18)
LVEF (n) LVEF (n)
< 50% 50%–59% ≥ 60% < 50% 50%–59% ≥ 60%
Time since CHF diagnosis
1.0–0.59 mos 4 0 0 3 1 0
6.0–11.9 mos 2 2 2 1 2 1
≥ 12 mos 2 1 3 3 4 3
Perez et al, 2005.

21. Key Takeaways
 Adjuvant trastuzumab after anthracycline-based
chemotherapy leads to an approximate 3-yr cumulative
incidence rate of 2.5%–3.5% of significant clinical
cardiac events
– The cardiac function in the majority of patients improved
following medical treatment
 Trend towards increased risk of cardiac toxicity with
increased patient age
 No correlation between radiation therapy cardiac toxicity
 No correlation between post-AC LVEF and subsequent
cardiac toxicity
– Differs from analysis of NSABP B-31
Perez et al, 2005.

22. Case Study 1
 65-yr-old, postmenopausal woman presented with a palpable left
axillary mass
 Mammogram and ultrasound demonstrated a 1.8-cm left breast
mass and 3.1-cm axillary mass
 PATHOLOGY: Core biopsy: Poorly diff. IDC, ER+ (20%), PR-, HER2
“3+” on IHC, FISH 9.2
– CT of chest/abdomen and bone scan: No evidence of metastasis
 COMORBIDITIES: Obesity, HTN, osteoarthritis, 3 yrs ago treated with
thrombolytics and stent placement
– LVEF normal (52%) by ECHO
 PRIMARY SURGERY: Left modified radical mastectomy
– Primary tumor 2.2 cm, margins negative
– 1/15 LN involved, 3.2 cm with no extracapsular extension
IDC = invasive ductal carcinoma; ER = estrogen receptor; PR = progesterone receptor;
IHC = immunohistochemistry; FISH = fluorescence in situ hybridization;
CT = computed tomography; HTN = hypertension; ECHO = echocardiogram;
LN = lymph node.

23. Case Study 1: Question 1
What adjuvant therapy would you recommend?
1) AC > TH as in N9831
2) TCH as in BCIRG 006
3) Dose-dense AC > wkly paclitaxel + trastuzumab
4) Taxane > FEC with concurrent trastuzumab
5) Other trastuzumab-based regimen

24. Case Study 1 (cont.)
 She was treated with the TCH regimen.
Docetaxel and carboplatin were dose reduced
for neuropathy after Cycle 4 but she otherwise
did well.
– LVEF after TCH Cycle 6 was 50%
 Shecontinued trastuzumab and proceed with
chest wall and regional node RT
– 3 mos later (2 wks after completing RT) she
complains of fatigue but otherwise feels well
(LVEF was 42%)

25. Case Study 1: Question 2
At this point you would:
1) Continue trastuzumab and refer to cardiology
2) Discontinue trastuzumab
3) Hold trastuzumab and repeat LVEF in 4–6 wks
4) Discontinue trastuzumab, complete planned adjuvant
therapy with lapatinib

26. Key Takeaways
 Bothanthracycline and non-anthracycline
regimens are supported by phase III data
 Riskof CHF is 2%–4% with anthracycline
regimens
– Higher risk in older patients
 Only1 trial evaluated a non-anthracycline
regimen (TCH)
– Risk of CHF ~ 0.5%
– Lower risk for leukemia
– Numerically higher risk of recurrence

27. Trastuzumab Progression:
Which Treatment Options Provide the Best
Outcomes for Patients With HER2+ Breast
Cancer After Progression on Trastuzumab?

28. Topics for Discussion
 Is continuation of HER2-targeted therapy with
either trastuzumab or lapatinib recommended
following progression on a trastuzumab-based
regimen?
 When should you switch to lapatinib?
 What emerging options are available after
relapse following trastuzumab/lapatinib
treatment?

29. TKI After Trastuzumab?
HER2+ LABC or MBC with Lapatinib 1,250 mg po qd continuously +
prior exposure to an Capecitabine 2,000 mg/m2/d
R po Days 1–14 q3wks
anthracycline, a taxane,
and trastuzumab* A
(n = 163)
N = 324 N
D
O
M
I Capecitabine 2,500 mg/m2/d
Stratification po Days 1–14 q3wks
Z
• Disease sites E (n = 161)
• Stage of disease Patients on treatment until progression or
unacceptable toxicity, then followed for survival
*Trastuzumab must have been administered for metastatic disease.
TKI = tyrosine kinase inhibitor; LABC = locally advanced breast cancer;
MBC = metastatic breast cancer.
Geyer et al, 2006.

30. Lapatinib Increases TTP
After Trastuzumab
TTP = time to progression.
Geyer et al, 2006.

31. Why Not Continue Trastuzumab?
GBG 26/BIG 3-05
(Closed Early With Poor Accrual)
Capecitabine 2,500 mg/m2/d
Women with HER2+ on Days 1–14 q3wks
Advanced Breast Cancer
or MBC That Progressed
on Trastuzumab Capecitabine 2,500 mg/m2/d
(N = 156) on Days 1–14 q3wks +
Trastuzumab 6 mg/kg q3wks
von Minckwitz et al, 2009.

32. Trastuzumab Remains Effective
After Disease Progression
Capecitabine Capecitabine + Trastuzumab
von Minckwitz et al, 2009.

33. Longer PFS With Lapatinib + Trastuzumab Vs.
Lapatinib Alone in Trastuzumab-Refractory MBC
Lapatin Lapatinib +
ib Trastuzum
PFS Outcome
(n = ab
145) (n = 146)
Progressed or
128 127
died, n
Median, wks 8.1 12.0
HR (95% CI) 0.73 (0.57–0.93)
p Value .008
Lapatini Lapatinib + Odds
Response (%) p Value
b Trastuzumab Ratio
ORR 6.9 10.3 1.5 .46
CBR 12.4 24.7
PFS = progression-free survival; ORR = overall response rate; CBR = clinical benefit rate. 2.2 .01
Blackwell et al, 2010.

34. Updated Overall Survival in ITT
L L+T
N = 145 N = 146
Died, N (%) 113 (78) 105 (72)
Median, mos 9.5 10
HR (95% Cl) 0.74 (0.57, 0.97)
Log-Rank p Value 0.26
Patients at Risk
L+T
148 121 88 64 43 25 1
L
148 102 65 47 28 13 –
Blackwell et al, 2009.

35. Novel Agents: HER2
HER1/2 TKI Neratinib (HKI-272), Afatinib (BIBW 2992), PKI-166, EKB-569
Pan HER TKI Canertinib, BMS-599626
HER1/2/VEGFR TKI XL647, AEE788
HER2 dimerization Pertuzumab (FDA Approved 06/2012 – first-line HER2+ MBC)
inhibitor
Bispecific antibody Ertumaxomab, MM111
Conjugated antibodies Trastuzumab-MCC-DM1, Trastuzumab-A-Z-CINN
310-paclitaxel
Targeted nanoparticles MM302
HSP90 inhibitors Tanespimycin, alvespimycin, CNF2024, IPI-504, AUY922,
SNX5422
IGF-1R inhibitors (mAb, TKI)CP-751871, EM164, IMC-A12, NVP-ADW742, INSM-
18
HDAC inhibitors Vorinostat, LBH589, Belinostat (PXD101), NVP-LAQ824,
depsipeptide, CI-994, MS-275
PI3K inhibitors SF1126, BEZ235, XL147, XL765, GDC-0941
Akt inhibitors Perifosine, XL418
mTOR inhibitors Sirolimus, temsirolimus, everolimus, ridaforolimus
HER2 vaccines E75 vaccine

36. T-DM1
 Multicenter phase II (N = 110)
– Prior anthracycline, taxane, capecitabine,
trastuzumab, lapatinib
 ORR (by independent review) 34.4%
 CBR (by independent review) 48.2%
 Median PFS 6.9 mos
– 7.3 mos in centrally confirmed HER2+
Krop et al, 2009.

37. Phase III T-DM1 Vs. Capecitabine +
Lapatinib in HER2+ MBC (EMILIA)
HER2+ T-DM1
(centrally confirmed) (3.6 mg/kg) q3wks IV
LABC or MBC Previously
Received Trastuzumab- Lapatinib
Based Therapy (n = 980) (1,250 mg/day) Days 1–21 po bid
+
Capecitabine
(1,000 mg/m2) Days 1–14 q3wks po qd
2
Primary end points: OS, PFS, Safety
Secondary end point: QOL
Key inclusion criteria
– Prior treatment to include a taxane and trastuzumab in adjuvant, locally advanced or metastatic setting
– Documented progression of disease during or after treatment for advanced/metastatic disease or
within 6 mos of completing adjuvant therapy
QOL = quality of life.
Blackwell et al. 2012

38. Case Study 2
 38-yr-old patient presented with inflammatory
breast cancer
– ER- and PgR-
– HER2+ by FISH (ratio 8.9)
– Imaging with PET/CT found regional nodal involvement
but was otherwise negative
 She was treated with neoadjuvant AC > TH
followed by mastectomy (2 cm residual disease,
LN-) and RT. She completed 1 yr of trastuzumab.
PgR = progesterone receptor; PET = positron emission tomography.

39. Case Study 2 (cont.)
3 yrs later she reports a persistent cough and
increased fatigue
– Imaging finds several lung lesions with
mediastinal and hilar adenopathy
– Biopsy confirms metastatic disease that remains
ER-/PgR-/HER2+
– CBC, total bilirubin, AST, ALT, calcium, albumin:
All normal
– LVEF 62% by MUGA
CBC = complete blood count; AST = aspartate aminotransferase;
ALT = alanine aminotransferase; MUGA = multi-gated acquisition scan.

40. Case Study 2: Question 1
Which of the following treatment options
would you recommend for this patient?
1) Taxane-based chemotherapy + trastuzumab
2) Capecitabine + lapatinib
3) Docetaxel + carboplatin + trastuzumab
4) Vinorelbine + trastuzumab
5) Trastuzumab + lapatinib

41. Case Study 2 (cont.)
 She was treated with vinorelbine + trastuzumab
– She had an excellent partial response with resolution
of symptoms
– Vinorelbine discontinued after 9 cycles due to
increased neuropathy (continued trastuzumab)
 10mos later, she develops headache and
diplopia
– Imaging finds a large cavernous sinus met with
several other small cerebral lesions

42. Case Study 2 (cont.)
 She is started on steroids and completes
whole brain radiation therapy
– CNS symptoms resolve
– Additional imaging finds asymptomatic
progression of her systemic disease with
increased lung nodules
CNS = central nervous system.

43. Case Study 2: Question 2
Which of the following strategies would you
recommend for this patient at this point?
1) Resume vinorelbine with continued trastuzumab
2) Capecitabine + lapatinib
3) Trastuzumab + lapatinib
4) Capecitabine + trastuzumab
5) Alternate chemotherapy + trastuzumab

44. Key Takeaways
 Continued HER2 blockade through multiple
lines of therapy is important for patients with
HER2+ disease
 Optimal sequence not defined
 Lapatinib
may have unique role in patients
with CNS disease
 Several new agents have activity and are
likely to be available soon

45. Combination Approaches:
What Combination Approaches
Are Options for Treating
HER2+ Breast Cancer?

46. Topics for Discussion
 Lessons from the neoadjuvant setting
 Dual regimens of HER2-targeted therapies
 Combined VEGF and HER2-targeted
therapies

47. Lessons Neoadjuvant Trials
Trast + Docetaxel
Pertuz + Docetaxel NEO-
R SPHERE
Pertuz + Trast + Docetaxel
n ~ 400
Pertuz + Trast
Trast Trast + Paclitaxel
NEO-
R Lapatinib Lapatinib + Paclitaxel ALTTO
n ~ 450
Trast/Lap Trast/Lap + Paclitaxel

48. Pathologic Response in Neo-ALTTO
No Difference in Proportion of Patients
Undergoing Breast Conservation
Baselga et al, 2010.

49. Pertuzumab and Trastuzumab:
Complementary Mechanisms of Action
HER2
HER 1/3/4
Trastuzumab Pertuzumab
Dimerization
domain
Subdomain IV
Trastuzumab Pertuzumab
 Inhibits ligand-independent  Inhibits ligand-dependent HER2
HER2 signaling dimerization and signaling
 Activates ADCC  Activates ADCC
 Prevents HER2 ECD shedding
Baselga et al, 2012.

50. Pathologic CR Rates in NeoSphere
ITT = intent-to-treat.
Gianni et al, 2010.

51. CLEOPATRA: Study Design
 Primary end point: PFS (independently
Stratified by geographic region assessed)
and previous (neo)adjuvant
chemotherapy  Secondary end points: PFS (investigator
assessment), ORR, OS, Safety
Trastuzumab 6 mg/kg q3wks* +
Women with Docetaxel 75–100 mg/m2 q3wks† +
previously Pertuzumab 420 mg q3wks‡ Treatment until
untreated, HER2+ (n = 402) disease
locally recurrent or progression or
Trastuzumab 6 mg/kg q3wks* + unacceptable
MBC
Docetaxel 75–100 mg/m2 q3wks† + toxicity
(N = 808)
Placebo q3wks
(n = 406)
 Pertuzumab was FDA Approved June 2012 based on the result of the CLEOPATRA trial for
first-line treatment of HER2+ MBC in combination with trastuzumab and docetaxel.
*Trastuzumab 8 mg/kg loading dose given.
†Minimum of 6 docetaxel cycles recommended; < 6 cycles permitted for unacceptable
toxicity or disease progression.
‡Pertuzumab 840 mg loading dose given.
Baselga et al, 2012; Perjeta™ prescribing information, 2012.

52. CLEOPATRA: Independently Assessed PFS
Baselga et al, 2012.

53. CLEOPATRA: Response Data
100 4.2
5.5
90
80
70 ORR
ORR CR
Patients (%)
60 65.2 69.3%
74.6 80.2% PR
50
SD
40
PD
30
Not evaluable
20 20.8
10 14.6
1.5 1.5 8.3
3.8
0
Trastuzumab + Docetaxel Trastuzumab +
+ Pertuzumab Docetaxel + Placebo
(n = 343) (n = 336)
CR = complete response; PR = partial response; Sde = stable disease;
PD = progressive disease.
Baselga et al, 2012.

54. CLEOPATRA: Safety
NR = not reported.
Baselga et al, 2012.

55. AVEREL: Study Design
 Primary end point: PFS (investigator assessed)
 Secondary end points: OS, ORR, DOR, TTF, Safety
Stratified by previous (neo)adjuvant taxane, Treatment until disease progression
adjuvant trastuzumab, hormone receptor
status, measurable disease or unacceptable toxicity*
Trastuzumab 6 mg/kg† +
Docetaxel 100 mg/m2 +
Women with Bevacizumab 15 mg/kg,
previously all given q3wks
untreated HER2+ (n = 216)
locally recurrent or Trastuzumab 6 mg/kg† +
MBC (N = 424) Docetaxel 100 mg/m2,
both given q3wks
(n = 208)
*Planned minimum of 6 docetaxel cycles administered.
†Trastuzumab 8 mg/kg loading dose given.
OS = overall survival; DOR = duration of response; TTF = time to treatment failure.
Gianni et al, 2011.

56. AVEREL: PFS, Interim OS Analysis,
and Response
 ORR similar between T + Doc + Bev and T + Doc in investigator assessment
(74.3% vs. 69.9, respectfully; p = .3492)
 ORR significantly higher for with addition of Bev in IRC assessment
(76.5% vs. 65.9, respectfully; p = .0265)
Gianni et al, 2011.

57. AVEREL Takeaways
 Addition of bevacizumab to first-line treatment
with trastuzumab and docetaxel may prolong PFS
– Findings not significant according to investigator-
assessed PFS (p = .0775)
– Findings significant according to independent review of
PFS (p = .0162)
 Bevacizumab-associated AEs led to higher
incidence of discontinuation of any study drug
AE = adverse events.
Gianni et al, 2011.

58. Case Study 3
 52-yr-old postmenopausal woman presented with a 3-cm
mass in the right breast, clinically LN Negative
 Biopsy found a grade III invasive ductal cancer, HER2 3+ by
IHC, ER 0, PR 0
 At surgery sentinel node was positive leading to completion
axillary dissection
– Total 11/15 LNs involved
 Post-operative imaging found 5 liver lesions (biopsy confirmed
diagnosis of metastatic disease, ER 0, PR 0, HER2 + by FISH
with ratio 13.5)
– Liver enzymes and Bili normal, ECOG PS = 0
ECOG = Eastern Cooperative Oncology Group; PS = performance status.

59. Case Study 3: Question 1
Assuming all of these options were available,
what systemic therapy would you recommend?
1) AC > TH
2) TCH
3) Docetaxel + trastuzumab + pertuzumab
4) Trastuzumab + lapatinib
5) Vinorelbine + trastuzumab

60. Case Study 3 (cont.)
 Sheis treated with docetaxel + trastuzumab
+ pertuzumab on the Cleopatra trial
– She has a complete response
– Docetaxel discontinued after 6 cycles, continued
trastuzumab + pertuzumab

61. Key Takeaways
 Neoadjuvant trials suggested combined HER2
inhibition was beneficial. Similar results seen in
the metastatic setting.
– Improved survival with trastuzumab + lapatinib in
heavily pretreated patients
– Improved ORR, DFS with addition of pertuzumab in
the first-line setting
 Combined HER2 and VEGF inhibition had less
activity than was hoped

62. Key Takeaways (cont.)
 T-DM1 demonstrated a CBR of 48% in heavily pre-treated patients
with HER2+ metastatic disease
 In the reported adjuvant trials, the risk of CHF with sequential
anthracycline chemotherapy followed by trastuzumab ranged from
2%–3.8%
 Older age has been consistently associated with cardiac toxicity in
patients receiving adjuvant trastuzumab
 In the GBG trial, ORR and PFS were improved for patients
continuing trastuzumab after progressing on trastuzumab
 In the neoadjuvant setting, combined pertuzumab and trastuzumab
increased pCR rate with chemotherapy compared to trastuzumab +
chemotherapy
 Toxicities increased with the triple-drug combination pertuzumab,
docetaxel, and trastuzumab. These included febrile neutropenia,
diarrhea, mucosal inflammation, and skin rash.
CBR = clinical benefit rate