Kathy D. Miller, MD

1
Clinical Updates
Advances in Targeted Therapies for Breast
Cancer A Report From SABCS 2009

• Kathy D. Miller, MD
• Associate Professor and Sheila D. Ward Scholar
• Indiana University Melvin and Bren Simon Cancer
  Center
• Indianapolis, IN

2
Discussion Topics

• HER2 positive disease
• Growing number of options
• Angiogenesis
• Bevacizumab questions answered and rephrased
• Small molecule success and disappointment

3
HER2 What We Knew Before SABCS

• Trastuzumab
• Active as single agent and adds to chemo/HRT
• Effective with chemo beyond PD
• Adds to lapatinib monotherapy (ORR, PFS)
• Lapatinib
• Active as single agent and adds to chemo/HRT
• Effective with chemo after PD on trastuzumab
• MULTIPLE new agents in development

4
Case 1

• 54 year old woman with newly diagnosed stage II
  breast cancer s/p lumpectomy and axillary
  dissection
• Primary tumor 1.9 cm
• Involves 1 of 14 LN (1/2 SN, 0/12 additional LN)
• Grade III
• ER 15, PR-
• HER2 2 by IHC (intense staining in 20 of cells)
• FISH equivocal with ratio 2.15
• Do you recommend adjuvant trastuzumab?

5
Background

• In 2007, ASCO/CAP recommended new guidelines to
  define HER2 positivity by both IHC 3 and
  FISH
• 3 IHC Uniform intense membrane staining of gt
  30 of invasive tumor cells
• FISH HER2/CEP17 ratio gt 2.2
• Original HER2 eligibility criteria in the pivotal
  N9831 Phase III Adjuvant HER2 Trial
• 3 IHC Uniform intense membrane staining of gt
  10 of invasive tumor cells
• FISH HER2/CEP 17 ratio 2.0

HerceptTest DAKO, Carpenteria, CA FISH
PathVysion, Abbott Molecular Masood S et al.
Ann Clin Lab Sci 199828(4)215-223 Perez EA et
al. SABCS 2009 701
6
N9831 DFS Based on Original Criteria HER2
Non-positive vs. HER2
HER2 Non-positive (IHC 10 and FISH Ratio lt
2.0) HER2 (IHC gt 10 or FISH Ratio 2.0)
Perez EA et al. SABCS 2009 701
7
N9831 DFS Based on 2007 ASCO/CAP HER2
Non-positive vs. HER2
HER2 Non-positive (IHC 30 and FISH Ratio
2.2) HER2 (IHC gt30 or FISH Ratio gt 2.2)
Perez EA et al. SABCS 2009 701
8
Conclusions

• A small percentage (by IHC3.7, FISH 1.4,
  both1.7) of N9831 pts did not meet ASCO/CAP
  2007 HER2 positivity guidelines when applied
  retrospectively
• Trastuzumab effect appeared similar for HER2 pts
  regardless of ASCO/CAP or originally used
  FDA-approved guidelines
• Data support determining eligibility for
  trastuzumab based on the original definition of
  HER2 positivity (IHC 3, gt10 staining FISH
  ratiogt2.0).

Perez EA et al. SABCS 2009 701
9
Case 1

• 54 year old woman with newly diagnosed stage II
  breast cancer s/p lumpectomy and axillary
  dissection
• Primary tumor 1.9 cm
• Involves 1 of 14 LN (1/2 SN, 0/12 additional LN)
• Grade III
• ER 15, PR-
• HER2 2 by IHC (intense staining in 20 of cells)
• FISH equivocal with ratio 2.15
• Do you recommend adjuvant trastuzumab?
• YES

10
Adjuvant Trastuzumab
1 v 2 years
IHC, immunohistochemistryFISH, fluorescence in
situ hybridisation
11
BCIRG 006 DFS Events

• First / Second / Third Planned Efficacy Analyses
  (cutoff dates 30June2005 / 01Nov2006 /
  16Oct2009)
• Median follow-up time 23/36/65 months
• 322/462/656 DFS events (42 additional events)
• Breast cancer relapse
• Second primary malignancy
• Death
• 84/185/348 deaths (88 additional deaths)

12
Current BCIRG 006Disease-Free Survival 3rd
Planned Analysis
13
Current BCIRG 006Overall Survival 3rd Planned
Analysis
14
Cardiac Deaths and CHF as per Independent Review
Panel
15
Therapeutic Index Most Recent Data
16

• Efficacy Analysis
• Patients eligible for crossover censored
• Data frozen on 11/3/2009

Perez EA et al, SABCS 2009
17
Control vs Sequential
Perez EA et al, SABCS 2009
18

• Efficacy Analysis
• Censoring based on temp closure of C,and
  eligibility for crossover
• Data frozen on 11/3/2009

N9831
Perez EA et al, SABCS 2009
19
Sequential vs Concurrent 1st Interim Analysis

• At 50 of planned number of events (312 events)
• 1,903 pts, median follow-up 5.3 yr
• 75 of pts followed for 5 yr
• DFS may differ with respect to the timing of
  trastuzumabs addition to AC ? T
• Log rank P0.019 (HR 0.77 95 CI 0.61-0.96)
• Not crossing the boundary for statistical
  significance, pre-set at 0.00116

Perez EA et al, SABCS 2009
20
Sequential vs Concurrent
Perez EA et al, SABCS 2009
21
Conclusions

• DFS is significantly improved with the
  additionof 52 wks of trastuzumab to AC ? T
• There is a statistically significant 33
  reduction in the risk of an event with the
  sequential addition of trastuzumab following AC ?
  T
• 5 yr DFS 72 vs. 80
• There is a strong trend for a 25 reductionin
  the risk of an event with starting trastuzumab
  concurrently with taxane relative to sequentially
• 5 yr DFS 80 vs. 84

Perez EA et al, SABCS 2009
22
Trastuzumab DFS
Piccart-Gebhart et al 2005 Romond et al
2005Slamon et al 2005 Joensuu et al 2005
23
Adjuvant Trastuzumab

• Test everyone for HER2, inquire about testing
  quality and look carefully at equivocal results
• Most important message -gt Give Trastuzumab!
• Either TCH or ACgtTH supported by data
• Differences between regimens modest
• Slightly more recurrence with TCH balanced by
  increased cardiac and long-term marrow toxicity
  with ACgtTH
• Give concurrently with chemo unless there is a
  compelling reason not to

24
Case 2

• 74 year old presents with 5 cm primary breast
  mass with associated axillary adenopathy.
• ER-, PR-, HER2 3 by IHC (FISH ratio 8.9)
• Staging finds several liver lesions, largest 2.2
  cm
• Biopsy of liver lesion confirms MBC, HER2
• LFTs normal
• LVEF 62
• She refuses chemotherapy but will consider other
  options, family supports her wishes
• What would you recommend?

25
Pathway ActivationHER Ligands
26
Lapatinib Trastuzumab
Lapatinib 1500 mg PO QD (n 148)
EGF104900
Primary endpoint PFS Secondary
endpoints OS ORR CBR
Optional crossover to trastuzumab arm if PD
after 4 wks (n 77)
Heavily pretreated patients with HER2-positive
MBC and progression on trastuzumab (N 296)
Lapatinib 1000 mg PO QD Trastuzumab 4 mg/kg
loading dose, then 2 mg/kg IV wkly (n 148)
Stratified by visceral disease and hormone
receptor status
PO, orally QD, once daily.
Blackwell K, et al. SABCS 2009 61.
27
Lapatinib Trastuzumab
52 of patients crossed over from single-agent
lapatinib to combination therapy on progression.
Blackwell K, et al. SABCS 2009 61.
28
Lapatinib Trastuzumab Safety Update

• Most AEs reported in 10 of patients were grade
  1/2
• Diarrhea was the only grade 3/4 AE reported in
  5 of patients
• 8 of patients receiving lapatinib plus
  trastuzumab vs 7 receiving lapatinib alone
• 1 fatal cardiac event in combination arm

Defined as grade 3 LV dysfunction, LVEF
decrease 20 from baseline and below lower
limit of normal defined by institution.
Blackwell K, et al. SABCS 2009 61.
29
Lapatinib Trastuzumab

• Lapatinib trastuzumab associated with 26
  improvement in OS vs lapatinib alone
• Significant survival benefit despite 52
  crossover
• Supports combination arm of ALTTO
• Lapatinib plus trastuzumab well tolerated
• AEs comparable to lapatinib alone
• Offers possible options for heavily pretreated
  patients who progress on trastuzumab

Blackwell K, et al. SABCS 2009 61.
30
T-DM1

• T-DM1, an antibody-drug conjugate, combines
  biologic effect of trastuzumab against
  HER2-expressing cells with highly potent
  antimicrotubule agent DM1
• MOA likely involves receptor-mediated
  internalization of T-DM1 after binding to HER2,
  resulting in intracellular release of DM1

Austin CD et al. Mol Biol Cell.
2004155268-5282.
31
T-DM1 Monotherapy

• Multicenter, single arm (N110)
• Primary endpoint ORR by IRF at 24 weeks
• Eligibility
• Prior anthracycline, taxane, capecitabine,
  trastuzumab, lapatinib
• Active disease progression on last therapy
• LVEF 50 or better

Krop I, et al. SABCS 2009.5090.
32
T-DM1 Monotherapy

• ORR (by independent review) 32.7
• Clinical benefit rate (by independent review)
  44.5
• Median PFS 7.3 months
• T-DM1 well tolerated
• Thrombocytopenia
• Offers a very real option for additional therapy
  for HER2 patients

Krop I, et al. SABCS 2009 5090.
33
Response Rates for Novel HER2-Targeting Agents
After Progression on Trastuzumab
Modi et al, ASCO 2008 Gelmon et al, ASCO 2008
Swaby et al, ASCO 2009 Burris et al, ESMO 2009.
34
Topics

• HER2 positive disease
• Growing number of options
• Angiogenesis
• Bevacizumab questions answered and rephrased
• Small molecule success and disappointment

35
Angiogenesis

• Angiogenesis is important for tumor growth
• Highly regulated, multiple redundant pathways
• VEGF among the most potent and frequently
  overexpressed
• Bevacizumab
• Modest activity as monotherapy
• Disappointing results in initial randomized trial
• E2100, then AVADO and RIBBON-1
• Now RIBBON-2

36
E2100
Miller K, et al. N Engl J Med. 20073572666-2676
37
AVADO

• Primary endpoint progression-free survival
• Secondary endpoints overall response rate,
  duration of response, time to treatment failure,
  overall survival, safety, quality of life
• Docetaxel was administered for a maximum of
  nine cycles, but earlier discontinuation was
  permitted

Miles D, et al. J Clin Oncol. 200826(18S). LBA
1011.
38
RIBBON-1

• Capecitabine (1000 mg/m2 BID x 14d)
• Taxane (docetaxel or protein-bound paclitaxel)
• Anthracycline-based chemotherapy (AC, EC, FAC,
  FEC)
• Placebo or bevacizumab (15 mg/kg)

Robert et al, ASCO 2009 1005
39
Study Design
1Miller K, et al. N Engl J Med.
20073572666-2676 2Miles D, et al. J Clin
Oncol. 200826(18S). LBA 1011.
39
40
Patient Population
1Miller K, et al. N Engl J Med.
20073572666-2676 2Miles D, et al. J Clin
Oncol. 200826(18S). LBA 1011.
41
Efficacy
Relative increase in RR 20-50
42
Case 3

• 63 year old with metastatic breast cancer
  consults you for advice on additional therapy
• Initial diagnosis 6 years ago, adjuvant AC x 4
  cycles followed by AI for stage I disease (T2.1
  cm, LN-, G2, ER, PR-, HER2-)
• Metastatic disease identified with bone
  invovlement and mediastinal and SC adneopathy
  28 months ago
• Initially treated with fulvestrant gt PR lasting
  12 months
• Tamoxifen gt SD lasting 6 months
• Exemestane gt PD after 2 months
• Capecitabine gt PR lasting 8 months, now with PD

43
Case 3

• Currently has minimally symptomatic bone
  involvement (does not require narcotics) with
  asymptomatic mediastinal nodes and new pulmonary
  nodules (largest 1.6 cm)
• PS 1
• Local oncologist has recommended taxane based
  therapy
• Would you add bevacizumab?

44
Ribbon 2
National Cancer Institute. Clinical Trials (PDQ).
Available at http//www.cancer.gov/search/clinica
l_trials/.
45
Key Eligibility Criteria

• One prior cytotoxic treatment for MBC
• ECOG performance status (PS) 0 or 1
• HER2-negative or HER2 status unknown
• No prior therapy with bevacizumab or other VEGF
  pathway- target therapy

46
Primary Endpoint of PFS(ITT Population)
Brufsky et al, SABCS 2009 42
47
Cohort-Specific Analyses of PFS(ITT Population)
Brufsky et al, SABCS 2009 42
48
What Weve Learned

• Bevacizumab is an important component of initial
  chemotherapy for metastatic HER2- breast cancer
• Increases RR
• Prolongs PFS
• Adds to second-line chemo in patients who didnt
  get bevacizumab with initial chemo
• Toxicity differs among reported regimens
• Bevacizumab associated toxicity consistent

49
Remaining Questions

• Combine with anti-HER2 and hormonal therapies
• Optimal duration of therapy
• Why have we failed to demonstrate a difference in
  OS?

50
In Search of OS

• There is no difference
• Subsequent therapy obscures benefit of 1st line
  therapy
• Reported trials individually underpowered
• Amenable to meta-analysis (see ASCO 2010)
• Resistance to bevacizumab more aggressive
  disease
• Rapid regrowth of vasculature after stopping
  bevacizumab

51
Remaining Questions

• Combine with anti-HER2 and hormonal therapies
• Optimal duration of therapy
• Why have we failed to demonstrate a difference in
  OS?
• Does the choice of chemotherapy matter?

52
Does the Choice of Chemo Matter?

• HR broadly similar but absolute improvements in
  PFS gain differ widely
• Ability to continue combined therapy
• Interval censoring
• May depend on mechanism(s) of action?
• Inherent anti-angiogenic effect of chemotherapy
• Chemotherapy induced release of bone marrow
  progenitors
• Role of VEGF on tumor cells

53
TKI Alternatives SorafenibTargets Both
Tumor-Cell Proliferation and Angiogenesis
Wilhelm et al, SABCS 2009 42
54
TIES ProgramTrials to Investigate the Efficacy
of Sorafenib in Breast Cancer
55
A Multinational Double-Blind, Randomized Phase 2b
Study Evaluating the Efficacy and Safety of
Sorafenib Compared to Placebo when Administered
in Combination with Capecitabine in Patients with
Locally Advanced Metastatic Breast Cancer
Baselga et al, SABCS 2009 45
56
A Double-Blind, Randomized Phase 2b Study
Evaluating the Efficacy and Safety of Sorafenib
Compared to Placebo when Administered in
Combination with Paclitaxel in Patients with
Locally Advanced Metastatic Breast Cancer
http//www.clinicaltrials.gov/ct/show/NCT00499525
Gradishar et al, SABCS 2009 44
57
Top Line Efficacy and Safety(SOLTI-0701 NU
07B1)
Chemotherapy placebo vs chemotherapy
sorafenib One-sided
58
Adverse Event Rates (Safety Population)
PPaclitaxel, SSorafenib, CCapecitabine,
PlPlacebo
59
PFS ITT Population
SABCS 2009 45
60
SOLTI-0701 Capecitabine /- Sorafenib

• 42 reduction in risk of disease progression or
  death
• PFS benefit observed in subgroup analyses
• PFS benefit noted in both first-line and
  second-line therapy
• Increased incidence of hand-foot syndrome
• Attention to dose modification critical
• Phase III registration trial planned for
  sorafenib/capecitabine in advanced breast cancer

61
Motesanib Blocks More Than One Mechanism Involved
in Tumorigenesis
62
Study Design
Mackey et al, SABCS 2009 47
Mackey et al, SABCS 2009 47
63
Objective Response Rate(ITT Population)
Mackey et al, SABCS 2009 47
Mackey et al, SABCS 2009 47
64
Progression-Free Survival(ITT Population)
Mackey et al, SABCS 2009 47
Mackey et al, SABCS 2009 47
65
Progression-Free Survival(ITT Population)
Mackey et al, SABCS 2009 47
66
Phase III Sunitinib vs. Capecitabine

• HER2 negative, prior anthracycline and taxane
  required
• N483
• ORR 11.3 vs. 16.4
• PFS 2.8 months vs. 4.2 months

Favors Capecitabine
Barrios et al, SABCS 2009 46
67
Conclusions

• Bevacizumab is an important component of initial
  chemotherapy for patients with HER2- disease
• Some benefit in second line if not given prior
• All bevacizumab containing regimens are not equal
• Toxicity differences clear
• Efficacy?
• Differences in chemotherapy affects may be
  important
• Small molecule VEGF TKIs have some activity as
  well but toxicity troublesome

68
The Future Is Possible
I dont know if heavier than air flight is
possible, but Im committed to living my life
dedicated to its possibility.
- Wilbur Wright