1. Progress in Treatment of Metastatic HER2+ Breast Cancer
Mohammad Jahanzeb, MD
Medical Advisor Global Initiatives, NCCN Professor of Clinical Medicine, Hematology-Oncology Director, UM Sylvester Deerfield Campus Associate Director Center for Community Outreach Sylvester Comprehensive Cancer Center University of Miami, Miller School of Medicine

2. This activity is supported by educational grant from Genentech
This activity is supported by educational grant from Genentech. The National Comprehensive Cancer Network® and Clinical Care Options® appreciate that supporting companies recognize the need for autonomy in the development of the content. All content for this session is produced completely independently.

3. Faculty Disclosures
Mohammad Jahanzeb, MD, has disclosed that he has received consulting fees from Genentech.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

4. About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (
Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

5. Pivotal Phase III Trastuzumab Studies in Metastatic Breast Cancer
Study
Median Survival, Mos
HR (95% CI)
P Value
Chemotherapy Alone
Chemotherapy + Trastuzumab
Paclitaxel
(Slamon)[1]
20.3
25.1
0.80 ( )
.046
Docetaxel
(Marty)[2]
22.7
31.2
Not reported
.0325
Slamon: Standard chemotherapy consisted of paclitaxel (if received prior anthracycline in adjuvant setting) or doxorubicin(or epirubicin) cyclophosphamide (if did not receive prior anthracycline in adjuvant setting)
Marty: Chemotherapy consisted of docetaxel 100 mg/m2 q 3 wks
1. Slamon DJ, et al. N Engl J Med. 2001;344: Marty M, et al. J Clin Oncol. 2005;23:

6. EGF100151: Phase III Trial of Capecitabine ± Lapatinib in Advanced or Metastatic Breast Cancer
Eligibility criteria:
Stage IIIB, stage IIIC with T4 lesion, or stage IV breast cancer that has progressed
ErbB-2 overexpression (IHC3+ or 2+ or FISH)
Unlimited previous therapies, but no previous capecitabine
Previous therapies must include
Trastuzumab in metastatic setting
Anthracycline and taxane in either metastatic or adjuvant setting
Arm 1
Lapatinib 1250 mg/day PO +
Capecitabine 2000 mg/m2/day on Days 1-14 q21 days
R A N D O M I Z E
Arm 2
Capecitabine 2500 mg/m2/day
on Days 1-14 q21 days
The EGF is a registration phase III trial to evaluate the ability of lapatinib to augment the efficacy of standard chemotherapy in refractory MBC patients.
Patients enrolled in the EGF trial must be women with advanced or metastatic breast cancer with documented ErbB2 overexpression (immunohistochemistry 3+ or 2+ with FISH confirmation). Patients must have progressed on both anthracycline and taxane-containing regimens ± prior treatment with trastuzumab. Eligible patients cannot have been treated with capecitabine prior to this trial. Patients will be randomized to receive 2,000 mg/m2/day capecitabine on days 1-14, every 21 days, with or with out oral lapatinib at a dose of 1250 mg/day. Patients will continue to receive treatment until disease progression.
The primary endpoint of this study is time to Progression (TTP). Secondary endpoints include response and clinical benefit rates, time to response, duration of response, 6-month progression free survival, and overall survival. Safety, tolerability, quality of life, and pharmacodynamics will also be analyzed.
Primary endpoint: TTP
Secondary endpoint: OS, PFS, ORR
Geyer C, et al. N Engl J Med 2006;355:

7. Time to Progression: ITT Population Independent Assessment
Capecitabine
Lapatinib + Capecitabine
< .001
P value 72 49
Progressed or died, n
4.4
8.4
Median TTP, mos
161
163
Patients, n
0.49 ( )
HR (95% CI)
100
Patients Free From Progression* (%) 80 60 40 20 10 20 30 40 50 60 70
Wks
Geyer C, et al. N Engl J Med. 2006;355:

8. Crossover at the time of progressive disease
Phase III Trial: Lapatinib ± Trastuzumab in Heavily Pretreated MBC Following Progression on Trastuzumab
Lapatinib 1500 mg/day PO
(n=148)
RANDOMI ZE
HER2+ (FISH+/IHC 3+)
Progressed on
anthracyclines, taxanes, and most recent trastuzumab regimen
Crossover at the time of progressive disease
Lapatinib 1000 mg/day PO + Trastuzumab 4 mg/kg load → 2 mg/kg/wk
(N=148)
Primary endpoint: PFS: investigator
Blackwell KL, et al. J Clin Oncol. 2012;30:

9. Lapatinib/ Trastuzumab (n = 146)
Lapatinib ± Trastuzumab in Heavily Pretreated MBC: Updated Survival Analysis
Endpoint
Lapatinib/ Trastuzumab (n = 146)
Lapatinib (n = 145)
HR/OR
P Value
Median PFS, wks
12.0
8.1
HR: 0.74
.011
Median OS, mos 14
9.5
.026
ORR, % 10 7
OR: 1.5
.46
Clinical benefit rate,* % 25 12
OR: 2.2
.01
*PR + CR + SD ≥ 6 mos.
Factors Affecting OS HR
P Value
Treatment (combination/single agent)
0.71
.0116
ECOG PS (0/≥ 1)
0.46
< .0001
Site of disease (nonvisceral/visceral)
0.68
.0181
Metastatic sites (< 3/≥ 3)
0.48
Time from diagnosis to randomization
0.93
.0012
Updated OS adjusted for baseline covariates: HR: 0.71; P = .0116
Blackwell KL, et al. J Clin Oncol. 2012;30:

10. Randomized Controlled Trial Comparing Taxane-Based CT With Lapatinib or Trastuzumab as First-line Therapy for HER2+ MBC
100 80
Median PFS TTAX/T: 11.4 mos Median PFS LTAX/L: 8.8 mos 60
HR: 1.33 (95% CI: ; P = .01)
PFS, ITT Analysis (%) 40 20
TTAX/T
LTAX/L 5 10 15 20 25 30 35 40
Mos
Pts at Risk, n
TTAX/T
318
223
110 44 21 8 1
LTAX/L
318
218 85 35 13 2
Gelmon KA, et al. ASCO Abstract LBA671.

11. Pertuzumab binds HER2 at which of the following domains?II
III IV

12. Pertuzumab binds HER2 at which of the following domains?II
III IV

13. Pertuzumab: Dimerization Inhibitor
HER2-specific monoclonal antibody
Binds HER2 at the dimerization domain II
Disrupts ligand-dependant HER2 heterodimerization and signaling
Preclinical activity in non-HER2 overexpressing tumors
Activity in trastuzumab-refractory cell lines
In vitro synergy with trastuzumab

14. CLEOPATRA: Study Design
Placebo + Trastuzumab PD
(n = 406)
Docetaxel* ≥6 cycles recommended
Patients with HER2-positive MBC centrally confirmed (n = 808)
1:1
Pertuzumab + Trastuzumab PD
Docetaxel* ≥6 cycles recommended
(n = 402)
Randomization stratified by geographic region and previous treatment status (neo/adjuvant chemotherapy received or not)
Study dosing q3w:
Pertuzumab/placebo mg loading dose, 420-mg maintenance
Trastuzumab 8-mg/kg loading dose, 6-mg/kg maintenance
Docetaxel 75 mg/m2, escalating to 100 mg/m2 if tolerated
*<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion.
Baselga J, et al. N Engl J Med. 2012;366:

15. CLEOPATRA: PFS Assessed at an IRF
100
Pertuzumab (median: 18.5 mos) Control (median: 12.4 mos) 90 80 70 60
PFS (%) 50 40
HR: 0.62 (95% CI: ; P < .001) 30 20 10 5 10 15 20 25 30 35 40
Mos
Pts at Risk, n Pertuzumab Control
139 93
83 42
32 17
10 7
0 0
0 0
Baselga J, et al. N Engl J Med. 2012;366:

16. CLEOPATRA: Confirmatory OS Analysis of Phase III Pertuzumab Study
A second interim analysis of OS was performed with an additional 1 yr of follow-up
(Results at median FU of 30 mos)
This survival benefit was observed in nearly all subgroups analyzed
This second interim OS analysis was considered significant and confirmatory
Now crosses the O-Brien-Fleming stopping boundary
Second Interim
OS Analysis
Pertuzumab Arm
Placebo Arm
HR (95% CI)
P Value
3-yr estimated, % 66 50
0.66 ( )
.0008
Median OS, mos
Not reached
37.6
Swain SM, et al. SABCS Abstract P

17. Trastuzumab + Docetaxel + Pertuzumab Trastuzumab + Docetaxel + Placebo
CLEOPATRA: Safety
Adverse Events, %
Trastuzumab + Docetaxel + Pertuzumab
(n = 407)
Trastuzumab + Docetaxel + Placebo
(n = 397)
All Grades
Grade 3/4
Diarrhea
66.8
7.9
46.3
5.0
Alopecia
60.9 NR
60.5
Neutropenia
52.8
48.9
49.6
45.8
Nausea
42.3
41.6
Fatigue
37.6
2.2
36.8
3.3
Rash
33.7
24.2
Decreased appetite
29.2
26.4
Mucosal inflammation
27.8
19.9
Asthenia
26.0
2.5
30.2
1.5
Peripheral edema
23.1
30.0
Constipation
15.0
24.9
Febrile neutropenia
13.8
7.6
Dry skin
10.6
4.3
Leukopenia
12.3
14.6
NR, not reported.
Baselga J, et al. N Engl J Med. 2012;366:

18. Ado-Trastuzumab Emtansine (T-DM1)
Antibody–drug conjugate combining trastuzumab with cytotoxic agent, DM1 (derivative of maytansine)
DM1: naturally occurring antitumor antibiotic
Significant preclinical activity, but significant clinical toxicity as free drug
T-DM1 is designed to preferentially deliver DM1 to HER2+ tumor cells
Improve therapeutic index of DM1
Maintain biologic effect of Tmab
On February 22, 2013, the FDA approved T-DM1 for use as a single agent for the treatment of patients with HER2-positive MBC who previously received trastuzumab and a taxane

19. Lapatinib + Capecitabine q3wk
EMILIA Study Design
HER2-positive (centrally confirmed) locally advanced or metastatic breast cancer (N = 991)
T-DM1 q3wk
(n = 495)
Treatment continues until disease progression or unmanageable toxicity
Lapatinib + Capecitabine q3wk
(n = 496)
No provision for cross-over
Primary endpoints: PFS by IRF, OS, safety
Secondary endpoints: OS, QOL: FACT-B
Key inclusion criteria
Previous 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
Verma S, et al. N Engl J Med. 2012;367:

20. What percentage of patients in the EMILIA trial had received previous therapy for MBC?
< 25%
25% to 50%
50% to 75%
> 75%

21. What percentage of patients in the EMILIA trial had received previous therapy for MBC?
< 25%
25% to 50%
50% to 75%
> 75%

22. Previous Systemic Treatment
Cap + Lap
(n = 496)
T-DM1
(n = 495)
Previous treatment type, n (%)
Taxanes
Anthracyclines
Endocrine agents
494 (100)
302 (61)
204 (41)
493 (100)
303 (61)
205 (41)
Previous therapy for MBC, n (%)
Yes No
438 (88)
58 (12)
435 (88)
60 (12)
Previous trastuzumab treatment, n (%)
Early breast cancer only
495 (100)
77 (16)
78 (16)
Duration of trastuzumab treatment, n (%)
< 1 yr
≥ 1 yr
212 (43)
284 (57)
210 (42)
285 (58)
Median time since last trastuzumab, mos (range)
1.5 (0-98)
1.5 (0-63)
Verma S, et al. N Engl J Med. 2012;367:

23. PFS by Independent (IRF) Review
100
Median No. of Mos
No. of Events
Lapatinib-capecitabine T-DM1 80
Stratified HR: 0.65 (95% CI: ; P < .001) 60
PFS (%) 40
T-DM1 20
Lapatinib-capecitabine 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Mos
Pts at Risk, n Lapatinib- capecitabine T-DM1
35 72
25 54
14 44
9 30
8 18
5 9
1 3
0 1
0 0
Verma S, et al. N Engl J Med. 2012;367:

24. OS: Second Interim Analysis
Median No. of Mos
No. of Events
100
85.2% (95% CI: )
Lapatinib-capecitabine T-DM1
Stratified HR: 0.68 (95% CI: ; P < .001) 80
64.7% (95% CI: )
Efficacy stopping boundary P = or HR: 0.73 60
78.4% (95% CI: )
T-DM1
OS (%) 40
51.8% (95% CI: )
Lapatinib-capecitabine 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Pts at Risk, n Lapatinib- capecitabine T-DM1
Mos
63 86
45 62
27 38
17 28
7 13
4 5
Data cutoff July 31, 2012; median follow-up: 18.6 mos.
Verma S, et al. N Engl J Med. 2012;367:

25. Adverse Events: Grade ≥ 3 AEs With Incidence ≥ 2%
Cap + Lap, %
(n = 488)
T-DM1, %
(n = 490)
Adverse Event
All Grades
Grade ≥ 3
Total
97.7
57.0
95.9
40.8
Diarrhea
79.7
20.7
23.3
1.6
Hand–foot syndrome
58.0
16.4
1.2
0.0
Vomiting
29.3
4.5
19.0
0.8
Neutropenia
8.6
4.3
5.9
2.0
Hypokalemia
4.1
2.2
Fatigue
27.9
3.5
35.1
2.4
Nausea
44.7
2.5
39.2
Mucosal inflammation
19.1
2.3
6.7
0.2
Thrombocytopenia
28.0
12.9
Increased AST
9.4
22.4
Increased ALT
8.8
1.4
16.9
2.9
Anemia
8.0
10.4
2.7
There was no increase in cardiotoxicity (LVEF <50% and ≥ 15-point decrease from baseline): Cap + Lap, 1.6% (445 evaluable patients); T-DM1, 1.7% (481 evaluable patients).
Verma S, et al. N Engl J Med. 2012;367:

26. MARIANNE: A Phase III Study of T-DM1 + Pertuzumab vs Trastuzumab + Taxane in Patients With MBC: Study Design
Trastuzumab + Taxane (until PD) (n = 364)
Patients with HER2+ progressive or recurrent locally-advanced breast cancer or previously untreated MBC (N = 1092)
T-DM1 + PTZ (until PD) (n = 364)
T-DM1 + PTZ placebo (until PD) (n = 364)
Stratified by:
World region
Neo/adjuvant therapy (Y/N)
Trastuzumab and/or lapatinib based therapy (Y/N)
Visceral disease (Y/N)
Primary endpoints: PFS as assessed by IRF, safety
Secondary endpoints: OS, PFS by investigator, PRO analyses, biomarkers
ClinicalTrials.gov. NCT

27. Other Trials With Completed or Ongoing Accrual in MBC
T-DM1 vs investigator’s choice (TH3RESA)
Addition of pertuzumab to vinorelbine and trastuzumab (VELVET)

28. Other Novel Compounds Combined With Trastuzumab
Neratinib
Sunitinib
Afatinib
Vorinostat
Everolimus
Ridaforolimus
Pazopanib
HSP90 inhibitors

29. Case A 57-yr-old woman felt a left breast mass and saw her internist
Physical exam and imaging confirmed the presence of a cm left breast mass with palpable left axillary adenopathy
A core biopsy of the breast mass revealed invasive ductal carcinoma ER/PgR-negative, HER2-positive by FISH
Imaging studies revealed multiple lung nodules and lytic bony lesions
CBC and chemistries, including LFTs, were normal
A biopsy of one of the lung lesions confirms metastatic adenocarcinoma consistent with breast primary, which was confirmed as HER2 positive

30. Which of the following is a category 1 recommendation for this patient in the NCCN guidelines?
Docetaxel + trastuzumab
Paclitaxel + carboplatin + trastuzumab
Docetaxel + pertuzumab + trastuzumab
Trastuzumab + lapatinib
T-DM1

31. Which of the following is a category 1 recommendation for this patient in the NCCN guidelines?
Docetaxel + trastuzumab
Paclitaxel + carboplatin + trastuzumab
Docetaxel + pertuzumab + trastuzumab
Trastuzumab + lapatinib
T-DM1

32. NCCN: First-line Treatment of HER2+ MBC With No Previous Trastuzumab Exposure
Preferred regimens
Docetaxel + trastuzumab + pertuzumab (category 1)
Paclitaxel + trastuzumab + pertuzumab
Other regimens
Trastuzumab with:
Paclitaxel ± carboplatin
Docetaxel
Vinorelbine
Capecitabine
According to the NCCN guidelines, patients with MBC whose tumors overexpress HER2 may benefit from trastuzumab monotherapy or in combination with chemotherapy.
CT regimens preferred in NCCN guidelines for use in combination with trastuzumab include
Single-agent CT: paclitaxel (either 175 mg/m2 q3w or 80 to 90 mg/m2 qw), docetaxel (either 80 to 100 mg/m2 q3w or 35 mg/m2 qw), or vinorelbine (25 mg/m2 qw)
Combination CT: paclitaxel + carboplatin (q3w)
Trastuzumab qw (4 mg/kg week 1, then 2 mg/kg/wk) or q3w (8 mg/kg week 1, then 6 mg/kg/wk)
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology – v2.2006; Breast Cancer. At: Accessed December 2005.
NCCN. Clinical practice guidelines in oncology: breast cancer. v

33. NCCN: Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure
Preferred agents
Ado-trastuzumab emtansine (T-DM1)
Other agents
Lapatinib + capecitabine
Trastuzumab + capecitabine
Trastuzumab + lapatinib (without cytotoxic therapy)
Trastuzumab + other agents
According to the NCCN guidelines, patients with MBC whose tumors overexpress HER2 may benefit from trastuzumab monotherapy or in combination with chemotherapy.
CT regimens preferred in NCCN guidelines for use in combination with trastuzumab include
Single-agent CT: paclitaxel (either 175 mg/m2 q3w or 80 to 90 mg/m2 qw), docetaxel (either 80 to 100 mg/m2 q3w or 35 mg/m2 qw), or vinorelbine (25 mg/m2 qw)
Combination CT: paclitaxel + carboplatin (q3w)
Trastuzumab qw (4 mg/kg week 1, then 2 mg/kg/wk) or q3w (8 mg/kg week 1, then 6 mg/kg/wk)
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology – v2.2006; Breast Cancer. At: Accessed December 2005.
NCCN. Clinical practice guidelines in oncology: breast cancer. v

34. Summary
HER2-positive patients now have an expanding menu of options for their treatment
Continued HER2 inhibition beyond progression seems important
Dual blockade appears better than single blockade
Continued exploration of mechanisms of resistance is necessary to be able to individualize therapy