1. 2nd annual San Antonio breast cancer symposium review january 28, 2012
Sponsored By:

2. SABCS 2011 Review: HER2-Directed Therapy in Breast Cancer
Chau Dang, MD
Assistant Professor of Medicine
Weill Cornell Medical College
Breast Cancer Medicine Service
Memorial Sloan-Kettering Cancer Center
January 28, 2012

3. Objectives Overview on Trastuzumab Lapatinib Neratinib Pertuzumab
Goss et al (abstract # S4-7)
Neratinib
Martin et al (abstract # S5-7)
Pertuzumab
Baselga et al (abstract # S5-5)
Schneeweiss et al (abstract # S5-6)
pCR as predictor of outcomes
Loibl et al (abstract # S5-4)

4. HER2-“Positive” Breast Cancer
20-25% of invasive breast cancers
Overexpression can activate signaling
Promotes cell proliferation and survival
HER2 is a member of the EGFR family of proteins and activation of HER2 by as yet unidentified mechanisms leads to downstream signalling cascades that ultimately culminate in cell proliferation, survival, mobility and invasiveness. The monoclonal antibody trastuzumab and the TKI lapatinib are the 2 currently FDA-approved HER2-targeted agents.
Hudis NEJM 2007

5. Trastuzumab in First-Line Treatment
Studies
Slamon et al,
20011
Vogel et al,
20022
Burstein et al, 20033
Marty et al, 20054
Kaufman et al, 20095
Valero et al 20116 N
469
114 54
186
207
263
Treatment
AC/EC + H or T+H vs chemo H VH
D+H vs D
Anas + H vs
Anas
DCbH vs
D+H
Response Rate
50% vs 32%*
35% (IHC 3+)
34% (FISH+)
68%
61% vs 34%*
20.3% vs 6.8%*
72% vs 72%
Median TTP
7.4 vs 4.6 mo*
3.8 mo (H at 4 mg/kg)
3.5 mo
(H at 2 mg/kg) NR
11.7 vs 6.1 mo*
4.8 vs
2.4 mo*
10.3 vs 11.1 mo
Median PFS
Median OS
25.1 vs 20.3 mo*
24.4 mo
31.2 vs 22.7 mo*
28.5 vs 23.9 mo
37.4 vs 37.1 mo
Have Slamon, vogel need to check
AC, anthracycline + cyclophosphamide; Anas, anastrozole; T, paclitaxel; D, docetaxel; EC, epirubicin + cyclophosphamide; H, trastuzumab; mo, months; PFS, progression-free survival; OS, overall survival; RR, response rate; TTP, time to progression; VH, vinorelbine + trastuzumab; *statistically significant
1Slamon DJ et al. N Engl J Med. 2001:344(11): ; 2Vogel CL et al. J Clin Oncol. 2002;20: ; 3Burstein HJ et al. J Clin Oncol. 2003;21(15): ; 4Marty M et al. J Clin Oncol. 2005;23(19): ; 5Kaufman B et al. J Clin Oncol. 2009;27(33): ; 6Valero V et al. J Clin Oncol. 2011;29:

7. “Other” HER Targeted Strategies
There are a number of ways to target EGFR dysregulation.
Antibodies against EGFR can act as receptor antagonists and prevent ligand binding, eg, cetuximab.
Antibodies may prevent receptor dimerization, eg, trastuzumab (HER2).
Antibodies against ligand also block binding, and this approach may be useful when 1 ligand binds to several receptors.
Using a small molecule that specifically targets and either reversibly or irreversibly inhibits the tyrosine kinase activity is an approach that may block signaling by all active EGFR forms, including those receptors with mutated or deleted extracellular domains.
Erlotinib and gefitinib are 2 ATP-competitive inhibitors of the EGFR tyrosine kinase.
Mutations in the tyrosine kinase domain that lead to increased growth factor signaling correlate with increased clinical responsiveness to these TKIs. These mutations demonstrate increased sensitivity to erlotinib and gefitinib.
Conjugates of a ligand and a cytotoxic agent (eg, TP-38 and DAB389EGF) or an antibody and a cytotoxic agent (eg, scFv-14e1-ETA fusion toxin) are another approach that may have the advantage of killing the cell after internalization, in addition to inhibiting tyrosine kinase activity.
Anti-ligand
blocking
antibodies
Anti-EGFR
blocking
antibodies
cetuximab
Tyrosine
kinase
Inhibitors
neratinib
lapatinib
erlotinib gefitinib
HER dimerization
inhibitors
pertuzumab
Ligand- or Ab-toxin
conjugates
T-DM1
Adapted from Noonberg and Benz. Drugs. 2000;59:753.

8. Lapatinib

9. Lapatinib Targets intracellular kinase domain of HER1 and HER2
1+1
2+2
1+2
Targets intracellular kinase domain of HER1 and HER2
Reversible inhibition of HER1 and HER2 homo and heterodimer formation
Inhibits growth in trastuzumab conditioned cell lines
Courtesy of E. Winer 9

10. Clinical Activity of Lapatinib in HER2+ MBC
ORR
Monotherapy in trastuzumab-refractory MBC1,2
4-8%
Monotherapy in trastuzumab-
naive MBC3
≈24%
With chemo (capecitabine) in chemo & trastuzumab-
refractory MBC4,5
24%
(vs 14% with X alone)
With chemo (paclitaxel) in first-line MBC setting6
63%
(vs 38% with T alone)
1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4Geyer NEJM 2006; 5Cameron BrCancerResTreat 2008; 6Di leo JCO 2008

11. TEACH trial: Tykerb Evaluation After Chemotherapy
Randomized, double-blind, placebo-controlled, phase III trial to evaluate the effects of delayed adjuvant lapatinib monotherapy
More than 3000 women
completed neo-adjuvant or adjuvant chemotherapy,
did not receive trastuzumab and
NED
Randomized to lapatinib or placebo for up to 12 months or until a DFS event
Median time from diagnosis to study entry: 3 years
Goss et al presented the results of the TEACH trial (Tykerb Evaluation after Chemotherapy) in the adjuvant setting.
This was a randomized DB, PC phase 3 study to eval effects of delayed L or placebo for up to 12 mo.
More than 3000 pts were enrolled who completed neo/adj Rx and who did not receive Tras in adjuvant setting.
Med time from dx to study entry was 3 yrs.
Goss abs S4-7

12. Delayed Adjuvant Lapatinib Results
Median follow up of 4 years
DFS events were 13% vs. 17% in favor of lapatinib vs placebo (HR = % CI, 0.70 to 1.00; 2 sided p=0.053), but not statistically significant.
No role for “delayed” lapatinib in the adjuvant setting !
What about “upfront” lapatinib in ALTTO ?
At a med FU was 4 yrs, DFS events occurred in 13% in pts on L vs 17% in placebo arm w/ HR of 0.83 and 2 sided p value of
Although a numerical improvement in DFS was in favor of L arm, this did not reach the pre-specified stat significance.
Thus, there is no role for “delayed” L in adjuvant setting.
But, is there a role for “upfront” lapatinib in another adjuvant trail, namely ALTTO?
Goss abs S4-7

13. Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization
ALTTO
Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization
Neo (adj) anthracycline-based chemo
TL (12 wks)
L (40 wks)
(L =1500 mg qd)
TH (12 wks)
THL (12 wks)
HL (40 wks)
(L =1000 mg qd)
TH (12 wks)
H (40 wks)
Washout (6 wks)
This is one design of the ALTTO study, which is the adjuvant study.
In this study 8000 pts w/ HER2+ dz are given an anthracycline based treatment and then they are randomized to 1 of 4 arms of Rx as shown, TH arm vs TL-L vs TH then L vs THL-HL arm.
Recently, based on the preliminary efficacy analysis by the ALTTO trial independent data monitoring committee, the lapatinib only arm (TL) was closed as it crossed the futility margin and as such its non-inferiority to trastuzumab will not be reached. While the overall study continues, the committee recommended that patients on this arm should be offered trastuzumab (Perez et al. Oral presentation-ASCO Breast Cancer Symposium, September, 2011.
It appears that lapatinib “upfront” is inferior to trastuzumab, but we await the results of ALTTO to show if there is any benefit to give L after 3 mo of standard TH or in combination w/ tras as in THL.
L (34 wks)
(L =1500 mg qd)
T=paclitaxel, H=trastuzumab, L=lapatinib
Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years
Radiotherapy if indicated

14. Neratinib

15. Lapatinib vs Neratinib in HER2+ MBC
Lapatinib ORR
Neratinib ORR
Monotherapy in H-refractory MBC
4-8%1,2
24%4
Monotherapy in H-naive MBC
≈24%3
56%4
Nerat is an irrev Her1/2/4 TKI.
Single agent N has clinical activity in MBC-tras-naive of 56% and pretx’d pts of 24%.
Comapred w/ L, N’s activity is very promising.
However, the most common AE of N is diarrhea.
1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4 Burstein JCO 2010

16. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
Study Design
Neratinib
240 mg/day
n = 117 R A N D O M I Z E
Phase 2, open-label trial in HER2+ locally advanced or metastatic BC patients
L + C
L 1,250 mg/day +
C 2,000 mg/m2 per day
n = 116
1○- PFS
2○ - ORR, CBR,
OS, Safety
G 3/4 Diarrhea and PPE
Originally, this was a phase 3 study powered to assess superiority of N over L+C (N=1000).
Due to poor accrual, it was amended to a phase 2 study (N=230) to assess non-inferiority of N against L+C.
Pts were randomized 1:1 to N or L+C at doses shown.
Non-inf margin in terms of PFS was set at 15% which is equivalent of a 50% benefit of L+C over C in Geyer study.
Primary Endpoint-PFS
Secondary Endpoint-ORR, CBR, OS, safety, and G ¾ diarrhea and PPE
A total of 163 PFS events were needed for analysis w/ the assumptions that:
-Med PFS for L+C was 27.5 wks and of N was 33.9 wks (25% improvement in med PFS, HR 0.8)
-Enrollment of 3/wk
-alpha 0.1, 85% power, 1-yr drop-out rate of 20%
Neratinib was administered orally at 240 mg/day continuously
L 1,250 mg/day was administered orally continuously;
C 2,000 mg/m2 was administered orally on D1 to 14 of each 21-day cycle
Martin et al, SABC 2011 abstract # S5-7
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17. Key Eligibility Criteria
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
Key Eligibility Criteria
Women with HER2+ locally advanced or metastatic BC not amenable to curative therapy
Disease progression on or following 1 to 2 prior trastuzumab-based regimens
Prior treatment with a taxane regimen
Prior anthracycline treatments at or below the maximum cumulative dose of 400 mg/m2 for doxorubicin, 800 mg/m2 for epirubicin, or equivalent dose for other anthracycline derivatives
Measurable disease (≥1 measurable lesion), as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
Eligibility criteria include:
HER2+ Locally adv or MBC
1-2 prior tras-based Rxs
Prior taxane and anthr
Measuarable dz
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18. Baseline Characteristics
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
Baseline Characteristics
Characteristic
Neratinib
(n = 117)
L + C
(n = 116)
Median age (range), y
52 (28–79)
56 (30–79)
ER–positive, %b 44 40
PR–positive, %c 27 28
No. of prior anti-cancer regimens, % 1 14 2 33 ≥3 53
Prior trastuzumab therapy, %
Adjuvant/neoadjuvant settings 20 32
Metastatic setting 79 68
Baseline Characteristics:
well balanced
> 50% had > 3 prior Rxs
2030% had prior tras in adjuvant setting
2/3 to 3/4 had tras in MBC setting
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19. Time since randomization (mo)
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
PFS: ITT Population 10 20 30 40 50 60 70 80 90
100
Neratinib
L + C
Non-inferiority of neratinib vs
L+C could not be demonstrated.
Probability of PFS (%) 30 5 10 15 20 25
In terms of PFS, the med PFS was higher w/ L+C at 6.8 vs 4.5 mo but this did not reach stat significance.
Non-inferiority of neratinib vs L+C could not be demonstrated. The HR for PFS was 1.19 which crossed the 1.15 barrier established for non-inferiority.
Time since randomization (mo) n
Median PFS
95% CI
P value
Neratinib
117
4.5 mo
3.1–5.7 mo
0.231
L + C
116
6.8 mo
5.9–8.2 mo
L, lapatinib; C, capecitabine; PFS, progression-free survival; CI, confidence interval.
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20. Overall Survival: ITT Population
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
Overall Survival: ITT Population 10 20 30 40 50 60 70 80 90
100
Neratinib
L + C
Probability of OS (%) 5 10 15 20 25 30
OS was numerically higher w/ L+C arm at 23.6 mo vs 19.7 mo, but again this did not reach stat signifcance.
Time since randomization (mo) n
Median OS
95% CI
P value
Neratinib
117
19.7 mo
18.2 mo–NE
0.280
L + C
116
23.6 mo
18.0 mo–NE
L, lapatinib; C, capecitabine; OS, overall survival; CI, confidence interval; NE, not estimable.
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21. Best Overall Response: ITT
Neratinib
N = 117
L + C
N = 116 CR 2% 4% PR
27%
36%
SD > 24 wks
15%
23%
SD < 24 wks
29%
24%
POD
17% 7%
Unknown/missing 9% 5%
The ORR was 40% in L+C arm vs 29% in neratinib arm.
The CBR was 63% in L+C arm vs 44% in neratinib arm.
L=lapatinib, C=capecitabine
The ORR was 40% in L+C arm vs 29% in neratinib arm.
The CBR was 63% in L+C arm vs 44% in neratinib arm.

22. Selected Treatment-related AEs (All Grades)
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
Selected Treatment-related AEs (All Grades)
Neratinib
(n = 116)
L + C
(n = 115)
Adverse event, %
Diarrhea
85%
(28% G 3/4)
68%
(10% G 3/4)
PPE 5%
(0% G 3/4)
65%
(14% G 3/4)
Nausea
35%
38%
Vomiting
24%
17%
Rash
19%
34%
Fatigue
16%
23%
Hyperbilirubinemia 1%
Increased ALT 7%
13%
Neutropenia
12%
In terms of AEs, there was more G 3/4 diarrhea w/ n vs L+C at 28% vs 10%. This was transient and manageable w/ loperamide.
There was more G3/4 HFS w/ L+C at 14% vs 0%.
There was a low incidence of cardiac events in both treatment arms: neratinib, 7%; L + C, 6%
Diarrhea was transient and manageable.
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23. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
Conclusions
Neratinib did not demonstrate non-inferiority for PFS against L+C.
Med PFS was numerically (not statistically) superior with L+C (6.8 mo vs 4.5 mo).
Diarrhea was the most frequently reported AE.
The ORR of neratinib in heavily pretreated patients was 29%, consistent with results from the preceding single-arm trial.1
Continued development of neratinib as monotherapy and in combination with other agents for treatment of recurrent HER2+ BC ?
Conclusions:
Neratinib did not demonstrate non-inferiority for PFS against L+C.
Med PFS was numerically (not statistically) superior with L+C (6.8 mo vs 4.5 mo).
Diarrhea was the most frequently reported AE.
The ORR of neratinib in heavily pretreated patients was 29%, consistent with results from the preceding single-arm trial.1
Continued development of neratinib as monotherapy and in combination with other agents for treatment of recurrent HER2+ BC ?
1. Burstein HJ, et al. J Clin Oncol. 2010;28(8):
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24. Pertuzumab

25. HER2-Targeted Therapy with Pertuzumab
Monoclonal antibody and pan-HER inhibitor
Binds to a distinct epitope on the HER2 extracellular domain
Prevents dimerization
Pertuzumab is a humanized monoclonal antibody which binds to the extracellular domain of HER2.
However unlike trastuzumab which binds at domain IV, pertuzumab binds domain II of the receptor and is thus able to disrupt HER2 dimerization and ligand-activated signaling with other growth factor receptors, including other HER family members.
Animal model studies using HER2 positive breast cancer xenografts have shown a synergistic antitumor activity for pertuzumab in combination with trastuzumab
Pertuzumab
Trastuzumab

26. Pertuzumab Activity With trastuzumab N= 661 Monotherapy N= 292 %
Best Objective Response CR 8% 0% PR
17% 7% SD
6 months
26% 4%
ORR
24%
Clinical Benefit Rate
50%
11%
Baselga et al published the result of the phase II, single arm study of efficacy and safety of HP in patients with HER2 (+) MBC who had relapsed during tras. The primary endpoints of the study were ORR and CB. Overall, ORR was 24% and clinical benefit rate was 50%.
The promising results of the combination of HP led to a protocol amendment to include a 3rd cohort of patients receiving P monotherapy, to assess the activity of P as a single agent.
Upon POD on P alone, then patients could have H added to P at the physician’s discretion.
Cortes et al reported the result of P as monotherapy. In this study, 29 patients were enrolled, and only 2/29 (7%) patients responded.
1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022

27. Trastuzumab added back in
Pertuzumab Activity
With trastuzumab N= 661
Monotherapy
N= 292
Trastuzumab added back in
N=142 %
Best Objective Response CR 8% 0% PR
17% 7%
14% SD
6 months
26% 4%
ORR
24%
Clinical Benefit Rate
50%
11%
Fourteen patients then had H added to P, and 2 of 14 (14%) had a response.
So P works better when combined w/ H, as dual anti-HER2 therapy !
1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022

28. CLEOPATRA: CLinical Evaluation Of Pertuzumab And TRAstuzumab
Baselga reported the result of CLEO which was the big news at SABC this past year.
CLEO is a randomized, DB, PC, phase 3 study for HER2+pts in the first-line setting.
Pts were randomized to TH +Placebo vs THP and it was rec’d that pts receive at least 6 cycles of the taxane.
The randomization was stratified by geographic region and prior Rx status.
Study dosing for P and H was every 2 weeks as shown. The doce dose was 75 m/m and this was escalated to 100 m/m if tolerated.

29. Eligibility Criteria
Centrally confirmed HER2+ (IHC 3+ and/or FISH > 2.0)
Locally recurrent, un-resectable, or MBC
Measurable and/or non-measurable
1 prior hormone Rx for MBC allowed
Prior neoadj/adj chemo and trastuzumab allowed if DFI > 12 mo
LVEF > 50%
No h/o CHF or LVEF < 50% during/after prior trastuzumab
Eligibility criteria included:
Centrally confirmed HER2+ (IHC 3+ and/or FISH > 2.0), locally recurrent, unresectable, or MBC
Measurable and/or non-measurable
1 prior hormone Rx for MBC allowed
Prior (neo)adj chemo and trastuzumab allowed if DFI > 12 mo
LVEF > 50%
No h/o CHF or LVEF < 50% during/after prior trastuzumab

30. Patient Characteristics
Placebo + trastuzumab + docetaxel (n = 406)
Pertuzumab + trastuzumab + docetaxel (n = 402)
Median age, years
54y
ER- and/or PR-positive
199 (49%)
189 (47%)
Prior (neo)adjuvant chemotherapy
192 (47%)
184 (46%)
Components of neoadj/adj therapy Anthracycline Hormones Taxane Trastuzumab
164 (40%) 97 (24%) 94 (23%) 41 (10%)
150 (37%) 106 (26%) 91 (23%) 47 (12%)
Pt characteristics are well balanced.
Med was 54 yrs.
About 50% were ER/PR +.
Almost 50% had received neo adj or adj Rx.
Only 10% received adj tras.

31. Primary endpoint was independently assessed (IA) PFS.
800 pts were required and 381 PFS events were needed to provide 80% power to detect a 33% ↑ in IA-PFS (HR 0.75) at 2-sided p value of 5%.
Secondary endpoint was OS. 385 OS events were needed to provide 80% power to detect 33% ↑ in OS (HR 0.75) at 2-sided p value of 5%.
Interim OS analysis (estimated at 50% of events for final analysis) was planned at time of IA-PFS analysis.
THP > TH in PFS w/ med of 12.4 vs 18.5 mo w/ delta of 6.1 mo.
The magnitude of PFS benefit was the highest ever seen, higher than that reported w. the pivotal Slamon and Marty trials.
Baselga abs #S5-5

32. PFS in predefined subgroups
This forest plot showed that the addition of P was beneficial regardless of prior neo(adj) Rx or not, region, age group, race, dz type, ER/PR status, and HER2 positivity by IHC or FISH.

33. Only 10% pts had prior Tras in adj/neoadj setting
Only 10% pts had prior Tras in adj/neoadj setting. This is b/c Tras was not approved in 2006 and this study was started in 2008 so many pts did not have Tras in adj setting.
Nevertheless, the benefit of P was similar whether pts had prior tras neo(adj) Rx or not w/ HR of 0.6 .
Baselga abs #S5-5

34. Data immature but Baselga abs #S5-5
Interim OS analysis showed a strong trend in favor of P.
However, this interim OS analysis did not cross the pre-specified OF stopping boundary of HR <0.0603, p < )
Thus, OS results are immature and we should await for the mature OS data.
Baselga abs #S5-5

35. Grade 3/4 Adverse Events (incidence > 5%)
Placebo + Trastuzumab + Doce
N=397
Pertuzumab + Trastuzumab + Doce
N=407
Neutropenia
182 (45.8%)
199 (48.9%)
Febrile neutropenia
30 (7.6%)
56 (13.8%)
Leukopenia
58 (14.6%)
50 (12.3%)
Diarrhea
20 (5.0%)
32 (7.9%)
In terms of G 3/4 AEs, there was slightly more neutropenia, FN and diarrhea w/ the addition of P.
As noted here, the G 3/ 4 diarrhea incidence was still low well under 10% w/ the addition of P.
P is a well tolerated Ab w/ a much lower incidence of diarrhea that than seen w/ the TKIs such as lapatinib or neratinib as discussed previously.
G 3/4 diarrhea was low !

36. Placebo + Trastuzumab + Doce Pertuzumab + Trastuzumab + Doce
Cardiac Safety
Placebo + Trastuzumab + Doce
Pertuzumab + Trastuzumab + Doce
Investigator-assessed
symptomatic LVSD*
1.8%
1.0%
Independently adjudicated
Decline in LVEF to
< 50% and by > 10% from baseline
6.6%
3.8%
There was no increased in cardiac toxicity w/ the addition of P.
*LVSD=left ventricular systolic dysfunction, defined as NYHA class III/IV

37. Conclusions
CLEOPATRA met its primary endpoint w/ a statistically significant PFS improvement from 12.4 to 18.5 months w/ addition of pertuzumab (HR 0.62, p < ).
OS data immature
Pertuzumab well tolerated
No increased cardiac toxicity
May be practice changing !

38. Questions Safe in combination with other chemotherapy foundations?
Adjuvant/neoadjuvant studies ?
Continuation beyond progression ?
APHINITY adj study

39. MSKCC IRB# 10-142 THP Schema Accrual Goal = 69 patients N = 69 HER2 +
0-1 prior Rx
Tissue bx optional
1° endpoint=6 mo PFS
q week ……………………………
q 3 weeks………………………….
q 3 weeks………………………….
♥ ♥ every 4 cycles…………………..
TNI, BNP, NRG-1ß every 2 cycles…………………………
Paclitaxel at 80 mg/m2
Pertuzumab at 840mg load → 420 mg q 3 w
♥ ECHO w/
strain imaging
Trastuzumab at 8 mg/kg load → 6 mg/kg q 3 w
PI: Dang 39

40. APHINITY: Adjuvant Pertuzumab Anthracycline-BasedF O L W U P 10
yrs R A N D O M I Z E
AC/EC x 4 or
FEC/FEC x 3-4
T x 3-4 S U R G E Y
Trastuzumab q 3 wks x 52 wks
Pertuzumab q 3 wks x 52 wks
Centrally
Confirm HER2
AC/EC x 4 or
FEC/FEC x 3-4
T x 3-4
Trastuzumab q 3 wks x 52 wks
Placebo q 3 wks x 52 wks
Breast/chest RT and endocrine Rx
as appropriate after chemo completion
Start w/i 1 wk
of randomization
Randomize w/i 7 wks of surgery

41. APHINITY: Adjuvant Pertuzumab Non-Anthracycline BasedF O L W U P 10
yrs R A N D O M I Z E
TC x 6 S U R G E Y
Trastuzumab q 3 wks x 52 wks
Pertuzumab q 3 wks x 52 wks
Centrally
Confirm HER2
TC x 6
Trastuzumab q 3 wks x 52 wks
Placebo q 3 wks x 52 wks
Breast/chest RT and endocrine Rx
as appropriate after chemo completion
Start w/i 1 wk
of randomization
Randomize w/i 7 wks of surgery

42. Can HER2-targeted antibody therapies be administered safely with anthracyclines?

43. TRYPHAENA
TRYHAENA is a multicenter study to assess tolerability of Neo HP w/ Anthra-Taxane based Rx or carbo-Taxane based Rx in HER2+ BCA pts.
225 pts were rand’d to A) FEC/HP-THP or B) FEC-THP w/ HP after FEC or C) TCH + P
After chemo, pts have breast surgery followed by a yr of Tras.
Doses of chemo and antibodies are shown here.

44. Study Endpoints Primary endpoint: Cardiac safety
Symptomatic LVSD (grade ≥3)
LVEF declines (≥10 percentage points and below 50%)
Secondary endpoints:
Toxicity
pCR
Clinical response rate
Rate of BCS
DFS, OS
Biomarker evaluation
Median tumor size by CBE, mm (range)
Arm A: 53 (10‒220)
Arm B: 49 (19‒120)
Arm C: 50 (15‒200)
½ HR-neg
Schneeweiss abs #S5-6

45. Eligibility Criteria
Centrally confirmed HER2-positive locally advanced, inflammatory, or early-stage breast cancer
Primary tumor ≥2 cm
Baseline LVEF ≥55%
ECOG PS 0 or 1
No previous anticancer therapy or radiotherapy for any malignancy
Adequate bone marrow, liver, and renal function
Median tumor size by CBE, mm (range)
Arm A: 53 (10‒220)
Arm B: 49 (19‒120)
Arm C: 50 (15‒200)
½ HR-neg
Schneeweiss abs #S5-6

46. Baseline Characteristics
FEC/HP →THP
N=72
FEC →THP
N=75
TCHP
N=76
Med age, yrs (range)
49 (27-77)
49 (24-75)
50 (30-81)
ECOG 0
65 (91.5%)
66 (88.0%)
67 (88.2%)
ECOG 1
6 (8.5%)
9 (12.0%)
9 (11.8%)
ER and/or PR +
39 (53.4%)
35 (46.7%)
40 (51.9%)
ER and/or PR-
34 (46.6%)
40 (53.3%)
36 (48.1%)
Disease Type
Operable
53 (72.6%)
54 (72.0%)
49 (63.6%)
LABC
15 (20.5%)
17 (22.7%)
24 (31.2%)
IBC
5 (6.8%)
4 (5.3%)
4 (5.2%)
HER2 IHC 0 and 1+
1 (1.4%)
0 (0.0%)
HER2 IHC 2+
1 (1.3%)
2 (2.6%)
HER2 IHC 3+
67 (91.8%)
74 (98.7%)
75 (97.4%)
HER2 FISH +
69 (94.5%)
69 (92.0%)
73 (94.8%)
HER2 FISH-
HER2 unknown
4 (5.5%)
5 (6.7%)
Med age was 49.
Half f pts had ER/PR + dz.
Most had operable dz.

47. Schneeweiss abs #S5-6 No pts in Arms A and C had LVSD.
2 pts in Arm B had symptomatic LVSD (or CHF).
About 4-5% had LVEF decline of >/= 10% to below 50%.
Schneeweiss abs #S5-6

48. Other Notable G 3/4 AEs Adverse events FEC/HP →THP N=72 FEC →THP N=75
TCHP
N=76
Neutropenia
34 (47.2%)
32 (42.7%)
35 (46.1%)
Febrile neutropenia
13 (18.1%)
7 (9.3%)
13 (17.1%)
Leukopenia
14 (19.4%)
9 (12.0%)
9 (11.8%)
Diarrhea
3 (4.2%)
4 (5.3%)
Other notable G 3/4 AEs include:
Neutropenia bordering 50% across the 3 arms.
FN was higher in Arms A and C when HP was given concurrently w/ all of the chemo’s.
Diarrhea appeared higher in the TCHP arm.

49. Regarding the pCR rate (no invasive cancer, DCIS allowed), it was 62% vs 57 % vs 66 % in Arms A, B, and C.
Regarding a conservative pCR rate (no invasive CA or DCIS), it was 51% vs 45% vs 52% in Arms A, B, and C.

50. Breast Conserving Surgery When Mastectomy Was Planned*
FEC/HP →THP
N=46
FEC →THP
N=36
TCHP
N=37
Achieved
(95% CI)
10 (21.7%)
( )
6 (16.7%)
( )
10 (27.0%)
( )
Not Achieved
36 (78.3%)
30 (83.3%)
27 (73.0%)
For those w/ T2-3 tumors for whom mastectomy was planned, the BCS rate was around 20% across the 3 arms.
* Patients in ITT population w/ T2-3 tumors for whom mastectomy was planned.

51. Conclusions
Low incidence of symptomatic/asymptomatic LVSD across all arms:
Concurrent admin of HP w/ Epi resulted in similar cardiac tolerability compared with sequential admin or the anthracycline-free regimen
Neutropenia, FN, leukopenia, and diarrhea were the most frequent G 3/4 AEs across all arms.
High pCR rates (57- 66%) w/ HP, regardless of chemotherapy chosen
TRYPHAENA supports ongoing APHINITY study, a Phase III trial to evaluate HP + standard chemo in adjuvant setting.
Conclusions:
Low incidence of symptomatic/asymptomatic LVSD across all arms:
Concurrent admin of HP w/ epi resulted in similar cardiac tolerability compared with sequential admin or the anthracycline-free regimen
Neutropenia, FN, leukopenia, and diarrhea were the most frequent G 3/4 AEs across all arms.
High pCR rates (57-66%) w/ HP, regardless of chemotherapy chosen
TRYPHAENA supports ongoing APHINITY study, a Phase III trial to evaluate HP + standard chemo in adjuvant setting
Schneeweiss abs #S5-6

52. Loibl et al for GBG and AGO-B Study groups
Comparison of OS according to pCR in Pts w/ HER2+ BCA Receiving Neoadjuvant Chemo w/ and w/o Trastuzumab Compared w/ Pts w/ HER2- Tumors
Loibl et al for GBG and AGO-B Study groups

53. pCR in HER2 + BCA
pCR is a surrogate for DFS and OS in pts w/ HER2+ BCA treated w/ neoadjuvant chemo w/ or w/o trastuzumab.1
Pts w/ pCR after neoadjuvant chemo + trastuzumab have excellent DFS and OS.2
1. Gianni, Lancet 2010; 2. Untch, JCO 2011

54. Von Minckwitz et al reported the meta-analysis of neoadjuvant trials at ASCO 2011.
All pts received anthra-taxane based Rx.
I’d like to draw your attention to the bottom 2 trials (TECHNO tral and Geparquattro trial) in which HER2 + pts receive Tras w/ chemo. As you can see, the pCR appears higher in the 23-29% than those who are HER2-.

55. Objectives Define 3 subgroups: Compare DDFS and OS in these subgroups
HER2+ w/ trastuzumab
HER2+ w/o trastuzumab
HER2-
Compare DDFS and OS in these subgroups
pCR vs no pCR
Hormone receptor + vs -tumors
They defined 3 subgroups as shown and compared HER2 + w/ tras w/ Her2 + w/o tras and HER2 + w/ tras to HER2- group.
They compared DDDFS and OS in these subgroups relative to pCR vs no pCR and HER2+ vs – status.

56. The flow of pts are outlined here.
Over 6300 pts were available
Of these, over 4300 were eligible due to known HER2 status.
Over 300 were HER2- w/ pCR rate of 14.8%.
Over 600 were HER2+ who did NOT receive Tras w/ pCR rate of 17.9%.
Over600 were HER2+ who received Tras w/ a pCR rate of 27.3%.

57. Patients’ Characteristics
Age
49 (22-81) yrs
cT1-3
87%
cN+
53%
IDC
82%
Grade 3
40%
Hormone Receptor +
66%
HER2-
70%
Med age was 49.
Majority had operable dz.
Clinical nodal involvement was present in 53%.
2/3 were HR+
70% was HER2-.

58. pCR > No pCR
DDFS and OS were better in pCR vs no pCR groups in all 3 subgroups:
HER2+ w/ tras
HER2+ w/o tras
HER2-

59. When 3 subgroups were compared together in terms of no pCR and pCR.
Pink-HER2+ w/ tras
Green-HER2+ w/o tras
Blue-HER2-
On left hand side, there was no stat significance in difference in all 3 groups. However, when looking at the her2+ w/ tras in pink, the event rate was ½ of that seen in Her2+ group w/o tras in green.
On right hand side, in the pCR groups, the HER2+ group w/ tras had the lowest event rate and was stat signif better than Her2 + group w/o tras.
Loibl abs #S5-4

60. When looking at DDFS on left and OS on right in all 3 subgroups, in terms of HR+ status, all curves are superimposed.
There is no stat signif.

61. However, when looking at DDFS on left and OS on right in all 3 subgroups in terms of HR- status, the HER2+ w/ tras had better DDFS over her2+ w/o tras and HER2-.
In terms of OS, HER2+ w/ tras had better OS than Her2- group.
This speaks to the effectiveness of tras in HER2+ group !

62. Author’s Conclusions HER2+ pts w/ tras + chemo had higher pCR.
DDFS and OS was better in pCR group than no pCR group in all 3 subgroups (HER2+ w/ tras, HER2+ w/o tras, HER2-).
In pCR pts, OS was better in HER2+ pts w/ tras than HER2+ pts w/o tras.
In hormone receptor- group, HER2+ pts w/ tras have better outcomes than HER2+ w/o tras and HER2- groups. Trastuzumab is effective !
pCR can be surrogate marker for HER2+ disease.

63. Summary No role for “delayed” adjuvant lapatinib
ALTTO may define role of lapatinib ?
Neratinib did not demonstrate non-inferiority for PFS against L+C.
Main toxicity was diarrhea.
Pertuzumab added to standard docetaxel + trastuzumab improves PFS !
Maybe new standard of care !
Adjuvant study APHINITY open !

64. Summary
No increased cardiac toxicity when HP given concurrently w/ epi-taxane Rx and carbo-taxane Rx.
However, concurrent anthracycline with trastuzumab or pertuzumab should not be given outside of clinical trial.
What to do for those w/ no PCR?
Need trials designed to assess utility of novel or optimal Rx for those w/o pCR

65. Thank You !

66. 2nd annual San Antonio breast cancer symposium review january 28, 2012
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