1. HER-2 targeting: dalla malattia avanzata alla fase pre-operatoria
Marco Venturini
Roma, Febbraio 2005

2. Tailored Treatment of HER2+ MBC
Hormonal therapy +/- Trastuzumab
ER+, Low Risk
HER2+
MBC
ER-, ER+, High Risk
No prior taxanes
Prior taxanes
Trastuzumab +
Taxanes
Trastuzumab + other CT
Trastuzumab monotherapy

3. Trastuzumab + Taxanes: Consistent Benefit
H0648g1,2
M770013
Outcome
H + P
(n=68) P
(n=77)
H + D
(n=92) D
(n=94)
ORR (%)
49.0
17.0
61.0
34.0
TTP (months)
7.1
3.0
10.6
5.7
OS (months)
24.8
17.9
30.5
22.1
1 Slamon et al. N Engl J Med. 2001;344:783–792.
2 Baselga J. Oncology. 2001;61(Suppl. 2):14–21. 3 Extra et al. Eur J Cancer. 2004;2:125. Abstract 239.

4. (no taxane for MBC or LABC; > 12 mo since adjuvant taxane)
CALGB 9840 Schema
N=735
N=580
First-Second Line MBC
(no taxane for MBC or LABC; > 12 mo since adjuvant taxane)
Pos Trastuzumab +
Paclitaxel 175 mg/m2 q 3 wk
Paclitaxel mg/m2 q wk R*
Stratify by
Her-2
Paclitaxel 175 mg/m2 q 3 wk
Paclitaxel mg/m2 q wk R*
Neg
Trastuzumab +
Recall that a simple 1:1 randomization between weekly and q3wk paclitaxel was abandoned in favor of a 3:2 weighting due to an interesting “patient resource conserving design”.
This “patient resource conserving design” involved identifying a patient population that had historically received paclitaxel at 175mg/m2 on a q3wk regimen for MBC for which results had been presented, and to include these patients in the analysis of CALBG 9840.
Such patients were found in CALGB 9342, which had been presented at ASCO1998 (Abs388) by Winer et al. One hundred and fifty eight q.3wk patients were then “borrowed” from CALGB 9342 for the analysis of CALGB As a consequence, randomization of new patients to CALGB 9840 had to be skewed to a 3:2 ratio in favor of weekly paclitaxel to balance study arms.
This controversial “patient resource conserving design” which applied patients from a historical study to an accruing study was a focal point of discussion during the ASCO2004 discussion period for this abstract. It was challenging to defend how this methodology was consistent with the design of randomized trials (to compensate for both known and unknown prognostic variables in study arms) which is at the core of clinical research. R
“borrow” 158 pts
Paclitaxel 175 mg/m2 q 3 wk
Paclitaxel mg/m2 q wk R*
CALGB 9342
Paclitaxel 175 mg/m2 q 3 wk
Paclitaxel 210 mg/m2 q 3 wk
Paclitaxel 250 mg/m2 q 3 wk R
*3:2 randomization q wk to q 3 wk

5. CALGB 9840 Efficacy Outcomes (all patients)**
Multivariate p-value
Although a response rate and TTP advantage has been reported for weekly paclitaxel over a q3wk regimen, a back-up slide shown at the oral presentation at ASCO2004 presented outcomes in which the patients from CALGB 9342 were censored.
Among new patients randomized in CALGB 9840 (after removal of the “borrowed” patients from CALGB 9342), the difference in response rate between weekly and q3wk paclitaxel decreased to 40% vs 32%; p=NS, which is consistent with what might be expected if the pool of poorer prognosis patients (CALGB 9342) are removed from the analysis. (This statistic has not been independently validated as these slides have not been released by ASCO2004 on its virtual meeting service).
In conclusion, while there may be a general feeling that weekly paclitaxel might be more effective than q3wk paclitaxel for palliating MBC patients, the confounding trastuzumab question in this study, the variable dosing used for weekly paclitaxel (100mg/m2 and 80mg/m2), and the “borrowing” of patients from a historical study (CALBG 9342) for analysis, suggests that is not a randomized Phase III study that provides level 1 evidence to answer the weekly vs q3wk question. .
* ITT Response rates are 39% (q.wk) and 27% (q.3wk)
** Includes 158 q.3wk patients “borrowed” from CALGB 9342
Seidman A et al. Proc ASCO 2004 Abs 512

6. + Paclitaxel 80 mg/m2 weekly fino a PRO
Weekly Paclitaxel  Trastuzumab Disegno dello studio
Ca mammario avanzato HER2-positivo (IHC 2+/3+ ) non pretrattato (n=160)
Paclitaxel 80 mg/m2 weekly fino a PRO
Paclitaxel 80 mg/m2 weekly fino a PRO +
Trastuzumab
4 mg/kg2 mg/kg weekly fino a PRO
Papaldo P. Roma ottobre 2004

7. Results T alone T+Trastuzum. ORR 60% 78% TTP (weeks) 28 52 1-yr PFS
21%
48%
Neutropenia
12%
13%
F. Neutropenia 2% -
Neuropathy 7% 4%
Asthenia 6%
Grade 3 & 4
Papaldo P. Roma ottobre 2004

8. Weekly or 3-weekly Docetaxel
R A N D O M I Z A T I O N
Docetaxel 40 mg/m2
6 weeks on and 2 weeks off
N=83
1st & 2nd line CT
Measurable disease
Docetaxel 100 mg/m2
every 3 weeks
Tabernero J et al. Ann Oncol 2004

9. Weekly or 3-weekly Docetaxel
ORR
34%
33%
TTP (months)
5.7
5.3
F. Neutropenia
4.9%
19.5%
Neuropathy
2.4%
17.1%
Stomatitis
7.3%
Fluid Retention
Fatigue
14.6%
12.2%
Grade 3 & 4
Tabernero J et al. Ann Oncol 2004

10. Trastuzumab + Docetaxel Weekly Multicenter Phase II Trial
TREATMENT
N = 26
HER2-positive MBC (IHC 2-3+ and/or FISH+)
Docetaxel 35 mg/m2 qw x 6; 2 wk rest +
Trastuzumab 4 mg/kg  2 mg/kg qw
 PD
Results
ORR 50% Median TTP 12.4 mo IHC 3+ only 63% Median OS 22.1 mo FISH+ 65% IHC 2+ & FISH (-) 0%
Tedesco et al. J Clin Oncol. 2004;22:

11. Standard vs. Investigational Agents Cross-over effect
Regimen
Crossover
survival benefit
Std
Invest
Agent n
Sledge 03
A or T AT
T or A
57% NO
Paridaens 00 A T
47%
Nabholtz 99 MV D
24%
YES
O’Shaughnessy 02 XD X
17%
Albain 04 GT G
14%
Bishop 99
CMFP 6%
Breast Cancer II ASCO2004 Discussant: Antonio C. Wolff, MD

12. Standard vs. Investigational Agents Cross-over effect
Regimen
Crossover
survival benefit
Std
Invest
Agent n
Slamon 01 CT
HCT H
65%
YES
Marty 03 D HD
44%
Sledge 03
A or T AT
T or A
57% NO
Paridaens 00 A T
47%
Nabholtz 99 MV
24%
O’Shaughnessy 02 XD X
17%
Albain 04 GT G
14%
Bishop 99
CMFP 6%

13. Trastuzumab Triple Combinations
Combining > 2 agents has the potential to further improve ORR and increase survival
Several Trastuzumab triple combinations under investigation:
Trastuzumab/paclitaxel/carboplatin
Trastuzumab/docetaxel/epirubicin
Trastuzumab/paclitaxel/gemcitabine
Trastuzumab/docetaxel/capecitabine (CHAT study)

14. TCH in HER2+ MBC: Results of Phase II Pilot Studies
Parameter
BCIRG 101
UCLA
No. eval. pts 62 59
Regimen
D 75 mg/m2 q3w x 6 Cis 75 mg/m2 q3w x 6
H 2 mg/kg qw* x 52
D 75 mg/m2 q3w x 6 Cb AUC=6 q3w x 6 H 2 mg/kg qw* x 52
ORR All FISH FISH-
79% 77% 84%
58% 63% 41%
TTP Median FISH FISH-
9.9 mo 12.7 mo mo
12.7 mo 15.6 mo mo
*Following 4 mg/kg loading dose; H = Trastuzumab; D = docetaxel; Cb = carboplatin; Cis= cisplatin.
Pegram et al. J Natl Cancer Inst. 2004;96:

15. Phase III Trial of 1st Line Trastuzumab + Paclitaxel ± Carboplatin
Primary end point: ORR
Secondary end points: DOR, TTP, OS
3-week cycle:
RANDOMI ZAT ION
196 patients HER2+ ABC
(IHC 3+ and/ or FISH+)
Trastuzumab
4 mg/kg day 1,
2 mg/kg qw
until PD
Paclitaxel 175 mg/m2 q3w × 6 cycles or more
Paclitaxel 175 mg/m2 + carboplatin AUC 6, q3w × 6 cycles or more
Robert et al. Breast Cancer Res Treat. 2002;76:S37. Abstract 35.
1. Update of Robert et al. Breast Cancer Res Treat. 2002;76:S37. Abstract 35.

16. Rand. ph III trial of trastuzumab + paclitaxel  carboplatin (196 pts)
TPC TP
OR % % p=.04
TTP m m p=.02
OS m m p= 0.2
Robert N et al. ASCO 2003

17. Trastuzumab + other CT

18. Cardiotossicità. Trastuzumab da solo o in associazione
Percentuale
+ AC
Trastuzumab
+ Cisplatino
+ Altre CT
+ Paclitaxel
Modified from Seidman A et al
J Clin Oncol 20(5): , 2001

19. Anthracyclines, Trastuzumab and Cardiotoxicity
Within 1 year of therapy
Reflects progressive injury and loss of cardiac myocites
Life-Threatening, related to cumulative doses, rapid onset and progression, may be resistant to treatment
Treatment with anthracyclines should be stopped
During trastuzumab therapy
The pathophysiology of cardiac dysfunction is nor clear defined
No dose related
It is almost always responsive to medical management
Treatment with trastuzumab may be continued

20. Ten patients. First line CT. No prior RT or prior doxo
Normal cardiac biopsy following co-administration of doxorubicin, cyclophosphamide and trastuzumab to women with HER2 positive metastatic breast cancer
Valero V. et al. Proc ASCO. Vol 22, No 14S, 2004:572
Ten patients. First line CT. No prior RT or prior doxo
Median doxo dose 360 mg/m2 ( ); median of 35 trastuzumab doses
Median LVEF 64% (baseline), 53% at week 22
Two patients had cardiac disfunction (NYHA grade II, and grade IV), one LVEF decline > 20%
Cardiac function normalized in all patients
Ten cardiac biopses, at 240 mg/m2. No cardiac abnormalities

21. Trastuzumab starting with or after doxorubicin and paclitaxel
Two cohorts of 16 patients
AT + Trastuzumab or AT  Trastuzumab
LVEF decrease in 75% of pts in AT+T, and 33% in ATT. No CHF
LVEF recovered to normal levels with continued trastuzumab, and cardiac function normalized in all patients.
Bianchi G. et al. Clin Cancer Res 9:5944, 2003

22. Study Design 2+/3+ by IHC- Dako Herceptest® no prior CT for MBC
Epirubicin 75 mg/m2 q 21 days x 8 cycles
Docetaxel 75 mg/ m2 q 21 days x 8 cycles
Herceptin 2 mg/kg weekly
LVEF
LVEF
LVEF
LVEF
LVEF
Inclusion criteria: metastatic breast cancer pts
2+/3+ by IHC- Dako Herceptest®
no prior CT for MBC
epirubicin permitted (<360 mg/m2)

23. HET (Roche M77022 Study) Cardiac events
First 29 pts:
● 2 asymptomatic decline of LVEF
● 1 CHF
Recruitment continued
During follow-up
● 4 asymptomatic decline of LVEF
● 3 CHF
Stop recruitment at 45th patient
Total of 10 cardiac events (22%)
Venturini M. et al. ASCO 2003

24. Dosage and Administration
Myocet 50 mg/m2 IV 1 hr infusion q 21d
Docetaxel 75 mg/m2 IV 1 hr infusion q 21 d
Trastuzumab 4 mg/Kg IV 90’ loading dose, 2 mg/Kg IV 30’ q 7 d

25. Trastuzumab and Anthracyclines
Metastatic Breast Cancer
Increased ORR, TTP, OS
Cardiac Toxicity in 25% of patients
Cardiac Disfunction improved in most patients, with standard medical treatment, and in some cases even when trastuzumab was continued
Acute reversible decline in LVEF do not necessarily portend a risk for chronic cardiac disfunction

26. Rational combination of trastuzumab with chemotherapeutics drugs used in the treatment of breast cancer
Pegram MD. et al. J Natl Cancer Inst Vol 96: 739, 2004
Four HER2-overexpressing breast cancer cell lines
Sinergistic interactions:
Carboplatin
4-hydroxycyclophosphamide
Docetaxel
Vinorelbine
Additive interactions:
Doxorubicin
Epirubicin
Paclitaxel
Gemcitabine (sinergistic at [low], antagonistic at [high]

27. Trastuzumab + Vinorelbine: Clinical Trials
Author
Jahanzeb et al. 2002*
Bernardo et al. 2002*
Burstein et al. 2003*
Burstein et al. 2001
Untch et al. 2004*
Bayo et al. 2004
Vinorelbine
dose
30 mg/m2
25 mg/m2
285 N 40 35 55 69 46
ORR (%) 78 84 68 75 59 66
*All patients treated first line.
Trastuzumab administered at standard dose of 4mg/kg loading followed by 2mg/kg weekly.

28. GEMZAR + Trastuzumab Reference Regimen mg/m2 N eval ORR % (CR) TTPD
(mos)
MS (mos)
O’Shaughnessy
Semin Onc Apr 2003
G 1200 (1,8)
HER 4 mg/kg 2 mg/kg q21 38 32
(0)
6.7
10.2
Christodoulou
ASCO 2003
G 1000 (1,8,15)
HER 4 mg/kg  2 mg/kg q28 28 36
(4)
7.8
18.7
Sledge
Oncology Dec 2003
P 175 (1)
HER 4 mg/kg  2 mg/kg q21 42 67
(10) 9 NR
Heinemann
ASCO 2002
G 750 (1,8)
CDDP 30 (1,8) 26
42.3
(7.7)
6.6
12.3

29. Breast cancers can acquire HER-2 gene amplification during tumor progression
Evaluation of HER2 status of CTCs (CK+ CD45-) in 42 patients with at least 10 CTCs/10 mL
97% (84%-100%) concordance, primary tumor and CTCs
At recurrence, 9/24 patients changed from HER2- to HER2+
80 patients HER2+ with asynchronous distant metastases
18% changed from HER2- to HER2+
6% changed from HER2+ to HER2-
authors suggested to test ECD HER2 levels (ECD HER2 levels >50 ng/mL (vn < 15) indicated HER2+ metastatic spread)
Meng S. et al. Proc Natl Acad Sci 101:9393, 2004
Lueftner DI. et al. Abstract 49 ESMO 2004

30. ECD HER2 levels and response to therapy
Pooled analysis on 375 patients enrolled in 4 phase II/III trials
ECD levels at baseline were not predictive of ORR
The magnitudine of ECD reduction was not predictive of a best outcome
The magnitudine of ECD increase was not predictive of a progressive disease
Leyland-Jones B. et al. Abstract 51 ESMO 2004

31. Primary Chemotherapy pCR Mono CT1 4% - 8% Poli CT1 4% - 31% AC
10% - 14%
CAF
16% - 19%
FEC
4% - 23%
ECisF or MVAC
27%
Antracycline/Taxane-based
8% - 31%
Trastuzumab2 non-antracycline-based
19% - 35%
1Randomized trials 2Non-randomized trials

32. Preoperative therapy with epidoxorubicin and docetaxel plus trastuzumab in patients with primary breast cancer: a pilot study
Wenzel C. et al. J Cancer Res Clin Oncol Vol 130: 400, 2004
Weekly doses of Epirubicin (30 mg/m2) and Docetaxel (35 mg/m2) plus trastuzumab.
Fourteen patients. Median epirubicin dose 360; median of 12 weeks of treatment and trastuzumab doses
No cardiotoxicity
pCR 7%

35. Preoperative Epirubicin and Trastuzumab
Epirubicin (30 mg/m2) Docetaxel (35 mg/m2) Trastuzumab, q. 7d
14 patients
Median of 12 weeks of treatment
Median epirubicin dose 360 mg/m2
No cardiotoxicity
pCR 7%
Paclitaxel225 24h x F E75C500 x 4 q 21d ±Trastuzumab q 7d
19 vs 25 patients
Median of 24 weeks of treatment
Median epirubicin dose 300 mg/m2
5/15 vs 7/23 EF >10%
pCR 26% vs 65%
Wenzel C. J Cancer Res Clin Oncol Vol 130: 400, 2004
Buzdar AU et al. Proc ASCO 2004

36. Adjuvant Trials

37. Early Breast Cancer: Trastuzumab Adjuvant Trials
Four large multicenter phase III trials; over 12,000 patients will be randomized
Two strategies:
Sequence approach
NSABP B-31, North American Intergroup (N9831), HERA
Combination approach
BCIRG 006: based on preclinical data on synergism between chemotherapy and Trastuzumab

38. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31
AC q3w x 4
RANDOMI ZAT ION
P q3w x 4 or P qw x 12*
Target N = 2,700
Total accrual as of Mar ’04 = 1,673
Patient Population
Operable Breast Cancer
HER-2+
Path Positive Axillary Nodes
AC q3w x 4
P q3w x 4 or P qw x 12*
Trastuzumab qw x 52
*Revised study design. Choice of paclitaxel schedule and hormonal therapy at discretion of investigator – stratification factors.

39. B-31 Design Assumptions
Potential increased incidence of 4% clinical CHF was anticipated with administration of Trastuzumab with paclitaxel following prior AC
This incidence of CHF would be acceptable if a 25% or greater relative risk reduction for death were demonstrated, particularly if cardiac effects were largely reversible

40. B-31 Cardiac Safety Study Primary Endpoint Analysis
% Trastuzumab pts with Cardiac Event* 4.28 % (23/538)
- % Control pts with Cardiac Event 0.78 % (4/510)
D = 3.50% (CI 1.6% - 5.3%)
*Defined as definite/probable cardiac death OR dyspnea at rest or with normal activity and decline of LVEF to below > 5% below lower limit of normal

41. N9831 Intergroup Trial (NCCTG)
AC q3w x 4
Paclitaxel qw x 12
RANDOMI ZAT ION
Target N = 3,300
Total accrual as of Mar ’04 = 2,342
AC q3w x 4
Paclitaxel qw x 12
Patient Population
N+ or high-risk N- breast cancer
HER2+ (IHC 3+ or FISH)
Trastuzumab qw x 52
AC q3w x 4
Paclitaxel qw x 12
Trastuzumab qw x 52

42. HERceptin Adjuvant (HERA) Trial
RANDOMI ZAT ION
Target N = 4,482
Trastuzumab q3w x 1 y
Stratification
Primary management
(surgery, [neo]adjuvant chemotherapy ± adjuvant RT)
Trastuzumab q3w x 2 y
Unique features:
Investigating the role of Herceptin® independently from previous (neo)adjuvant chemotherapy regimen
Investigating 2 years of Herceptin® treatment
3-weekly schedule from the start
more convenient
gives similar exposure to Herceptin® as weekly administration of lower doses
Observation*
*Observation group to receive the same follow-up as the Trastuzumab treatment groups

43. HERA Trial: Interim Cardiac Safety Analyses
Three cardiac safety interim analyses have been completed
June 2003 (1,360 patients)
September 2003 (1,924 patients)
November 2003 (2,265 patients)
 No safety concerns identified

44. Breast Cancer International Research Group (BCIRG) 006 Trial
4 x AC 60/600 mg/m2
4 x Docetaxel
100 mg/m2
RANDOMI ZAT ION
Target N = 2,700
Accrual completed as of Mar ’04
Patient Characteristics:
HER2+ (FISH)
Node +
High-risk N-
1-year Trastuzumab
6 x Docetaxel + Carboplatin 75 mg/m AUC 6
1-year Trastuzumab

45. BCIRG 006: Interim Cardiac Analyses
March 2003: First cardiac analysis patients with 9 months follow-up
Sept 2003: Second cardiac analysis patients with 9 months follow-up
IDMC did not express any concerns; recommended the study to continue as planned
April 2004: Third cardiac analysis 1,500 patients with 9 months follow-up