1. Targeting HER family receptors in breast cancer
Prof. Sabino De Placido
Dip. di Endocrinologia ed Oncologia Molecolare e Clinica
Università Federico II --- Napoli, Italia

2. Targeting HER2: Key points
HER2 gene amplification and/or overexpression occurs in about 20% of breast cancers and is associated with more-aggressive disease and, until the advent of HER2-targeted agents, a worse outcome
The monoclonal antibody, trastuzumab (which targets HER2), and the small molecule tyrosine kinase inhibitor, lapatinib (which targets HER1 and HER2), have considerable efficacy in HER2-positive breast cancer

3. Adjuvant Setting What we know
Trastuzumab has changed the natural history of early HER2+ BC
Year

4. Adjuvant Trastuzumab predicted to prevent recurrence in almost 28,000 patients over a 10-year period in the 5 major EU countries
No. of patients prevented from developing metastases
Patients, n
20,000
Incidence of MBC without Herceptin
Herceptin introduced
18,000
27,737
16,000
14,000
12,000
10,000
8000
6000
4000
2000
2000
2005
2010
2015
Year
Weisgerber-Kriegl et al, ASCO 2008 4

5. More than 14.000 patients were recruited in 4 international clinical trials
HERA (ex-USA)
BCIRG 006 (global)
Observation
IHC / FISH (n=5,090)
FISH (n=3,222)
1 year
1 year
2 years
1 year
NCCTG N9831 (USA)
NSABP B-31 (USA)
IHC / FISH (n=3,505)
IHC / FISH (n=2,030)
1 year
1 year
1 year
Doxorubicin + cyclophosphamide
Docetaxel + carboplatin
Standard CTx
Docetaxel
Trastuzumab
Paclitaxel
IHC, immunohistochemistry FISH, fluorescence in situ hybridisation
CTx, chemotherapy
Piccart-Gebhart et al Romond et al 2005; Slamon et al 2006

7. Neoadjuvant setting What we know

9. Adjuvant setting What we do not know
Small, node negative tumors are under represented in clinical trials

10. Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Results
Overall 7,164 pts. with pT1pN0 tumors
median follow-up yrs.)
600 pts. with HER-2 + tumors
% HER-2 + disease
ranging between 7 and 10%
Absolute risks of distant relapse HER2+
5 yrs. ± 10-15%
10 yrs %
Increased risk of disease relapse if HER-2 +
hazard ratios ranging between 2.4 and 8.99
Reviewed by Oakman C et al, Educational book – ESMO meeting, Milan – October 2010

11. Caveats “Take-home” messages - heterogeneity in adjuvant therapies
Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Caveats and Conclusions
Caveats
- heterogeneity in adjuvant therapies
- HRs status not always centrally revised
- in 3 out of 7 studies pT1c tumors were eligible
- only 2 out of 7 studies evaluate outcome by combination of HER-2 and HRs status
“Take-home” messages
- there is a substantial degree of concordance in considering HER-2 + patients with pT1pN0 tumors at increased risk of relapse compared to the HER-2 negative population (2 to 9 fold increase)
Reviewed by Oakman C et al, Educational book – ESMO meeting, Milan – October 2010

12. Key question
Is proportional benefit from adjuvant systemic therapies dependent on disease stage ?

13. Potential options for adjuvant treatment of endocrine-resistant pT1b pN0 tumors
HER-2 +
Docetaxel-Cyclophosphamide (TC) x 4 + Trastuzumab*
(lack of phase III data)
Docetaxel-Carboplatin-Trastuzumab (TCH) x 6
(BCIRG 006 data)
Trastuzumab
Trastuzumab
* concomitant trastuzumab > sequential trastuzumab

14. Treatment decision: a multi-factorial process
Tumor* :
Size
Vascular invasion
Ki-67
Patient :
Co-morbidities
Age
Patient :
Expectations
Preferences
Treatment decision

15. Adjuvant setting What we do not know
Duration of Trastuzumab

16. Adjuvant trials with different duration of trastuzumab administration
HERA (PI M. Piccart): sample size ~34001
12 vs 24 months of H following adjuvant CT
Phare (PI X. Pivot): sample size ~34002
6 vs 12 months of H following adjuvant CT
Persephone (UK-NCRI): sample size ~40003
Hellenic Oncology Group (Greece): sample size 4784
6 vs 12 months of H with ddDoc after FEC
SOLD (PI H. Joensuu): sample size ~30006
HD 3-wkly x3 ->FE75C x3 vs
HD 3-wkly x3 ->FE75C x3 -> H 3-wkly x14
ShortHER (PI PF. Conte): sample size ~12505
D 3-wkly x3 + H weekly x 9 -> FE60C x3
AC or EC x 4 -> HD or HP 3-wkly x4 -> H 3-wkly x14

17. Metastatic Disease

18. Overall Survival by Trastuzumab Treatment Groups
1.0
0.0
Overall Survival Probability
Months from Diagnosi
0.6
0.4 60
0.2
0.8 12 24 48 36
Negative
No Trastuzumab
Trastuzumab
HER2+ / Herceptin
HER2+ /
No Herceptin
HER2-

19. What we Know
The first line

20. HERNATA Study

21. HERNATA study : results
Time to Progression
Overall Survival
Andersson JCO 2010

22. HERNATA study: results
Time to Treatment Failure
Andersson JCO 2010

23. HERNATA study : safety profile
In summary, the results from this randomized phase III trial of first-line therapy in HER2-positive MBC or LABC failed to demonstrate
superiority in terms of efficacy of docetaxel plus trastuzumab compared with vinorelbine plus trastuzumab.
However, toxicity was much more pronounced with docetaxel, and thus vinorelbine plus trastuzumab should be considered as an alternative first-line option with a favorable risk/benefit balance
Andersson JCO 2010

24. What we Know
The second line

25. Cumulative progression-free (%)
Tyverb plus capecitabine: significantly longer TTP in difficult to treat population (EGF100151, independent assessment)
Tyverb + capecitabine
Capecitabine
HR: 0.57 (95% CI: 0.43, 0.77) p=
Cumulative progression-free (%)
18.6 wks
(4.3 mos)
27.1 wks
(6.2 mos)
1. Cameron et al. Breast Cancer Res Treat 2008;[Epub ahead of print].
Figure Adapted from Cameron D, Casey M, Press M et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat, 2008 Epub ahead of print, with kind permission of Springer Science and Business Media.

26. What we Know
Beyond the second line

27. Cumulative progression-free (%) Time from randomisation (weeks)
Lapatinib in combination with trastuzumab significantly prolonged PFS compared with lapatinib alone (EGF104900)
Subjects at risk:
148
Lapatinib
Lapatinib + trastuzumab 53 73 21 42 13 27 5 8 2
6-month PFS
Cumulative progression-free (%)
13%
28% 20 40 60 80
100 10 30 50
Time from randomisation (weeks)
Lapatinib
Lapatinib + trastuzumab
n=145
n=146
Progressed or died, n
128
127
Median, wks
8.1
12.0
HR (95% CI)
0.73 (0.57, 0.93)
p value
0.008

28. Updated overall survival in ITT (EGF104900)
100 L
n=145
L+T
n=146
Died, n (%)
113 (78)
105 (72)
Median, months
9.5 14
Hazard ratio (95% CI)
0.74 (0.57, 0.97)
Log-rank p value
.026
80% 80
70% 60
Cumulative % alive without progression
56%
6 month OS 40
41% 20
L+T L
12 month OS 5 10 15 20 25 30 35
Patients at risk
Time from randomization (months) L
L+T
148
121
102 88 65 64 47 43 28 25 13 1

29. Lapatinib effect on ErbB2 accumulation at cell membrane: novel mechanism for enhanced effects of combined anti-ErbB2 therapy
Lapatinib has been shown to enhance antitumour effect of trastuzumab in vitro and in clinical studies
This study explored the mechanism for this effect by investigating impact of lapatinib and trastuzumab on receptor expression and signalling
Treatment:
lapatinib, trastuzumab, or both
ErbB2-positive BC cells (SKBR3 and MCF7-HER2)
In vitro assays:
Receptor expression, phosphorylation, signalling, tumour growth
Mouse xenograft
Scaltriti et al., J Clin Oncol ASCO Annual Meeting Proceedings 2008; 26(Suppl.): Abstract 3594 and poster
Scaltriti et al., Oncogene 2009; 29

30. What we Know
HER2+ and HR+

32. HER2 and hormone receptor-positive BC Clinical trials to assess therapy
Cortes Nat Rev Clin Oncol 2010

33. Overall response rates (%)
HER2 and hormone receptor-positive BC Clinical trials to assess therapy
100 80 60 40 20
Combination with
chemotherapy
H0648g
M77001
Overall response rates (%)
Combination with
Aromatase inhibitors
EGF30008
TAnDEM
Trastuzumab +
anastrozole
Lapatinib +
letrozole
Trastuzumab +
paclitaxel
Trastuzumab +
docetaxel
Drug regimen
Figure 1: Overall response rates in HER2-positive and hormone receptor-positive metastatic breast cancer. Anti-HER2 therapy was combined either with chemotherapy or aromatase inhibitors in four pivotal trials. The combination with chemotherapy showed higher overall response rates
Cortes Nat Rev Clin Oncol 2010

34. What else we Know
The Future
Trastuzumab + Pertuzumab

35. Pertuzumab and trastuzumab have complementary mechanisms of action
HER2
HER1/3/4
Trastuzumab
Dimerization domain
Subdomain IV
Trastuzumab:
Inhibits ligand-independent HER2 signaling
Activates ADCC
Prevents HER2 ECD shedding
Pertuzumab:
Inhibits ligand-dependent HER2 dimerization and signaling
Activates ADCC
ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain

36. Pertuzumab + trastuzumab
CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st-line setting
Placebo + trastuzumab PD
n=406
Docetaxel* ≥6 cycles recommended
Patients with HER2-positive MBC centrally confirmed
(N = 808)
1:1
Pertuzumab + trastuzumab PD
n=402
Docetaxel* ≥6 cycles recommended
Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)
Study dosing q3w: − Pertuzumab/Placebo: 840 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
MBC, metastatic breast cancer; PD, progressive disease

37. Primary endpoint: Independently assessed PFS n = 433 PFS events10 20 30 40 50 60 70 80 90
100
Ptz + T + D: median 18.5 months
∆ = 6.1 months
Pla + T + D: median 12.4 months
Progression-free survival (%)
HR = % CI 0.51‒0.75 p<0.0001 5 10 15 20 25 30 35 40
Time (months)
n at risk
Ptz + T + D
402
345
267
139 83 32 10
Pla + T + D
406
311
209 93 42 17 7
Stratified by prior treatment status and region
D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

38. Overall survival: Predefined interim analysis Median follow-up: 19
Overall survival: Predefined interim analysis Median follow-up: 19.3 months, n = 165 OS events
100 90 80 70
HR = 0.64* 95% CI 0.47‒0.88 p = * 60
Overall survival (%) 50 40 30
Ptz + T + D: 69 events 20
Pla + T + D: 96 events 10 5 10 15 20 25 30 35 40 45
Time (months)
n at risk
Pertuzumab + T + D
402
387
367
251
161 87 31 4
Placebo + T + D
406
383
347
228
143 67 24 2
* The interim OS analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p ≤0.0012)
D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

39. Cardiac tolerability Placebo + trastuzumab + docetaxel (n = 397)
Pertuzumab + trastuzumab + docetaxel (n = 407)
Investigator-assessed
symptomatic LVSD*
1.8%
1.0%
Independently adjudicated symptomatic LVSD*
Fall in LVEF to <50% and by ≥10 percentage points from baseline
6.6%
3.8%
* LVSD was defined as NYHA class III/IV
LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction

40. Adverse events (all grades) ≥25% incidence or ≥5% difference between arms
Adverse event, n (%)
Placebo + trastuzumab + docetaxel (n = 397)
Pertuzumab + trastuzumab + docetaxel (n = 407)
Diarrhea
184 (46.3)
272 (66.8)
Alopecia
240 (60.5)
248 (60.9)
Neutropenia
197 (49.6)
215 (52.8)
Nausea
165 (41.6)
172 (42.3)
Fatigue
146 (36.8)
153 (37.6)
Rash
96 (24.2)
137 (33.7)
Decreased appetite
105 (26.4)
119 (29.2)
Mucosal inflammation
79 (19.9)
113 (27.8)
Asthenia
120 (30.2)
106 (26.0)
Peripheral edema
119 (30.0)
94 (23.1)
Constipation
99 (24.9)
61 (15.0)
Febrile neutropenia
30 (7.6)
56 (13.8)
Dry skin
17 (4.3)
43 (10.6)

41. Summary and conclusions
CLEOPATRA met its primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in PFS (HR = 0.62) in patients with HER2-positive MBC
Median PFS increased by 6.1 months from 12.4 to 18.5 months
The PFS improvement was consistent across subgroups and supported by the secondary endpoints of ORR and OS (immature)
The combination of pertuzumab and trastuzumab plus docetaxel increased rates of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin
These adverse events were primarily grades 1‒2, manageable, and occurred during docetaxel therapy
There was no increase in cardiac adverse events or LVSD
This new regimen may be practice-changing in HER2-positive first-line MBC

42. What else we Know
The Future
T-DM1

43. Trastuzumab emtansine (T-DM1): the first-in-class HER2-targeted antibody-drug conjugate
Monoclonal antibody: trastuzumab
Target expression: HER2
Highly potent chemotherapy
(maytansine derivative)
Cytotoxic agent: DM1
Systemically stable
Breaks down in target cancer cell
Linker
T-DM1

44. HER2-positive, recurrent locally advanced breast cancer or MBC (N=137)
Study Design TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in first-line HER2-positive MBC
Trastuzumab
8 mg/kg loading dose; 6 mg/kg q3w IV
+ Docetaxel
75 or 100 mg/m2 q3w
(n=70)
Crossover to
T-DM1
(optional)
PDa
HER2-positive, recurrent locally advanced breast cancer or MBC (N=137)
1:1
T-DM1
3.6 mg/kg q3w IV
(n=67)
PDa
Randomized, phase II, international, open-label studyb
Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval
Primary end points: PFS by investigator assessment, and safety
Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover
Key secondary end points: OS, ORR, DOR, CBR, and QOL
aPatients were treated until PD or unacceptable toxicity.
bThis was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred.

45. Progression-Free Survival by Investigator Randomized Patients
Median
PFS, mos
Hazard ratio
95% CI
Log-rank P value
9.2
14.2
0.594
0.364–
0.0353
1.0
0.8
0.6
0.4
0.2
0.0
Trastuzumab + docetaxel (n=70)
T-DM (n=67)
Proportion progression-free
Time (months)
Number of patients at risk
T+D
T-DM
Hazard ratio and log-rank P value were from stratified analysis.

46. Duration of Response by Investigator Patients with Measurable Disease at Baseline with an Objective Response
Median
DOR, mos
95% CI
9.5
NRa
6.6–10.6 –
1.0
0.8
0.6
0.4
0.2
0.0
Trastuzumab + docetaxel (n=40)
T-DM (n=43)
Proportion progression-free
Duration of objective response (months)
Number of patients at risk
T+D T-DM
Kaplan-Meier estimates are shown.
aNR, not reached; longer follow-up is needed to estimate the duration of response in the T-DM1 arm.

47. Trastuzumab + docetaxel (n=66)c
Incidence of Nonhematologic Adverse Events: ≥30% (All Grade) and/or ≥5% (Grade ≥3) of Patientsa AE
All grade, n (%)
Grade ≥3b, n (%)
Trastuzumab + docetaxel (n=66)c
T-DM1 (n=69)c,d
Alopecia
44 (66.7)
3 (4.3) e
Fatigue
30 (45.5)
34 (49.3)
3 (4.5)
Nausea
29 (43.9)
33 (47.8)
2 (2.9)
Diarrhea
11 (15.9)
2 (3.0)
Peripheral edema
7 (10.1)
Increased AST
4 (6.1)
27 (39.1)
6 (8.7)
Pyrexia
15 (22.7)
1 (1.5)
Headache
12 (18.2)
25 (36.2)
Back pain
20 (30.3)
18 (26.1)
1 (1.4)
Increased ALT
16 (23.2)
Pneumonia
4 (5.8)
Green represents those AEs with ≥20% difference between treatment arms.
aIn either treatment arm.
bNo adverse events listed were grade 5.
cTwo patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses.
dIncludes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel.
eNational Cancer Institute Common Terminology Criteria for Adverse Events v.3 only categorizes alopecia as grade 1 or grade 2; there is no grade ≥3 for this AE.

48. Trastuzumab + docetaxel
Cardiac Safety
Cardiac function was assessed locally and centrally based on cardiac ECHO/MUGA
Prior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectively
Asymptomatic LV dysfunction
There were no clinically significant cardiac events reported
LVEF assessment
Trastuzumab + docetaxel
T-DM1
Local assessment
Patients assessed 65 67
Patients with post-baseline LVEF ≤40% 2a
Central assessment 60 1b
aBoth patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting.
bThis patient did not receive prior treatment with an anthracycline.

49. Summary and Conclusions
This is the first randomized study to evaluate an antibody-drug conjugate for HER2-positive MBC
First-line treatment of HER2-positive MBC with T-DM1, compared with trastuzumab + docetaxel was associated with:
A significant improvement in PFS (14.2 vs 9.2 mos; HR=0.594; P value=0.0353)
Similar ORR but more durable responses (64.2%, median duration not reached vs. 58.0%, median duration 9.5 months)
A lower rate of grade ≥3 AEs (46.4% vs 89.4%)
These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index
Improved PFS with T-DM1 may result from improved tolerability/duration of treatment/response and intrinsic potency of HER2-targeted DM1
T-DM1 is being evaluated in phase III randomized clinical trials for HER2-positive MBC

50. TDM4370g (EMILIA) Phase III Study: T-DM1 vs Capecitabine + Lapatinib in HER2-Positive MBC
T-DM1 (3.6 mg/kg) q3w
HER2-positive LABC or MBC (N=980)
Previously received trastuzumab-based therapy
1:1
Lapatinib (1250 mg/day, days 1–21)
+ capecitabine (1000 mg/m2, days 1–14) q3w
Multicenter, randomized, open-label study
Treatment continues until progressive disease/unacceptable toxicity
Primary end points: PFS by IRF, OS, 1-y and 2-y survival rates, Safety
Secondary end points: PFS by INV, ORR, CBR, DoR, QOL, TTF
NCT

51. MARIANNE: Primary efficacy objective: Primary safety objective:
Trastuzumab + taxane
(n=364)
HER2-positive progressive or recurrent locally advanced BC or previously untreated MBC
(n=1092)
T-DM1 + pertuzumab
(n=364)
T-DM1 + placebo
(n=364)
Primary efficacy objective:
PFS assessed by an independent review facility
Primary safety objective:
To compare the safety of T-DM1 + pertuzumab or T-DM1 + placebo vs trastuzumab + taxane
BC = breast cancer; MBC = metastatic breast cancer; PFS = progression-free survival