1. Chicago 2008: Post - ASCO Analysis: Metastatic Breast Cancer
CONTENT
Take Home Message
Chemotherapy
Navelbine
Targeted therapy
Navelbine 9
ASCO 08 MBC

2. ASCO 08 Metastatic Breast : Take Home Message
No major trials presented during the meeting
Main chemotherapy options remain the same
Many interesting communications on Navelbine in MBC
More and more trial results of targeted therapies
Role of Avastin in MBC: improvement of PFS with no specific targeting of pts, is this enough?
Herceptin more than ever the standard for HER2+ patients, even after relapse
ASCO 08 MBC

3. ASCO 2008: Chemotherapy
ASCO 08 MBC

4. Chemotherapy duration in MBC Meta-analysis (Gennari, #1067p)
Meta-analysis including 8 randomized studies evaluating longer vs shorter CT duration (1942 pts)
Overall, in terms of PFS, longer CT duration was associated with a 35% reduction in the risk of relapse (p=s)
Longer CT duration was associated with an 8% reduction in the risk of death (p=ns)
Confirmed benefits of a longer chemotherapy duration
ASCO 08 MBC

5. Short follow up. Previous treatments not detailed in the poster
Taxotere (Txt) + Epi (ET) vs Txt + Capecitabine (XT) Randomized ph II in 1st-line – Bachelot, #1049p
Schedule
(mg/m²/ Q3W)
ET:
E 75 D1
T 75 D1
XT:
X 2000 D1 to D14
Evaluable pts 24 23
Median age 56
Previous treatments
NR (Not Reported) NR
OR (%) 54
CR (%) 4 9
MDR (mo)
PFS (mo)
8.8
12.4
MS (mo) 28
Median follow-up was 14.8 months
# = N Abstract; O = Oral presentation ; P = Poster
Short follow up. Previous treatments not detailed in the poster
ASCO 08 MBC

6. Taxotere + Epi (ET) vs Ttx + Capecitabine (XT) Randomized ph II in 1st-line – Bachelot, #1049p
Toxicity G3-4 (% pts) ET XT
Evaluable pts 47 45
Neutropenia 44 34
HFS 17
Infection 6
Mucositis 2 8
Asthenia 4
Diarrhea 10
# = N Abstract; O = Oral presentation ; P = Poster
Expected toxicity rates in both arms (prophylactic G-CSF given in ET arm)
ASCO 08 MBC

7. Txt + Epi (ET) +/- Cap (X) Randomized ph III in 1st-line (Mansutti, #1034p)
Schedule
(mg/m²/ Q3W)
ET:
E 75 D1
T 75 D1
TEX:
X 2000/D D1 to D14
Evaluable pts
135
134
Previous anthracycline 28 29
OR (%) 53 67
CR (%) 5 16
PFS (mo) p=NS 10 12
OS (mo) p=NS 34
# = N Abstract; O = Oral presentation ; P = Poster
Negative trial: Modest improvement in efficacy from addition of Capecitabine
ASCO 08 MBC

8. Very high toxicity rates in both arms
Txt + Epi (ET) +/- Cap (X) Randomized ph III in 1st-line (Mansutti, #1034p)
Toxicity G3-4 (% pts) ET
TEX
Evaluable pts
172
168 FN 12 15
HFS 2 22
Mucositis 45 60
Diarrhoea 30 50
Nausea/Vomiting
60/30
64/38
Alopecia 70 80
Toxic deaths 6 3
# = N Abstract; O = Oral presentation ; P = Poster
Very high toxicity rates in both arms
ASCO 08 MBC

9. ASCO 2008: Navelbine and Chemotherapy
21 abstracts overall
15 accepted for presentation during the meeting
14 in combination with CT
7 in combination with a targeted therapy
ASCO 08 MBC

10. Navelbine in ABC at ASCO 2008 : Chemotherapy Combinations
With Capecitabine
7 Trials
With Platinum salts
3 Trials
With Gemcitabine
2 Trials
With Anthracyclines
1 Trial
With 5 FU
ASCO 08 MBC

11. Navelbine Oral + Capecitabine in metastatic setting Phase II in pretreated pts. (Gil-Delgado, #1135p)*
Toxicity G3-4 (% pts)
Schedule
(mg/m²/ Q3W)
NVB ORAL 60 D1 & D8
CAP 2000/day D1-D14
Evaluable pts 23
Previous 1 line for MBC
28%
Previous 2 lines for MBC
> than 2 lines
44%
OR (%) 26
CR (%) 13
Clinical Benefit (%) 95
TTP (mo) 6
MS (mo) 48
* HER-2 positive and negative patients were included.
Evaluable pts 25
Neutropenia 1
Fever/Infection
Anemia
Thrombocytopenia
Nausea / Vomiting
HFS
Mucositis
Diarrhoea
Alopecia
# = N Abstract; O = Oral presentation ; P = Poster
Excellent clinical benefit and safety in heavily pretreated pts
Ongoing evaluation with bevacizumab (HER2 -) and trastuzumab (HER2 +)
ASCO 08 MBC

12. Navelbine IV/Oral + Capecitabine: Sequential Phase II trials (Lorusso, #1114p)
Schedule
(mg/m²/ Q3W)
NVB IV 25 D1 + D8
CAP 2000 D1- D14
NVB O 60 D1 + D8
Evaluable pts 38
Prior anthra + taxane
76 %
Prior anthra alone
16 %
Prior taxane alone
8 %
OR (%) 37 39
CR (%) 5
Disease control (%) 60 76
TTP (mo)
6.8 7
MS (mo)
11.3 10
Median follow-up: 24 months
# = N Abstract; O = Oral presentation ; P = Poster
NVBoral & Xeloda: An active combination for pre-treated anthra/taxanes pts
ASCO 08 MBC

13. Well-tolerated regimen
Navelbine IV/Oral + Capecitabine: Sequential Phase II trials (Lorusso, #1114p)
Toxicity G3-4 (% pts)
NVB IV + CAP
NVB ORAL + CAP
Evaluable pts 38
Neutropenia 10 21
Anemia (grade 2-3) 13
Thrombocytopenia 3
HFS (grade 2-3) 5
Diarrhea (grade 2) 8
# = N Abstract; O = Oral presentation ; P = Poster
Well-tolerated regimen
ASCO 08 MBC

14. Navelbine Oral + Capecitabine: Feasibility study for dose optimisation (Anton, #1105p)
Schedule
(mg/m²/ Q3W)
NVB ORAL D1 & D8, different dose levels
CAP D1-D14, different dose levels
Number of pts 18
Prior CT (% pts)
in adjuvant setting: 55%
In metastatic setting: 22%
Both: 5%
OR (%)
33% for dose levels III and IV
Recommended dose (level IV)
NVB ORAL 80 D1 + D8
CAP 2000/day D1 to D14, both q3w
No further dose escalation performed in this study
Both agents safely used at recommended single agent dose
# = N Abstract; O = Oral presentation ; P = Poster
Feasible combination with a dose of NVBO of 80 mg/m2 D1 and D8 q3w
ASCO 08 MBC

15. High response rate with NVB + CAP
Navelbine IV + Capecitabine Phase II in 1st line MBC (El Ghazaly, # P 1125 )
Schedule
(mg/m²/ Q3W)
NVB IV 25D1 & D8
Cap 2000/day D1-D14
Evaluable pts 45
Prior CT (% pts)
Patients pre-treated by anthracycines in adjuvant or neoadjuvant setting (95%)
OR (%) 64
CR (%) 4
Disease control (%) 82
TTP (mo)
9.0
MS (mo) NP
# = N Abstract; O = Oral presentation ; P = Poster
High response rate with NVB + CAP
ASCO 08 MBC

16. Navelbine IV + Capecitabine Phase II in 1st line MBC (El Ghazaly, # P 1125 )
Toxicity G3-4 (% pts)
Evaluable pts 45
Neutropenia 13
Febrile Neutropenia 2
Anemia 4
Thrombocytopenia
Nausae/Vomiting 16
HFS 7
Mucositis 11
Diarrhoea 9
Local Phlebitis
# = N Abstract; O = Oral presentation ; P = Poster
7% of peripheral phlebitis could be avoided with the ALL ORAL combination
ASCO 08 MBC

17. Similar efficacy in both arms: why a sequential taxane?
Navelbine IV + Capecitabine (NavCap) in 1st line: R Ph II + sequential Taxotere (Ghosn, #1119p)
Schedule
(mg/m²/ Q3W)
Navcap (8 cycles):
NVB IV 25 D1 + D8
CAP 1650 per day D1 to D14
Navcap(4 cycles) followed by
D 25 weekly x 12
Evaluable pts 30 28
Median age 49 50
Prior anthracycline (%) 67 62
OR (%) 70 78
TTP (mo) 10 11
MS (mo) 34
Preliminary analysis of this trial including 60% of the expected patient population
# = N Abstract; O = Oral presentation ; P = Poster
Similar efficacy in both arms: why a sequential taxane?
ASCO 08 MBC

18. Low toxicity rates in both arms
Navelbine IV + Capecitabine (NavCap) in 1st line: R Ph II + sequential Taxotere (Ghosn, #1119p)
Toxicity G3-4 (% pts)
NAVCAP
NAVCAP -> TXT
Evaluable pts 30 28
Neutropenia 3 5
Anemia 6
HFS
Diarrhea
Nausea / Vomiting
# = N Abstract; O = Oral presentation ; P = Poster
Low toxicity rates in both arms
ASCO 08 MBC

19. ASCO 2008: Targeted Therapy
ASCO 08 MBC

20. CT + Herceptin remain the best treatment for HER2 positive patients
Herceptin (H) + Taxotere (T) vs H T 1st line ABC: Randomized ph II study in HER2+ pts (Bontembal, # O 1014 )
Schedule
(mg/m2/q3w)
Herceptin weekly
+ TXT 100 until PD
Herceptin weekly followed (at PD) by
TXT 100
Evaluable pts 53 46
Prior adjuvant CT 55 52
Median age 50
OR (%) (p=s) 73
CR (%) 14 2
Median PFS (mo) (p=NS)
9.4
10.8
Median OS (mo) (p=NS)
30.5
20.2
Duration of trastuzumab treatment was longer in the combination arm
# = N Abstract; O = Oral presentation ; P = Poster
CT + Herceptin remain the best treatment for HER2 positive patients
ASCO 08 MBC

21. Very toxic combination arm: neurotoxicity, 2 toxic deaths
Herceptin (H) + Taxotere (T) vs H T in ABC: Randomized ph II study in HER2+ pts (Bontembal, # O 1014 )
Toxicity G3-4 (% pts)
Herceptin weekly + TXT
Herceptin  TXT
Evaluable pts 53 46
Infection 18 13
Neutropenic fever 23 15
Toxic deaths 2
Vomiting 4 6
Stomatitis 8 11
Neurotoxicity
LVEF < 45%
Pulmonary
# = N Abstract; O = Oral presentation ; P = Poster
Very toxic combination arm: neurotoxicity, 2 toxic deaths
ASCO 08 MBC

22. Capecitabine (CAP) vs CAP + Herceptin (H) in ABC: Phase III in HER2+ pts in PD with H (Von Minckwitz, 1025p)
Schedule
(mg/m²/ Q3W)
CAP 2500 per day, D1 to D14
CAP 2500 per day, D1 to D14 + Herceptin q3w
Evaluable pts 78
Median age 59 52
OR (%) 27 48
CR (%) 3 8
Clinical Benefit (%) 54 75
TTP (mo) p = 0.034
5.6
8.2
MS (mo) p = NS
20.4
25.5
Trial stopped with 65% of the planned number of pts because of poor accrual
# = N Abstract; O = Oral presentation ; P = Poster
Continuation of treatment with Herceptin beyond progression is an active option
ASCO 08 MBC

23. Classic adverse events of capectabine observed in this trial
Capecitabine (CAP) vs CAP+ Herceptin (H) in ABC: Phase III in HER2+ pts in PD with H (Von Minckwitz, 1025p)
Toxicity G3-4 (% pts)
CAP
CAP + H
Evaluable pts
131
HFS 24 31
Diarrhoea 21 15
Mucositis 3 2
Vomiting 6
Neuropathy 5
Asthenia
Cardiac
# = N Abstract; O = Oral presentation ; P = Poster
Classic adverse events of capectabine observed in this trial
ASCO 08 MBC

24. Lapatinib (L) and Herceptin (H) vs Lapatinib in ABC: Phase III in HER2+ PD pts with H (O’Shaughnessy, # 1015o)
Schedule
Lapatinib 1500 mg/day PO
Lapatinib 1000 mg/day PO
+ Herceptin weekly
Evaluable pts
148
149
Prior treatments
All patients pretreated by anthra, taxane and herceptin
Median age 51 52
OR (%) 7 10
Clinical Benefit (%) 12 25
6 month PFS (%) 13 28
12 month OS (%) 36 45
Significant improvement of PFS with the combination
# = N Abstract; O = Oral presentation ; P = Poster
After Herceptin 2 options: Herceptin + new CT or Lapatinib + CT
ASCO 08 MBC

25. Lapatinib (L) and Herceptin (H) vs Lapatinib in ABC: Phase III in HER2+ PD pts with H (O’Shaughnessy, # 1015o)
Toxicity All Grades (% pts) L LH
Evaluable pts
146
149
Diarrhoea 48 60
Rash 29 22
Nausea 28
Fatigue 19 21
Vomiting 18 14
Dyspnea 10 12
Anorexia 11
Headache 9
# = N Abstract; O = Oral presentation ; P = Poster
Main adverse event observed is diarrhoea
ASCO 08 MBC

26. Positive trend in efficacy for Avastin in MBC: but is this meaningful?
Avastin* (A) + Taxotere (T) in 1st line ABC Phase III: Placebo-contolled, AVADO study (Miles, #1011o)
Schedule
(mg/m²/ Q3W)
T 100
+ placebo
+A 7.5 mg/kg
+ A 15 mg/kg
Eligible pts
241
248
247
Previous anthra 55 53
Previous taxane 15 17
Median age 54
OR (%) 44
55 (p=0.02)
63 (p=0.0001)
CR (%) 1 3
PFS (mo)
8.0
8.7 (p=0.03)
8.8(p=0.009)
1-year survival (%) 73 78 83
Median follow-up: 10.2 months
* Avastin® (Bevacizumab) : monoclonal antibody to VEGF inhibiting tumor angiogenesis
# = N Abstract; O = Oral presentation ; P = Poster
Positive trend in efficacy for Avastin in MBC: but is this meaningful?
ASCO 08 MBC

27. Avastin significantly increases toxicity
Avastin* (A) + Taxotere (T) in 1st line ABC Phase III: Placebo-contolled, AVADO study (Miles, #1011o)
Toxicity G3-4 (% pts)
T + placebo
T + A 7.5mg/Kg
T + A 15 mg/Kg
Eligible pts
233
250
247
Any grade 3-4 67 75 74
Toxic death
2.6
1.6 FN 12 15 17
Hypertension
1.3
0.4
3.2
GI perforation
0.9
Peripheral neuropathy 2 3
4.5
Diarrhoea 7
PPE 1 5 6
# = N Abstract; O = Oral presentation ; P = Poster
Avastin significantly increases toxicity
ASCO 08 MBC

28. ASCO 2008: Navelbine and Targeted Therapy
21 abstracts overall
15 accepted for presentation during the meeting
14 in combination with CT
7 in combination with a targeted therapy
ASCO 08 MBC

29. Navelbine in ABC at ASCO 2008 : Targeted Therapy Combinations
+ Trastuzumab
4 Trials
+ RAD001 (everolimus)
2 Trials
+ PTK787/ZK222584
1 Trial
ASCO 08 MBC

30. NVB ORAL is an excellent choice for HER2 positive patients
Navelbine IV/Oral + Herceptin: Ph II in 1st-line HER2 positive pts (Laessig, #1061p)
Schedule
(mg/m²/ Q3W)
NVB IV 25 D1
NVB ORAL 60 D8 & 15
Herceptin q3w
Evaluable pts 42
OR (%) 60
CR (%) 17
Clinical benefit (%) 81
MDR (mo)
7.5
TTP (mo)
9.4
OS (mo)
28.6
# = N Abstract; O = Oral presentation ; P = Poster
NVB ORAL is an excellent choice for HER2 positive patients
ASCO 08 MBC

31. Excellent tolerability with few grade III-IV events
Navelbine IV/Oral + Herceptin: Ph II in 1st-line HER2 positive pts (Laessig, #1061p)
Toxicity G3-4 (% pts)
Evaluable pts 42
Leucopenia 12
Febrile Neutropenia
Anemia
Thrombocytopenia
Nausea 2
Vomiting
Neurotoxicity
Cardiotoxicity
# = N Abstract; O = Oral presentation ; P = Poster
Excellent tolerability with few grade III-IV events
ASCO 08 MBC

32. Navelbine + Taxotere + Herceptin with G-CSF: Ph II in 1st-line HER2 positive pts (Kash, #1033p)
Schedule
(mg/m²/ Q3W)
TXT 60 D1
NVB D8 + D15
Weekly Herceptin
G-CSF D2 to D21
Evaluable pts 76
Prior CT (% pts)
First-line CT in HER2 positive patients
OR (%) 71
PFS (mo) 19
MS (mo) 39
# = N Abstract; O = Oral presentation ; P = Poster
Best survival rate published to date in this population
ASCO 08 MBC

33. Navelbine + Taxotere + Herceptin with G-CSF: Ph II in 1st-line HER2 positive pts (Kash, #1033p)
Toxicity G3-4 (% pts)
Evaluable pts 76
Grade IV event 21
Grade III event 30
Neutropenia
Predominant grade IV event
Fatigue 10
Hyperglycemia 7
# = N Abstract; O = Oral presentation ; P = Poster
Very aggressive regimen for HER2 positive patients
ASCO 08 MBC