1. Azienda Ospedaliero Universitaria Policlinico Modena
Taxanes and bevacizumab are the standard first line theraphy for Her 2 – metastatic breast cancer
Chieti, 27 Giugno 2016
Luca Moscetti
DH Oncologia
Dipartimento di Oncologia, Ematologia e Malattie dell’Apparato Respiratorio
Azienda Ospedaliero Universitaria Policlinico Modena
Chieti, 27 Giugno 2016

2. E2100—Study Design
Paclitaxel: 90 mg/m2 IV infusion over 1 hr every wk for 3 wk followed by 1 wk of rest
Avastin: 10 mg/kg following paclitaxel treatment on Wk 1 and 3 of every cycle
MBC not previously treated with chemotherapy
(N = 685)
Stratification
- Disease-free interval
- Adjuvant therapy
- ER+, ER–, unknown
- Number of metastatic sites R A N D O M I Z E
Paclitaxel: 90 mg/m2 IV infusion over 1 hr every wk for 3 wk followed by 1 wk of rest
Miller K, et al New England Journal of Medicine 2007.

3. E2100—Endpoints Primary endpoint Secondary endpoints
Progression-free survival (PFS)
Secondary endpoints
Objective response rate (ORR)
Overall survival (OS)
Quality of life (QoL)
Safety
Miller K, et al New England Journal of Medicine 2007.

4. Paclitaxel weekly + bevacizumab St III-IV breast cancer HER2-negative
ECOG 2100: Randomized Phase III Trial of Bevacizumab Added to Paclitaxel in Stage IV Breast Cancer
Paclitaxel weekly + bevacizumab
ECOG 2100
St III-IV breast cancer HER2-negative
N = 722
Paclitaxel weekly
1.0
Pac. + Bev months
0.8
Paclitaxel months
0.6
HR = 0.51 ( )
PFS Probability
0.4
0.2
0.0 6 12 18 24 30
Months
Miller K, et al New England Journal of Medicine 2007.
Miller K, SABCS 05

5. E2100 response rates Investigator assessment IRF assessment
48%
50%
Patients, %
Patients, %
23%
22%
Paclitaxel
Bevacizumab + paclitaxel
Paclitaxel
Bevacizumab + paclitaxel
Miller K, et al New England Journal of Medicine 2007.
Miller K, SABCS 05

6. E2100 Overall Survival 81.4% 74.0% 55.0% 50.1% 1.0 1.0 p = 0.017*
PAC (n = 354): Median OS 24.8 mo
PAC + AVA (n = 368): Median OS 26.5 mo
0.8
0.8
50.1%
55.0%
p = 0.191*
0.6
0.6
HR = (0.722, 1.046)
Log-rank test, p =
Proportion surviving
0.4
0.4
0.2
0.2
* Post-hoc
0.0
0.0 6 6 12 12 18 18 24 24 30 30 36 36 42 42 48 48 54 54 60 60
No. of patients at risk
Months
PAC+AVA
368
344
297
249
193
104 48 23 5
PAC
354
307
258
215
165
103 48 19 8

7. Option to receive bevacizumab with second-line chemotherapy
AVADO: Bevacizumab + Docetaxel in First- line Treatment of Advanced Breast Cancer
Stratified by region previous taxane therapy, disease-free internal, measurable disease, hormone receptor status
Docetaxel* 100 mg/m2 + Placebo† (n = 241)
Women with HER2-negative, untreated locally recurrent or metastatic breast cancer
(N = 736)
Option to receive bevacizumab with second-line chemotherapy
Docetaxel* 100 mg/m2 + Bevacizumab† 7.5 mg/kg (n = 248)
Docetaxel* 100 mg/m2 + Bevacizumab† 15.0 mg/kg (n = 247)
*Docetaxel given every 3 wks up to 9 cycles. †Bevacizumab or placebo given until unacceptable toxicity or disease progression.
Miles DW, et al. SABCS Abstract 41.

8. Avastin Taxanes overall response rate Investigator assessment
AVADO2
Overall response rate (%)
100
P alone Avastin 10 mg/kg q2w + P
100
Placebo + D
Avastin 7.5 mg/kg q3w + D
Avastin 15 mg/kg q3w + D 80 80
IRF assessment (n=472)
Investigator assessment
63 (n=206)
55 (n=201) 60 60 50
44 (n=207) 40 40 22 20 20
CR + PR p<0.0001
CR + PR p<0.0001
CR + PR
CR + PR
p=0.0295a
CR + PR
p=0.0001a
aVersus placebo + D IRF, Independent Review Facility
1Klencke et al, ASCO 2008; 2Miles et al, ASCO 2008 8

9. AVADO: PFS by BEV doses
The trial was not designed to detect a statistically significant difference between bevacizumab doses
Miles DW, et al Journal Clinical Oncology 2010.

10. PFS in subgroup analyses: patient characteristics
AVADO3
Baseline risk factor n
555
722
167
Favors Avastin + P
Favors P n
488
489
402
410 86 79
296
297
185
Favors Avastin + D
Favors placebo + D
All patients
Age
<65 years
>65 years
ECOG PS
Not analyzed 1
0.25
0.5 1 2 4
0.25
0.5 1 2 4
Avastin 10 mg/kg q2w + P
Avastin 7.5 mg/kg q3w + D
1Klencke et al, ASCO 2008; 2Schneeweiss et al, ESMO 2008; 3Miles et al, ASCO 2008
Avastin 15 mg/kg q3w + D 10

11. PFS in subgroup analyses: disease characteristics
AVADO3
Baseline risk factor n
722
446
265
296
426
514
208
Favors Avastin + P
Favors P n
488
489
348
349
138
137
161
188
327
301
263
264
221
Favors Avastin + D
Favors placebo + D
All patients
ER status
positive
negative
Disease-free interval
=24 months
>24 months
No. metastatic sites
<3 =3
0.25
0.5 1 2 4
0.25
0.5 1 2 4
Avastin 10 mg/kg q2w + P
Avastin 7.5 mg/kg q3w + D
1Klencke et al, ASCO 2008; 2Schneeweiss et al, ESMO 2008; 3Miles et al, ASCO 2008
Avastin 15 mg/kg q3w + D 11

12. PFS in subgroup analyses: prior therapy
AVADO3
Baseline risk factor n
475
247
142
580
364
358
722
Favors Avastin + P
Favors P n
323
318
165
171 77 73
411
416
269
264
219
225
488
489
Favors Avastin + D
Favors placebo + D
All patients
Prior adjuvant chemo
Yes No
Prior taxane
Yes No
Prior anthracycline
Yes No
0.25
0.5 1 2 4
0.25
0.5 1 2 4
Avastin 10 mg/kg q2w + P
Avastin 7.5 mg/kg q3w + D
1Klencke et al, ASCO 2008; 2Schneeweiss et al, ESMO 2008; 3Miles et al, ASCO 2008
Avastin 15 mg/kg q3w + D 12

16. TURANDOT: Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine
Phase III
Pts 564
BEVA PAC vs BEVA CAPE
mPFS 11 mo vs 8,1 mo
1,28 p=0.0052
HR 1.04

17. FDA withdraw EMA approval November 18, 2011
Withdraw approval of bevacizumab for breast cancer
Initial benefits in PFS not confirmed from two additional studies
AVADO and RIBBON1 did not confirmed the clinical benefit showed in ECOG2100
Avastin (bevacizumab) in combination with paclitaxel is indicated for first-line treatment of patients with locally recurrent or metastatic breast cancer
Avastin in combination with capecitabine is indicated for first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Avastin in combination with capecitabine

18. Progression-Free Survival in E2100, AVADO, and RIBBON1
FDA withdraw
Progression-Free Survival in E2100, AVADO, and RIBBON1
U.S. BL /191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010

19. Primary Analysis of Overall Survival in E2100, AVADO, and RIBBON1
FDA withdraw
Primary Analysis of Overall Survival in E2100, AVADO, and RIBBON1
U.S. BL /191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010

20. Updated Analysis of Overall Survival in E2100, AVADO, and RIBBON1
FDA withdraw
Updated Analysis of Overall Survival in E2100, AVADO, and RIBBON1
U.S. BL /191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010

21. Only ECOG 2100 used weekly paclitaxel
FDA withdraw
Only ECOG 2100 used weekly paclitaxel
Is effect drug or schedule related?
No reason to believe that the effect should be the same
Effect of capecitabine in combination diluted by taxane and anthracycline arms
51% of patients in the non-bev arm received bevacizumab post-progression compared to 40% who continued bev after first-line
42% vs 35% (non bev vs bev) received 3 or more subsequent lines of therapy following progression

22. FDA withdraw
This extensive use of subsequent therapy at investigator discretion may have affected later survival, making it more difficult to assess the effect of Avastin on overall survival in the first-line HER2-negative MBC setting
U.S. BL /191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010

23. Bevacizumab: First-line trials
Efficacy
E-2100
AVADO
Ribbon-1 Capecitabine
Ribbon-1
A/T
Control arm
Beva
Arm
Placebo
arm
Beva arm
PFS months
5.9
11.8
8.2
9/10.1
5.7
8.6
8.0
9.2 HR
0.60
P<.0001
0.86 P=.12 (7.5 mg)
0.77 P=.006 (15 mg)
0.69
P=.0002
0.64
OS months
25.2
26.7
31.9
30.8/30.3
21.2 29
23.8
0.88
P=.16
1.05/1.03
P=.72/.85
0.85
P=.27
1.03
P=.83
SPP
months
19.3
14.9
23.7
21.8/20.2
15.5
20.4
15.8 16

24. Chemotherapy + Bevacizumab
Pooled Efficacy Analysis of Bevacizumab + Chemotherapy vs Chemotherapy Alone
Outcome
Chemotherapy + Bevacizumab
(n = 1439)
Chemotherapy Alone
(n = 1008)
Median PFS, mos
9.2
6.7
HR (95% CI)
0.64 ( )
ORR,* % 49 32
Median OS, mos
26.7
26.4
0.97 ( )
1-yr OS, % 82 77
*Assessed in patients with measurable disease at baseline: n = 1105 for chemotherapy
plus bevacizumab; n = 788 for chemotherapy alone.
O’Shaughnessy et al. ASCO Abstract 1005.

25. Meta-Analysis crossover and post-study therapies
Therapies used upon progression in AVADO and RIBBON-1a
Therapy, %
CT + Beva
(n=1071) CT
(n=654)
Chemotherapy 65 71
Bevacizumab 40 51
Hormonal therapy 23 25
Number of subsequent agents 1 2 3
≥ 4 15 26 12 10 27
aData not available from E2100
O’Shaugnessy J et al, ASCO Abstract 1005

26. Beva Pac/Cape/other CTs
Bevacizumab: real life
ATHENA
obs
AVAREG
AVANTI
ML21165
# pts
2251
220
1807
865 Tx
Beva Taxs/
other CTs
Beva Taxs
Beva Pac/Cape/other CTs
Beva Pac
B cont / B stop
PFS months
9.7
11,6 Beva cont
6,7 Beva stop
9,3
9.5
9,6
18,4 Beva cont HR -
OS months 25
30 Beva cont
18 Beva stop
21,6
35,7 Beva cont

27. 53% Continue Bevacizumab
Final overall survival results and effect of prolonged (>1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial
53% Continue Bevacizumab
2264 pts
Bevacizumab +CT
47% Stop Bevacizumab
Smith I Breast Cancer Res Treat (2011)

28. OS PFS ATHENA trial mOS Cont’d Stop’d 25,2 mo 30 18,4 mPFS Cont’d
9.7 mo
11,7
6,7
Smith I Breast Cancer Res Treat (2011)

29. Bevacizumab maintenance in first line treatment for metastatic breast cancer
54% Continue Bevacizumab
314 pts
Bevacizumab+CT
46% Stop Bevacizumab (8,3% PD)
mPFS 14,6 mo
L. Mentuccia, ASCO 2015 annual meeting, P549.

30. Meta-analysis of First-line Bevacizumab Plus Chemotherapy in Triple-Negative Breast Cancer
Bevacizumab/ Chemo
(n = 363)
Chemo
(n = 258)
HR (95% CI)
P Value
Median Progression-Free Survival
8.1 months
5.4 months
0.649 ( )
< .0001
Overall Response Rate
42%
23% NR
Median Overall Survival
18.9 months
17.5 months
0.959 ( )
.6732
1-Year Overall Survival Rate
71%
65%
.1140
This meta-analysis represents the largest reported population of patients randomized to treatment for metastatic TNBC.
The addition of bevacizumab significantly improved PFS but not OS.
O’Shaughnessy et al. SABCS 2010; abstract P

31. First-line Bevacizumab Plus Chemotherapy in Triple-Negative Breast Cancer
Trial
Chemo Partner
Number of Patients With TNBC (%)
Median PFS
Bev/Chemo
Chemo HR
E2100
Weekly paclitaxel
122 (33%)
110 (31%)
10.6 mo.
5.3 mo.
0.49
AVADO
Docetaxel q 3 weeks
58 (23%)
52 (22%)
8.1 mo.
6.1 mo.
0.68
RIBBON-1 (Taxane/ Anthracycline)
Docetaxel/nab paclitaxel or anthracycline combination
96 (23%)
46 (22%)
6.5 mo.
6.2 mo.
0.78
RIBBON-1 (Capecitabine)
Capecitabine
87 (21%)
50 (24%)
4.2 mo.
0.72
8,1 mo
5.4 mo
ATHENA
Taxanes 68%
585 (25%) -
7,2 mo.
AVAREG
Paclitaxel
106 (48%)
8,3 mo.
TURANDOT
Cape or Pac
130 (23%)
9/5.6 mo.
O’Shaughnessy et al. SABCS 2010; abstract P , modified.

32. HR+
Months
HR -

33. Capecitabine docetaxel Gemcitabine paclitaxel Paclitaxel Bevacizumab
Outcome
Anthra Paclitaxel
Docetaxel
Capecitabine docetaxel
Gemcitabine paclitaxel
Paclitaxel Bevacizumab
Nabholtz 2003
Jones
2005
O’shaugnessy 2002
Melemed
2008
Miles
2007
Number of pts
213
211
256
266
368
Median PFS, mos
6,2
5,7 6
11.4
Median OS, mos
22,5 16 14
18,6
26.7
ORR% 59 32 42
41,4 50

34. It seems to be the same curves
7,4 mo
4,6 mo

35. Practice changing ???
Practice changing !!!
7,4 mo
4,6 mo

36. Bevacizumab combined with a chemotherapy as 1st or 2nd line therapy for MBC provides only a moderate benefit in PFS and no benefit in OS. The absence of known predictive factors for bevacizumab efficacy renders recommendations on its use difficult.
Bevacizumab can only therefore be considered as an option in selected cases in these settings and is not recommended after 1°/ 2nd line.
ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)*

37. Taxanes and bevacizumab are the standard first line theraphy for Her 2 – metastatic breast cancerNo
Yes..
Maybe