Key CRC data from ASCO 2013: FIRE-3, CAIRO3 and more

Key CRC data from ASCO 2013
FIRE-3 Phase III 1L Avastin + FOLFIRI vs cetuximab + FOLFIRI
CAIRO3 Phase III Maintenance Avastin + capecitabine vs observation
New EPOC Phase III
Peri-operative cetuximab + CT vs CT in patients with
resectable colorectal liver metastases
CALGB-80405
(QoL analysis)
Phase III
1L Avastin + FOLFOX/FOLFIRI vs
cetuximab + FOLFOX/FOLFIRI
SAKK 41/06 Phase III Maintenance Avastin vs observation
EAGLE Phase III
2L Avastin 5mg/kg + FOLFIRI vs Avastin 10mg/kg +
FOLFIRI following progression on 1L Avastin
TRIBE Phase III
1L Avastin + FOLFOXIRI vs Avastin + FOLFIRI, followed by
maintenance Avastin

PEAK
(KRAS/NRAS analysis)
Phase II
1L Avastin + mFOLFOX6
vs panitumumab + mFOLFOX6
PRIME
(KRAS/NRAS analysis)
Phase III 1L panitumumab + FOLFOX4 vs FOLFOX4
PRIME
(by KRAS exon 2 status )
Phase III 1L panitumumab + FOLFOX4 vs FOLFOX4
DREAM Phase III Maintenance Avastin ± erlotinib
AVEX Phase III
1L Avastin + capecitabine vs capecitabine in elderly
mCRC patients
TML Phase III
Avastin + chemotherapy beyond first progression vs
chemotherapy
OLIVIA Phase II
Avastin + mFOLFOX6 vs Avastin + FOLFOXIRI in initially
unresectable liver-limited mCRC
SOFT Phase III
S-1/oxaliplatin (SOX) + Avastin vs
mFOLFOX6 + Avastin
Key CRC data from ASCO 2013
(cont’d)

FIRE-3: phase III H2H trial comparing 1L Avastin + FOLFIRI
with cetuximab + FOLFIRI
Heinemann, et al. ASCO 2013
Previously
untreated
KRAS WT mCRC
(n=592)
Cetuximab + FOLFIRI
(n=297)
Avastin + FOLFIRI
(n=295)
R
• Phase III
• Primary endpoint: ORR
• Secondary endpoints: PFS, OS, time to failure of first-line therapy,
‘deepness of response’ (% tumour shrinkage compared to baseline),
secondary R0 resection rate, safety

Cetuximab + FOLFIRI Avastin + FOLFIRI
ITT population (n=592) (n=297) (n=295)
ORR (95% CI), % 62.0 (56.2–67.5) 58.0 (52.1–63.7)
Odds ratio 1.18 (0.85-1.64)
p valueǂ 0.183
CR 4.4 1.4
PR 57.6 56.6
SD 17.5 28.8
PD 7.1 5.4
Not evaluable 13.1 7.8
FIRE-3: no significant increase in the primary endpoint of ORR*
with cetuximab-based therapy
*ITT population; investigator-reported; ǂFisher’s exact test (one-sided)
• With a p value of 0.183, the futility of the primary analysis was substantial
• The main reason for missing the primary endpoint was the higher than expected
ORR in the Avastin arm

ORR subgroup data in patients assessable for response1
Assessable for response (n=526) Cetuximab + FOLFIRI (n=255)
Avastin + FOLFIRI
(n=271)
ORR (95% CI), % 72.2 (66.2–77.6) 63.1 (57.1–68.9)
Odds ratio 1.52 (1.05-2.19)
p-value* 0.017
*Fisher’s exact test (one-sided)
1. Heinemann, et al. ASCO 2013; 2. Bergsland, et al. ASCO 2013
• The ‘assessable for response’ subgroup includes patients who had at least one additional CT scan to
compare with their baseline scan in order to measure response and at least three completed cycles of
chemotherapy
• The significant increase in ORR in patients assessable for response should be interpreted with caution
as the number of patients excluded was significantly different in each treatment arm (n=42 in
cetuximab arm vs n=24 in Avastin arm, p=0.026 [2-sided Fisher’s exact test]); of the 42 patients
excluded from the cetuximab arm, 13 patients were excluded due to allergic reaction, 28 for ‘other
reasons’ and one for early death2
ORR in the assessable for response subgroup was not defined as the primary endpoint; the study was
designed and powered to show superiority of cetuximab over Avastin in the ITT population

Patients at risk
297 100 19 10 5 3
295 99 15 6 4
FIRE-3: PFS was similar with Avastin- and cetuximab-based
therapy
PFSestimate
1.0
0.75
0.50
0.25
0
Cetuximab +
FOLFIRI Avastin + FOLFIRI
Events, n/N (%) 250/297 (84.2) 242/295 (82.0)
Median, months 10.0 10.3
HR (95% CI)
p value
1.06 (0.88–1.26)
p=0.547
10.0 10.3
Time (months)
0 12 24 36 48 60 72

Patients at risk
297 218 111 60 29 9
295 214 111 47 18 2
FIRE-3: OS (secondary endpoint) higher in FOLFIRI/cetuximab
arm
OSestimate
1.0
0.75
0.50
Time (months)
0 12 24 36 48 60 72
Median duration of treatment
= 5 months (all 3 agents)
Median PFS
= 10.0 months
Cetuximab +
FOLFIRI Avastin + FOLFIRI
Events, n/N (%) 158/297 (53.2) 185/295 (62.7)
HR (95% CI)
p value
0.77 (0.62–0.96)
p=0.017
Median follow-up >30 months in both treatment arms; Heinemann, et al. ASCO 2013
The separation of OS curves observed at ~24 months is highly unlikely to be attributable to the first-line treatment effect of ~5
months of biological treatment
0.25
0

Subsequent anti-cancer therapy
Cetuximab +
FOLFIRI (n=297)
Avastin + FOLFIRI
(n=295) p value*
Any second-line therapy, % 65.7 61.7 0.347
Second-line Avastin, % 48.2 17.6
Second-line anti-EGFR therapy, % 14.4 42.9
*Two-sided Fisher exact test

FIRE-3: no difference in haematological toxicity
between treatment arms
Adverse event, %
Cetuximab + FOLFIRI
(n=297)
Avastin + FOLFIRI
(n=295) p value
(grade ≥3)Any grade Grade ≥3 Any grade Grade ≥3
Leucopenia 66.7 12.8 66.8 11.2 0.613
Anaemia 87.9 2.4 90.9 1.4 0.545
Thrombocytopenia 25.6 0.3 23.4 0.3 >0.999
Neutropenia 61.3 24.2 60.3 22.8 0.699
Febrile neutropenia 1.7 1.7 3.0 1.0 0.725

FIRE-3: no major difference in non-haematological toxicity
Adverse event, %
Cetuximab + FOLFIRI (n=297)
Avastin + FOLFIRI
(n=295)
p value (grade
≥3)Any grade Grade ≥3 Any grade Grade ≥3
Any adverse event 100.0 71.0 100.0 63.7 0.066
Nausea 48.2* 3.4 62.4* 4.8 0.414
Vomiting 24.6ǂ 2.4 32.9ǂ 3.4 0.473
Diarrhoea 57.2 11.5 62.7 13.6 0.458
Mucositis/stomatitis 42.1 3.7 44.8 4.1 0.835
Fatigue 50.2 0.7 54.9 1.4 0.449
Pain 50.2 5.4 58.0 7.1 0.401
Hand-foot syndrome 26.6§ 3.4 14.2§ 0.7 0.037
Fatal adverse events N/A 0.0 N/A 1.7 0.030
Significant differences in any-grade toxicity: *p=0.0005; ǂp=0.03; §p=0.0002

FIRE-3: significant increase in grade ≥3 adverse events of
special interest to cetuximab
Adverse event, %
Avastin + FOLFIRI
(n=295)
p value (grade
Acneiform exanthema 77.4* 16.8 7.8* 0.0 <0.0001
Desquamation 35.4* 6.7 11.5* 0.7 0.0001
Paronychia 37.4* 5.7 9.2* 0.0 <0.0001
Infusion-related allergic
reaction
7.7* 4.0 0.0* 0.0 0.0004
Hypocalcaemia 27.6ǂ 4.0 15.3ǂ 2.4 0.351
Hypomagnesaemia 63.3* 4.4 39.7* 0.7 0.007
Significant differences in any-grade toxicity: *p<0.0001; ǂp=0.0003
Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%
• Cetuximab resulted in significantly increased grade ≥3 adverse events of special
interest to anti-EGFR therapy

FIRE-3: no significant difference in grade ≥3 adverse events
of special interest to Avastin
Significant differences in any-grade toxicity: *p<0.001; ǂp=0.046; §p=0.006
Adverse event, %
Avastin + FOLFIRI
(n=295)
p value (grade
Hypertension 21.2* 6.4 38.3* 6.8 0.870
Proteinuria 2.7 0 2.0 0.3 0.498
Bleeding 21.2ǂ 0.7 28.5ǂ 0.3 >0.999
Abscess/fistula 1.4§ 0.3 5.4§ 1.0 0.372
GI perforation 0.3 0.3 0.7 0.7 0.623
Thrombosis (any) 9.4 6.1 11.5 6.1 >0.999
Thromboembolic event 7.4 5.1 7.1 5.8 0.720
Wound healing
complications
2.0 0.3 2.7 1.4 0.216
• Avastin did not lead to any significant difference in grade ≥3 adverse events of
special interest to anti-VEGF treatment

CAIRO3: maintenance Avastin + capecitabine
versus observation
Koopman, et al. ASCO 2013
• Phase III trial
• Primary endpoint: PFS after re-introduction = PFS2
• Secondary endpoints: PFS1, OS, TTP2, ORR, safety
• PFS2 was considered to be equal to PFS1 for patients in whom Avastin + XELOX was not
reintroduced after PFS1 for any reason
• Upon PD1, 75% of patients received Avastin + XELOX in arm A and 47% in arm B
Previously
untreated
mCRC
(n=558)
R
Avastin +
XELOX
(x6)
CR
PR
SD
Avastin +
capecitabine
Observation Avastin + XELOX PD2PD1
PFS2
PFS1
TTP2
Arm A
Arm B
Avastin + XELOX PD2PD1

CAIRO3: study profile
Data cut-off 190413; median duration of follow-up 40 months
558 patients enrolled
279 patients
observation
279 patients
maintenance
212 patients
(76%)
Avastin + XELOX
67 patients
(24%)
• Ongoing
observation
• No treatment
• Other treatment
131 patients
(47%)
Avastin + XELOX
148 patients
(53%)
• Ongoing
maintenance
• No treatment
• Other treatment

CAIRO3: PFS1 significantly improved
with maintenance AvastinPFS1estimate
279 85 18 9 6 6 3Observation
279 172 89 44 29 15 9Maintenance
*Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013
Maintenance Observation
Median PFS1, months 8.5 4.1
Stratified HR (95% CI) 0.44 (0.36–0.53)
p<0.00001
Adjusted* HR 0.41
p <0.001
4.1 8.5
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)

CAIRO3: PFS2 significantly improved
with maintenance Avastin
Time (months)
PFS2estimate
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
279 207 111 42 16 11 4Observation
279 207 130 66 38 23 12Maintenance
10.5 11.8
Median PFS2, months 11.8 10.5
Stratified HR (95% CI) 0.81 (0.67–0.98)
p=0.028
Adjusted* HR 0.77
p=0.007

Time (months)
OSestimate
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
279 248 184 122 78 53 28Observation
279 252 192 143 95 58 33Maintenance
CAIRO3: OS significantly improved with maintenance
Avastin (preliminary analysis)
Median OS, months 21.7 18.2
Stratified HR (95% CI) 0.87 (0.71–1.06)
p=0.156
Adjusted* HR 0.80
p=0.035
18.2 21.7

CAIRO3: safety profile during observation/
maintenance
Grade 3/4 adverse event, %
Observation
(n=279)
Maintenance
(n=279)
Hypertension 18 24
Neutropenia 0 2
Thrombocytopenia 0 1
Diarrhoea 1 3
Vomiting 1 0.4
Nausea 0 2
Hand-foot syndrome 0 22
Neurotoxicity 5 10
GI perforation 0 1
Venous thromboembolic events 2 3
Fatigue 2 4
Red box indicates a difference in incidence between treatment arms of ≥5%

• Phase III
• Primary endpoint: PFS
• Secondary endpoints: OS, pre-operative response, pathological resection status, peri-operative safety
findings, QoL, measures for cost-effectiveness
• New EPOC is an extension to the EPOC study, which randomised patients to surgery alone versus surgery +
chemotherapy
Following IDMC recommendation, new EPOC was terminated early when the study met a
protocol predefined futility analysis (after 123 of the required 212 expected events had
occurred, with 272 patients)
New EPOC: peri-operative cetuximab + CT vs CT alone
CT = FOLFOX4, XELOX or FOLFIRI
Primrose, et al. ASCO 2013
Resectable or borderline
resectable colorectal
liver mets and
KRAS WT mCRC
(n=272)
CT alone
12 weeks
(n=134)
Cetuximab + CT
12 weeks
(n=137)
R
Surgery
Surgery
CT alone
12 weeks
(n=134)
Cetuximab + CT
12 weeks
(n=137)

New EPOC: significantly poorer PFS with cetuximab + CT
compared to CT alone
Cetuximab + CT
(n=116)
CT alone
(n=117)
HR (95% CI)
p value
1.49 (1.04–2.12)
0.030
Patients at risk
CT aIone 116 89 65 38 23 12 5 2 1 1 0
Cetuximab + CT 117 87 54 24 15 5 3 2 1 0 0
PFSestimate
1.0
0.75
0.5
0.25
0
Time (months)
0 6 12 18 24 30 36 42 48 54 60
14.1 20.5
The primary endpoint of PFS was not met; cetuximab-based therapy resulted in
significant detrimental effect on PFS
Primrose, et al. ASCO 2013; CT = FOLFOX4, XELOX or FOLFIRI

0 6 12 18 24 30 36 42 48 54 60
CT alone
(arm A)
Cetuximab + CT
(arm B)
Median OS,
months
NR 39.1
HR (95% CI)
p value
1.48 (0.85‒2.58)
0.163
CT = FOLFOX4, XELOX or FOLFIRI; NR = not reached
39.1 NR
Patients at risk
CT aIone 127 113 90 61 40 29 12 4 2 1 0
Cetuximab + CT 127 99 81 55 38 22 7 2 1 0 0
New EPOC: numerically shorter OS with cetuximab + CT
compared to CT alone
OSestimate
1.0
0.75
0.5
0.25
0
Time (months)

New EPOC: safety
Grade ≥3 adverse event, %
CT alone
(n=134)
Cetuximab + CT
(n=137)
Pre-operative chemotherapy
Overall 40.3 46.7
Nausea/vomiting 3.0 4.4
Skin rash 1.5 15.3
Peripheral neuropathy 4.5 0.7
Hypomagnesaemia 0 1.5
Embolic event 4.5 5.8
Post-operative chemotherapy
Overall 21.2 27.9
Nausea/vomiting 3.8 1.9
Skin rash 0 7.7
Peripheral neuropathy 1.9 3.8
Hypomagnesaemia 0 0
Embolic event 1.9 2.9
CT = FOLFOX4, XELOX or FOLFIRI
Red box indicates a difference in incidence between treatment arms of ≥5%

CALGB 80405 QoL analysis comparing 1L cetuximab vs Avastin, in
combination with FOLFOX/FOLFIRI
Previously untreated
KRAS WT mCRC
(n=2,900)
(n=518 in QoL analysis)
*Use of FOLFOX or FOLFIRI was at the physician’s discretion
Naughton, et al. ASCO 2013
• Phase III
• Primary endpoint: QoL at 3 months
• QoL was assessed at baseline, 6 weeks, and 3, 6 and 9 months post-randomisation,
using the EORTC QLQ-30 and the Dermatology- Specific Quality of Life (DSQL) scales
• As the QoL analysis enrolled the first 518 patients randomised to CALGB 80405, the
majority were enrolled prior to a protocol amendment eliminating the dual biologic arm
and restricting participation to patients with KRAS WT tumours
Cetuximab +
FOLFOX/FOLFIRI*
Avastin +
FOLFOX/FOLFIRI*
R
Cetuximab + Avastin +
FOLFOX/FOLFIRI*
A protocol amendment
meant that this dual biologic
arm was eliminated during
trial

CALGB 80405: cetuximab-associated skin toxicity impacts on QoL
Avastin +
FOLFOX/FOLFIRI
Cetuximab +
FOLFOX/FOLFIRI
Cetuximab + Avastin +
FOLFOX/FOLFIRI
EORTC QLQ-C30
Global health/quality of life p=0.164
Physical functioning p=0.22
Role functioning p=0.263
Social functioning p=0.756
Emotional functioning p=0.769
Cognitive functioning p=0.785
Dermatology-specific QoL (DSQL)
Skin symptoms p<0.001
Limitations in social activities due
to skin condition
p=0.008
Concern about appearance p<0.0001
• Patients randomised to Avastin + FOLFOX/FOLFIRI reported fewer skin symptoms and fewer social limitations
and appearance concerns than patients receiving cetuximab alone or cetuximab + Avastin
• Results were independent of chemotherapy partner (FOLFOX or FOLFIRI)
• Global QoL and major QoL domains (physical, role, social and emotional functioning)
were not significantly different across treatment arms
Naughton, et al. ASCO 2013

SAKK 41/06: non-inferiority trial of Avastin continuation vs no
continuation after 1L Avastin + CT
Previously
untreated mCRC
(n=262)
Continued Avastin
(n=131)
R
No treatment
(n=131)
• Phase III
• Primary endpoint: non-inferiority in TTP (from randomisation)
• Secondary endpoints: PFS, time to second-line treatment, OS,
adverse events related to Avastin, treatment costs
Avastin +
chemotherapy
(4–6 months)
Koeberle, et al. ASCO 2013
PD
PD

SAKK 41/06: TTP (from randomisation) was numerically increased
with continued Avastin vs no Avastin
Patients at risk
Avastin 131 40 14 8 6 5 3 2 1
No Avastin 131 22 10 7 5 1 1 1 0
TTPestimate
1.0
0.8
0.40
0.20
0
Time (months)
0 6 12 18 24 30 36 42 48
0.60
Continued Avastin No Avastin
No. of events 124 123
Median (95% CI) 4.1 (3.1–5.4) 2.9 (2.8–3.8)
HR 95% CI 0.74 (5.7–0.95)
Non-inferiority p=0.47
2.9 4.1

SAKK 41/06: increased TTP with continued Avastin vs
no Avastin across subgroups
0.5 0.727 1.0 1.5
Favours Avastin Favours no Avastin
All
Age >59
Age >59
Female
Male
WHO 0
WHO 1
First-line OD/PR
First-line SD
First-line dur 19–20
First-line dur 21–24
First-line iri + fluo
First-line oxa + fluo
First-line fluo mono
1 organ
>1 organ
Hazard ratio (95% Cl)

SAKK 41/06: PFS (from start of first-line therapy)
significantly increased with continued Avastin vs no Avastin
Avastin No Avastin
Events, n 126 124
Median PFS, months 9.5 8.5
HR (95% CI)
p value
0.75 (0.58‒0.96)
0.021
0
0.2
0.4
0.8
1.0
0.6
PFSestimate
131 122 40 13 6 6 5 3 2 1
131 116 18 8 7 4 1 1 0 0
Avastin
No Avastin
Pts at risk
0 6 12 18 24 30 36 42 48 54 60
Time (months)
8.5 9.5

SAKK 41/06: OS (from start of first line therapy) numerically
increased with continued Avastin vs no Avastin
Avastin No Avastin
Events, n 84 84
HR (95% CI)
p value
0.83 (0.61‒1.12)
0.218
131 130 115 86 52 33 22 10 3 1
131 131 107 76 44 25 13 6 1 1
Avastin
No Avastin
No. at risk
1
0
0 6 12 18 24 30 36 42 48 54 60
Time (months)
64
0
0.2
0.4
0.8
1.0
0.6
OSestimate
22.8 25.1

SAKK 41/06: safety
Adverse event, %
Avastin
(n=131)
No Avastin
(n=131)
Grade 1–2 3–4 5 1–2 3–4 5
Haemorrhage 5 – – 1 – –
Hypertension 15 6 – 3 1 –
Proteinuria 15 – – 1 – –
Thrombosis – 2 – – – –
GI perforation – – – – – –
No new safety signals when continuing Avastin until first progression

EAGLE: 2L Avastin + FOLFIRI in patients with mCRC who have
failed 1L Avastin + oxaliplatin-based therapy
*Evaluated using RECIST criteria (version 1.1)
Tamagawa, et al. ASCO 2013
• Phase III
• Primary endpoint: PFS*
• Secondary endpoints: safety, RR, TTF, OS, OS from the start of the IL treatment, PFS
from start of 1L treatment
Patients with mCRC
previously treated with
oxaliplatin-based CT
+ Avastin 5mg/kg
(n=387)
Avastin 5mg/kg + FOLFIRI
(n=193)
Avastin 10mg/kg + FOLFIRI
(n=194)
R
Arm A
Arm B
PD
PD

EAGLE: no significant difference in PFS between Avastin 5mg/kg and
Avastin 10mg/kg, combined with FOLFIRI
• No significant difference was seen between Avastin doses in PFS from start of 2L
therapy (HR=1.00; p=0.976)
1.0
0.8
0.6
0.4
0.2
PFSestimate
0 6 12 18 24 30 36
181 86 22 2 1 0 0
187 88 18 3 1 0 0
Time (months)Avastin 5mg/kg
+ FOLFIRI
Avastin 10mg/kg
+ FOLFIRI
0
Avastin 5 mg/kg
+ FOLFIRI (arm A)
(n=180)
Avastin 10 mg/kg
+ FOLFIRI (arm B)
(n=187)
HR (95% CI)
p value
0.95 (0.75–1.21)
p=0.676
6.1 6.4

Internal Use Only
EAGLE: Avastin 5mg/kg and 10mg/kg combined with FOLFIRI show no
significant difference in PFS from
start of 1L therapy
Avastin 5mg/kg
+ FOLFIRI (arm A)
(n=180)
Avastin 10mg/kg
+ FOLFIRI (arm B)
(n=187)
HR (95% CI)
p value
1.00 (0.79–1.26)
0.976
Avastin
5mg/kg 181 176 137 76 42 18 6 3 2 1 0
10mg/kg 186 183 146 72 40 18 12 5 3 1 0
1.0
0.6
0.2
0
PFSestimate
0 6 12 18 24 30 36 42 48 54 60
0.8
0.4
Time (months)
17.4 17.6

NE = not evaluable
EAGLE: no significant difference in 2L response between Avastin 5mg/kg
and Avastin 10mg/kg combined with FOLFIRI
Avastin 5 mg/kg + FOLFIRI
(n=180)
Avastin 10 mg/kg + FOLFIRI
(n=187)
Partial response, % 11.1 10.7 p=1.00
Stable disease, % 70.6 70.6
Disease progression, % 13.9 11.8
Not evaluable, % 4.4 7.0

EAGLE: toxicity in both arms was consistent with previously reported
studies and showed no increase with higher doses of Avastin
All
(n=365)
Avastin 5mg/kg
+ FOLFIRI
(n=180)
Avastin 10mg/kg
+ FOLFIRI
(n=185)
Adverse event, % Grade ≥3 Any grade Grade ≥3 Any grade Grade ≥3 Any grade
WBC 16.2 64.1 15.0 67.2 17.3 61.1
Neutropenia 44.9 64.9 48.3 67.0 41.6 63.2
Haemoglobin 3.0 64.7 2.2 66.5 3.8 63.2
PLT 0.8 35.1 0.6 34.6 1.1 35.7
T-Bill 0.0 7.7 0.0 6.7 0.0 8.6
AST 0.8 40.3 0.0 43.6 1.6 37.3
ALT 0.5 25.2 0.0 25.1 1.1 25.4
ALP 0.3 49.3 0.6 52.5 0.0 46.5
Fatigue 9.9 60.3 8.3 58.7 11.4 62.2
Anorexia 5.8 62.7 6.1 62.6 5.4 63.2
Nausea 4.7 51.0 5.0 50.8 4.3 51.4
Vomiting 3.3 22.2 2.8 19.6 3.8 24.9
Diarrhoea 2.5 41.4 3.3 39.7 1.6 43.2
Stomatitis 3.3 48.5 2.8 49.7 3.8 47.6
Alopecia 0.0 41.1 0.0 39.7 0.0 42.7

EAGLE: toxicity in both arms was consistent with previously reported
studies and showed no increase with higher doses of Avastin
All
(n=365)
Avastin 5mg/kg
+ FOLFIRI
(n=180)
Avastin 10mg/kg
+ FOLFIRI
(n=185)
Adverse event, % Grade ≥3 Any grade Grade ≥3 Any grade Grade ≥3 Any grade
Hypertension 1.1 16.7 1.1 14.5 1.1 18.9
Proteinurea 0.5 38.1 1.1 39.7 0.0 36.8
Constipation 0.0 7.7 0.0 5.6 0.0 9.7
Neuropathy 3.8 58.1 3.9 57.5 3.8 58.9
GI haemorrhage 0.3 4.1 0.6 5.0 0.0 3.2
Epistaxis 0.3 19.2 0.0 16.2 0.5 22.2
Arterial thrombosis 0.8 0.8 0.6 0.6 1.1 1.1
Venous thrombosis 1.1 1.4 1.1 1.1 1.1 1.6
GI perforation 0.5 0.5 0.6 0.6 0.5 0.5
Treatment-related death 1.1 1.1 1.1

TRIBE: 1L Avastin + FOLFOXIRI vs Avastin + FOLFIRI followed by
Avastin until progression
Loupakis, et al. ASCO GI 2013
Previously
untreated,
unresectable
mCRC
(n=508)
Avastin
+ FOLFOXIRI
(up to 12 cycles)
Avastin
+ FOLFIRI
(up to 12 cycles)
R
Avastin + 5-FU/LV
Avastin + 5-FU/LV
PD
PD
Induction Maintenance
• Phase III
• Secondary endpoints: response rate, secondary R0 resection rate, OS, safety,
biomarker evaluation

1.0
0.6
0.2
0
PFSestimate
0 6 12 18 24 30 36 42 48 54
0.8
0.4
Time (months)
9.7 12.1
FOLFIRI +
Avastin
(n=256)
FOLFOXIRI +
Avastin
(n=252)
Progressed, n 213 226
Unstratified HR (95% CI)
p value
0.77 (0.64‒0.93)
0.006
Stratified HR (95% CI)
p value
0.75 (0.62–0.80)
0.003
TRIBE: 1L FOLFOXIRI + Avastin produces superior PFS to
FOLFIRI + Avastin
Falcone, et al. ASCO 2013

TRIBE: Avastin + FOLFOXIRI improved PFS vs Avastin + FOLFIRI in
all subgroups except those treated with adjuvant therapy
Factor n HR p
Adjuvant treatment
No 444 0.7 0.039
Yes 64 1.3
Performance status
0 456 0.79 0.2
1–2 52 0.53
Site of primary
Left 330 0.82 0.288
Right 149 0.66
Liver only disease
No 402 0.74 0.293
Yes 105 0.95
Type of metastases
Metachronous 103 0.92 0.356
Synchronous 404 0.73
Resection of primary
No 166 0.77 0.997
Yes 341 0.77
Kohne score
High 47 0.83 0.822
Intermediate 224 0.72
Low 213 0.81
Experimental better Control better
0.5 1 1.5 2

TRIBE: Avastin + FOLFOXIRI improved PFS vs Avastin + FOLFIRI in
all subgroups analysed by KRAS or BRAF status
Experimental
better
Control
better
Factor n HR p
KRAS status
MT 200 0.84 0.973
WT 193 0.83
BRAF status
MT 28 0.55 0.323
WT 365 0.83
0.4 0.6 0.8 1

Avastin + FOLFIRI
(n=256)
Avastin + FOLFOXIRI
(n=252) p value
Overall response rate (%) 53 65 0.006
Complete response (%) 3 5
Partial response (%) 50 60
Stable disease (%) 32 25
Progressive disease (%) 11 6
Not assessed (%) 4 4
Secondary surgery with radical
intent (%)
21 26 0.210
R0 secondary surgery (%) 12 15 0.327
Liver-only subgroup (n=46) (n=59)
Secondary surgery with radical
intent (%)
41 39 1.000
R0 secondary surgery (%) 28 32 0.823
TRIBE: significant increase in response rate but not R0
resection rate with Avastin + FOLFOXIRI

1.0
0.6
0.2
0
Time (months)
OSestimate
0 6 12 18 24 30 36 42 48 54
0.8
0.4
Patients at risk:
FOLFIRI +
Avastin 256 233 216 172 109 69 36 15 5 0
FOLFIRI +
Avastin 252 234 205 175 119 70 35 15 4 0
FOLFIRI +
Avastin
FOLFOXIRI +
Avastin
Median OS, mos 25.8 31.0
Unstratified HR (95% CI)
p value
0.83 (0.66–1.05)
0.125
p value
0.79 (0.63–1.00)
0.054
25.8 31.0
TRIBE: trend towards improved OS with Avastin +
FOLFOXIRI (data immature)
Median follow-up 32.3 months

TRIBE: toxicity profile – safety population
Grade 3/4 adverse events (%)
FOLFIRI + Avastin
(n=254)
FOLFOXIRI + Avastin
(n=250) p value
Nausea 3 3 1.000
Vomiting 3 4 0.492
Diarrhoea 11 19 0.012
Stomatitis 4 9 0.048
Neutropenia 20 50 <0.001
Febrile neutropenia 6 9 0.315
Neurotoxicity 0 5 <0.001
Hypertension 2 5 0.157
Venous thrombosis 6 7 0.593
Arterial thrombosis 2 1 1.000
Bleeding 1 1 1.000

Previously untreated,
KRAS exon 2 WT mCRC
(n=285)
Panitumumab + mFOLFOX6
(n=142)
Avastin + mFOLFOX6
(n=143)
R
• Secondary endpoints: OS, ORR, resection rate, safety, treatment effect in WT RAS tumours
and WT RAS/BRAF tumours
• Patients with disease WT for KRAS exon 2 may have mutations in KRAS exons 3 or 4 or
NRAS exons 2, 3 or 4. This retrospective analysis compared outcomes in these patients vs
patients with disease WT in KRAS and NRAS (exons 2, 3 and 4) [no activating mutations]
• ‘Gold standard’ bidirectional Sanger sequencing and WAVE-based SURVEYOR scan kits were
used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF
exon 15
• An additional analysis was performed ~1 year after the last patient was enrolled: primary
analysis data cutoff was 30 May 2012; additional OS analysis data cutoff was 3 January 2013
PEAK: phase II retrospective analysis of efficacy by
KRAS/NRAS mutation status
Schwartzberg , et al. ASCO 2013

PEAK: RAS mutations outside KRAS exon 2 and in NRAS are
associated with resistance to EGFR inhibition
Outcome
Panitumumab +
FOLFOX6
Avastin +
FOLFOX6 HR (95% CI)
Data cut-off May 2012
KRAS exon 2 WT PFS 10.9 10.1 0.87 (0.65‒1.17); p=0.35
KRAS WT/ RAS WT* PFS 13.0 9.5 0.65 (0.44‒0.96); p=0.03
KRAS exon 2 WT OS NR 25.4 0.72 (0.47‒1.11); p=0.14
KRAS WT/ RAS WT* OS NR 29.0 0.61 (0.34‒1.09); p=0.09
KRAS WT/ other RAS MT‡ PFS 7.8 8.9 1.39 (0.73‒2.64); p=0.32
Data cut-off January 2013
KRAS exon 2 WT PFS 10.9 10.1 0.84 (0.64‒1.11); p=0.22
KRAS WT/ RAS WT* PFS 13.0 10.1 0.66 (0.46‒0.95); p=0.03
KRAS exon 2 WT OS 34.2 24.3 0.62 (0.44‒0.89); p=0.009
KRAS WT/ RAS WT* OS 41.3 28.9 0.63 (0.39‒1.02); p=0.058
NR = not reached
* WT in exons 2, 3 and 4 of KRAS/NRAS
‡ WT KRAS (exon 2) and MT NRAS (exons 2, 3 or 4)
Data cut-off 3 January 2013

PEAK KRAS/NRAS analysis – improved PFS in patients with WT RAS mCRC treated with
panitumumab + mFOLFOX
Panitumumab
+mFOLFOX6 (n=142)
Avastin +
mFOLFOX6
(n=143)
Events, n/N (%) 100/142 (70) 108/143 (76)
p value
0.84 (0.64‒1.11)
0.22
Panitumumab
+mFOLFOX6 (n=88)
Avastin +
mFOLFOX6
(n=82)
Events, n/N (%) 57/88 (65) 66/82 (80)
p value
0.66 (0.46‒0.95)
0.03
0
0.2
0.4
0.6
0.8
1.0
0
0.2
0.4
0.6
0.8
1.0
Time (months) Time (months)
PFSestimate
PFSestimate
WT KRAS exon 2 (ITT set) WT RAS (exons 2, 3, 4 of
KRAS/NRAS)
10.1 10.9 10.1 13.0
Schwartzberg , et al. ASCO 2013; data cut-off 3 January 2013
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
• Decreased PFS was observed in patients with MT RAS tumours in the
panitumumab + FOLFOX6 arm compared to the Avastin + FOLFOX6 arm

Internal Use Only
0 2 4 6 8 10 12 14 16 18 20
PEAK KRAS/NRAS analysis – no improvement in PFS with panitumumab + mFOLFOX
compared to Avastin + mFOLFOX6
in patients with KRAS exon 2 WT/RAS MT mCRC
Data cut-off 30 May 2013
Schwartzberg, et al. ASCO 2013
Panitumumab
+ mFOLFOX6
(n=24)
Avastin
+ mFOLFOX6
(n=27)
Events, n/N (%) 21/24 (88) 18/27 (67)
Median, months (95% CI) 7.8 (6.5‒9.8) 8.9 (7.3‒12.0)
p value
1.39 (0.73‒2.64)
0.32
1.0
0.6
0.2
0
PFSestimate
0.8
0.4
Time (months)
7.8 8.9

PEAK KRAS/NRAS analysis – OS in pts with WT RAS exon 2 and WT RAS mCRC treated
with panitumumab + mFOLFOX6
Panitumumab
+mFOLFOX6 (n=142)
Avastin +
mFOLFOX6
(n=143)
Events, n/N (%) 52/142 (37) 78/143 (55)
p value
0.62 (0.44‒0.89)
0.009
WT KRAS exon 2 (ITT set) WT RAS (exons 2, 3, 4 of
KRAS/NRAS)
0
0.2
0.4
0.6
0.8
1.0
0
0.2
0.4
0.6
0.8
1.0
Time (months) Time (months)
OSestimate
OSestimate
24.3 34.2 28.9 41.3
Schwartzberg , et al. ASCO 2013; data cut-off 3 January 2013
Panitumumab
+mFOLFOX6 (n=88)
Avastin +
mFOLFOX6
(n=82)
Events, n/N (%) 30/88 (34) 40/82 (49)
p value
0.63 (0.39‒1.02)
0.058
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 3234 36 3840 42 44 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42

PEAK: ORR and safety
*WT in exons 2, 3 and 4 of KRAS/NRAS
ǂWT KRAS (exon 2) and MT KRAS (exons 3 or 4) or MT NRAS (exons 2, 3 or 4)
Data cut-off 30 May 2012
Panitumumab + FOLFOX6 Avastin + FOLFOX6
Primary analysis (n=142) (n=142)
ORR, % 58 54
WT RAS* (n=88) (n=81)
ORR, n (%) 64 60
WT KRAS-2, MT RASǂ (n=24) (n=27)
Median OS (months) 58 56
• The safety profile in both treatment arms was similar to previously reported
studies and treatment discontinuation rates due to adverse events were similar
• Biomarker subpopulations showed similar adverse event rates compared with the
primary analysis population

PRIME: retrospective analysis of efficacy by KRAS/NRAS
mutation status
Previously
untreated mCRC
(n=1,183)
(n=641 in KRAS/NRAS
analysis)
Panitumumab + FOLFOX4
(n=593)
(n=325 KRAS WT (exon 2);
n=320 in KRAS/NRAS analysis)
FOLFOX4
(n=590)
(n=331 KRAS WT (exon 2);
n=321 in KRAS/NRAS analysis)
• Phase III
• Secondary endpoints: OS, ORR, TTP, DOR, safety
• Sponsor: Amgen
• PRIME was amended prior to efficacy analysis and completion of enrolment to focus on hypothesis testing in the KRAS
WT subset: the primary objective was to evaluate treatment effect on PFS and OS in pts WT for RAS (WT for KRAS and
NRAS exons 2, 3 and 4) or WT for RAS and BRAF (WT for KRAS and NRAS exons 2, 3 and 4 and BRAF exon 15)
• Interaction texts were conducted to compare panitumumab treatment effect between WT RAS and MT RAS or WT RAS
and WT KRAS exon 2/MT other RAS to assess the predictive value for RAS
• A new testing method was used (‘gold standard’ bidirectional Sanger sequencing and
WAVE-based SURVEYOR scan kits) to detect mutations in KRAS exon 3, exon 4;
NRAS exon 2, exon 3, exon 4; and BRAF exon 15
R
Oliner, et al. ASCO 2013

PRIME: panitumumab + FOLFOX4 has a detrimental effect in
patients with RAS MT mCRC
Panitumumab
+ FOLFOX4
(n=320)
FOLFOX4
(n=321) HR; p value
WT KRAS exon 2 [original test]
Median OS (months) 23.9 19.7 0.83; 0.072
Median PFS (months) 9.6 8.0 0.80; 0.02
WT KRAS exon 2/MT other RAS [new test]
Median OS (months) 17.1 18.3 1.29; 0.305
WT RAS [new test]
Median OS (months) 26.0 20.2 0.78; 0.043
MT RAS [new test]
Median OS (months) 15.6 19.2 1.25; 0.034
• The addition of panitumumab to FOLFOX4 produced
– significantly increased PFS and OS in patients with RAS WT mCRC
– significantly detrimental effect on PFS and OS in patients with RAS MT mCRC

PRIME: poorer PFS with panitumumab + FOLFOX4 in mCRC WT for KRAS exon
2 but MT for other RAS exons
WT KRAS exon 2
(original KRAS WT testing)
WT KRAS exon 2/MT other RAS
(new testing)
8.0 9.6
Time (months)
PFSestimate
7.3 8.0
PFSestimate
Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22
Panitumumab
+ FOLFOX4
FOLFOX4
alone
Events, n 199/325 (61) 215/331 (65)
Median PFS, months 9.6
(9.2–11.1)
8.0
(7.5–9.3)
HR (95% CI)
p value
0.80 (0.56‒0.97)
0.02
Panitumumab
+ FOLFOX4
FOLFOX4
alone
Events, n 38/51 (75) 35/57 (61)
Median PFS, months 7.3
(5.3–9.2)
8.0
(6.4–11.3)
HR (95% CI)
p value
1.28 (0.79‒2.07)
0.326
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0

PRIME: poorer OS with panitumumab + FOLFOX4 in mCRC KRAS exon 2 WT
but MT for other RAS exons
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 14 24 30 32 34 3642 8 10 16 18 2620 28 0 6 12 14 24 30 32 3442 8 10 16 18 2620 2822 22
1.0
0.8
0.6
0.4
0.2
0.0
Panitumumab
+ FOLFOX4
FOLFOX4
alone
Events, n 185/325 (51) 190/331 (57)
Median OS, months 23.9
(20.3–28.2)
19.7
(17.6–22.6)
HR (95% CI)
p value
0.83 (0.67‒1.02)
0.072
Panitumumab
+ FOLFOX4
FOLFOX4
alone
Events, n 35/51 (69) 33/57 (58)
Median OS, months 17.1
(10.8–19.4)
18.3
(13.0–23.2)
HR (95% CI)
p value
1.29 (0.79‒2.10)
0.305
19.7 23.9 18.317.1
WT KRAS exon 2
(original KRAS WT testing)
WT KRAS exon 2/MT other RAS
(new testing)
Time (months)
OSestimate
OSestimate
Time (months)

PRIME: mutations in BRAF do not appear to be predictive
for panitumumab treatment effect
Panit
+ FOLFOX4
(n=320)
FOLFOX4
(n=321) HR; p value
WT RAS/WT BRAF
Median OS (months) 28.3 20.9 0.74; 0.023
WT RAS/MT BRAF
Median OS (months) 10.5 9.2 0.90; 0.764
MT RAS or MT BRAF
Median OS (months) 15.3 18.0 1.21; 0.064
WT KRAS exon 2/MT other RAS or MT BRAF
Median OS (months) 14.5 15.8 1.14; 0.508

PRIME: adverse events in panitumumab arm similar to those
reported for patients with KRAS exon 2 WT mCRC
WT RAS MT RAS
%
Panit +
FOLFOX4
(n=256)
FOLFOX4
alone (n=250) Total (n=506)
Panit +
FOLFOX4
(n=268)
FOLFOX4
alone (n=275) Total (n=543)
Any adverse event 100 99 100 99 99 99
Worst grade of 3 57 50 53 57 53 55
Worst grade of 4 28 20 24 24 20 22
Worst grade of 5 5 6 6 7 4 5
Any serious adverse
event
43 37 40 45 31 38
Leading to permanent
discontinuation of any
study drug
25 16 21 22 13 18
Not serious 19 11 15 19 9 14
Serious 9 6 8 6 5 6

Patients
with
previously
untreated
mCRC
(n=700)
Avastin* + mFOLFOX7
RAvastin*+ XELOX2
Avastin* + FOLFIRI
NOPROGRESSION
Avastinǂ
+ erlotinib
(n=224)
Avastinǂ
(n=228)
PD
PD
DREAM: maintenance Avastin with or without erlotinib in
mCRC, by KRAS status
*5 mg/kg q2w; ǂ7.5 mg/kg q3w
Tournigand, et al. ASCO 2013
• Phase III
• Primary endpoint: PFS on maintenance therapy
• Secondary endpoints include: OS, survival according to KRAS status
Induction (n=700) Maintenance (n=452)
REGISTRATION

DREAM: PFS (from randomisation) significantly increased with maintenance
Avastin + erlotinib vs Avastin alone (ITT population)
Avastin
(n=228)
Avastin +
erlotinib
(n=224)
HR (95% CI)
p value
0.7 (0.61‒0.94)
0.0096
Patients at risk
Avastin 228 179 115 74 42 29 17 13 10 7 3 2 1
Avastin + erlotinib 224 182 124 82 58 39 30 20 17 12 7 4 2
1.0
0.6
0.2
0
PFSestimate
0 2 4 6 8 10 12 14 16 18 20 22 24
0.8
0.4
Time (months)
4.6 5.9

DREAM: similar OS (from registration) with maintenance Avastin +
erlotinib vs Avastin alone (ITT population)
Avastin
(n=228)
Avastin +
erlotinib
(n=224)
HR (95% CI)
p value
0.89 (0.70‒1.12)
0.8857
Patients at risk
Avastin 228 224 193 143 99 77 46 25 10 3 0
Avastin + erlotinib 224 220 187 140 99 73 43 31 20 11 4
1.0
0.6
0.2
0
PFSestimate
0 6 12 18 24 30 36 42 48 54 60
0.8
0.4
Time (months)
27.9 28.4

DREAM: similar PFS (from randomisation) with maintenance
Avastin + erlotinib vs Avastin alone in KRAS WT mCRC
Avastin
Avastin +
erlotinib
WT KRAS, n 111 129
HR (95% CI)
p value
0.86 (0.64‒1.16)
0.135
Patients at risk
Avastin 111 91 60 42 25 19 11 9 7 5 3 2 1
1.0
0.6
0.2
0
PFSestimate
0 2 4 6 8 10 12 14 16 18 20 22 24
0.8
0.4
Time (months)
5.9 6.0

Avastin
Avastin +
erlotinib
MT KRAS, n 95 78
HR (95% CI)
p value
0.77 (0.54‒1.08)
0.124
Patients at risk
Avastin 95 76 47 27 17 10 6 4 3 2 0 0 0
1.0
0.6
0.2
0
PFSestimate
0 2 4 6 8 10 12 14 16 18 20 22 24
0.8
0.4
Time (months)
4.4 4.7
DREAM: similar PFS (from randomisation) with maintenance
Avastin + erlotinib vs Avastin alone in KRAS MT mCRC

DREAM: toxicity of Avastin was consistent with the
reported safety profile
Grade 3/4 adverse events, %
Avastin
(n=228)
Avastin + erlotinib
(n=224)
Vomiting 0 1
Diarrhoea 1 9
Proteinuria <1 <1
Hypertension 3 3
Skin toxicity 0 20

• Phase III
• Secondary endpoints: OS, response rate, safety
• Patients had a median age of 76 (70‒87) years and were recruited in 10 countries
• This was a post-hoc analysis of PFS, OS and safety in patients grouped
according to age: 70–74 years, 75–79 years and ≥80 years
Patients aged ≥70
years with previously
untreated mCRC
(n=280)
Capecitabine
Avastin + capecitabine
R
PD
PD
AVEX age subgroup analysis: Avastin + capecitabine vs capecitabine
for the 1L treatment of elderly mCRC patients
Saunders, et al. ASCO 2013

AVEX age subgroup analysis: PFS significantly improved with Avastin
+ capecitabine across age subgroups
70–74 years 75–79 years ≥80 years
Outcome
Avastin +
cape
(n=55)
Cape
(n=46)
Avastin +
cape
(n=57)
Cape
(n=66)
Avastin +
cape
(n=28)
Cape
(n=28)
PFS
Median, months 7.6 5.0 9.8 5.1 10.5 5.1
HR (95% CI) 0.52 (0.32‒0.83) 0.60 (0.40‒0.89) 0.36 (0.19‒0.71)
p value <0.001 0.016 0.003
OS
Median, months 20.7 22.2 19.8 17.4 19.7 12.6
HR (95% CI) 0.91 (0.50‒1.66) 0.79 (0.48‒1.30) 0.62 (0.31‒1.24)
p value 0.55 0.37 0.24
• PFS was significantly improved with the addition of Avastin to capecitabine in
all age subgroups analysed
• Differences in OS between treatment arms were not significant in any of the age
subgroups evaluated

AVEX age subgroup analysis: ORR numerically improved with Avastin
+ capecitabine across age subgroups
Outcome, %
Avastin +
cape
(n=55)
Cape
(n=46)
Avastin +
cape
(n=57)
Cape
(n=66)
Avastin +
cape
(n=28)
Cape
(n=28)
ORR 25.5 10.9 15.8 12.1 14.3 3.6
p=0.076 p=0.607 p=0.352
CR 3.6 0 1.8 1.5 0 3.6
PR 21.8 10.9 14.0 10.6 14.3 0
SD 49.1 56.5 61.4 43.9 53.6 42.9
PD 12.7 17.4 8.8 21.2 7.1 28.6
DCR 74.5 67.4 77.2 56.1 67.9 46.4
• ORR and DCR were numerically improved in the Avastin + capecitabine arms in
each of the three age subgroups
• In the primary analysis of AVEX (median patient age 76 (70‒87) years) ORR was
significantly increased with Avastin + capecitabine compared to capecitabine alone (19.3% vs
10.0%; p=0.042)

• Grade ≥3 AEs were more common in the Avastin + capecitabine arm across age subgroups
• Patients aged 70–74 years receiving Avastin + capecitabine had a higher incidence
of serious AEs than those receiving capecitabine
AVEX age subgroup analysis: AEs of special interest to Avastin
occurred at similar rates in each age subgroup
Grade ≥3 adverse events, %
Avastin +
cape
(n=54)
Cape
(n=46)
Avastin + cape
(n=53)
Cape
(n=64)
Avastin + cape
(n=27)
Cape
(n=26)
Bleeding/haemorrhage – 2.2 – – – –
Hypertension 5.6 2.2 – 1.6 – –
VTE 9.3 6.5 11.3 4.7 – –
Proteinuria 1.9 – 1.9 – – –
ATE 1.9 – 1.9 – 11.1 7.7
Wound-healing
complications
– – – – – –
Pulmonary haemorrhage/
haemoptysis
– – – – – 3.8
CHF – 2.2 – – – –
Fistulae – – – – – –
GI perforation – – – – – –
RPLS – – – – – –

Grade ≥3 adverse events,
%
Avastin + cape
(n=54)
Cape
(n=46)
Avastin + cape
(n=53)
Cape
(n=64)
Avastin + cape
(n=27)
Cape
(n=26)
Hand-foot syndrome 16.7 6.5 13.2 9.4 14.8 –
Diarrhoea 3.7 4.3 7.5 4.7 11.1 15.4
Asthenia 1.9 – 5.7 6.3 11.1 7.7
Fatigue 3.7 – 3.8 – 3.7 3.8
Nausea – – – – 3.7 –
Vomiting – – 1.9 – 3.7 7.7
Stomatitis – – – – – 3.8
Neutropenia – – – – 3.7 3.8
AVEX age subgroup analysis: AEs of special interest to
chemotherapy occurred at similar rates in each age subgroup

• Phase II
• Primary endpoint: overall resection rate (R0/R1/R2)
• Secondary endpoints: ORR (by RECIST), PFS, RFS, OS and safety
OLIVIA: phase II study of Avastin + mFOLFOX6 vs Avastin + FOLFOXIRI in
initially unresectable
liver-limited mCRC
mCRC patients
with liver-only
metastases
defined by an MDT as
unresectable
(n=80)
Avastin + mFOLFOX6
(up to 12 cycles)
(n=39)
Avastin + FOLFOXIRI
(up to 12 cycles)
(n=41)
R
Gruenberger, et al. ASCO 2013

OLIVIA: Avastin + FOLFOXIRI is associated with higher resection and response
rates than Avastin + mFOLFOX6 in mCRC (ITT population)
Avastin +
FOLFOXIRI (n=41)
Avastin +
mFOLFOX6 (n=39)
Difference (95%
CI) p value
Resection rate, %
R0/R1/R2 61.0 48.7 12.3 (‒11.0–35.5) 0.271
R0/R1 51.2 33.3 17.9 (‒5.0–40.7) 0.106
R0 48.8 23.1 25.7 (3.9–47.5) 0.017
ORR, % 80.5 61.5 18.9 (‒2.1–40.0) 0.061
Median PFS, months 18.8 12.0 – 0.0002
• The primary endpoint of overall resection rate (R0/R1/R2) was numerically higher
with Avastin + FOLFOXIRI than with Avastin + FOLFOX6
• R0 resection rate and median PFS were significantly higher and ORR was
numerically higher with Avastin + FOLFOXIRI than with Avastin + mFOLFOX6

1.0
0.6
0.2
0
PFSestimate
0 4 8 12 16 20 24 28 32
0.8
0.4
Pts at risk:
39 37 26 16 5
41 38 35 27 21
2 1 0 0
12 4 2 0
12.0 18.8
Time (months)
OLIVIA: prolonged PFS in Avastin + FOLFOXIRI vs Avastin +
mFOLFOX6 in 1L mCRC (ITT population)
mFOLFOX6 +
Avastin
FOLFOXIRI +
Avastin
p-value p=0.0002

OLIVIA: no new safety concerns
Grade 3–5 adverse event, % Avastin + FOLFOXIRI (n=40) Avastin + mFOLFOX6 (n=37)
Any adverse event 95.0 83.8
Neutropenia 47.5 35.1
Febrile neutropenia 12.5 8.1
Diarrhoea 27.5 13.5
Vomiting 7.5 2.7
Fatigue 7.5 2.7
Wound dehiscence 7.5 0
Pulmonary embolism 2.5 5.4
Deep vein thrombosis 5.0 5.4
Constipation 0 5.4
Gamma-glutamyltransferase
increased
0 5.4
• The most common grade 3–5 haematological adverse event was neutropenia
• The most common non-haematological adverse events were diarrhoea and vomiting

Ml18147 (TML) – patterns
of disease progression and
outcomes based on extent of
disease

ML18147 (TML): phase III trial comparing Avastin + chemotherapy
beyond first progression vs chemotherapy
Avastin + 1L doublet CT
(n=820)
Avastin + 2L doublet CT
(n=409)
2L doublet CT
(n=411)
R
• Phase III
• Primary endpoint: OS from randomisation
• Secondary endpoints: PFS from randomisation, best ORR, safety
PD
PD
Greil, et al. ASCO 2013

64
50
6
14
4 2
19
67
42
7
12
4 2
23
80
60
40
20
10
0
Site of metastasis
Patients(%)
Lung Liver Peritoneum Lymph Bone Pleura Other
nodes
70
50
30
Chemotherapy
Avastin + chemotherapy
ML18147: similar patterns of PD in patients treated
with Avastin + CT vs CT beyond progression
(all progressions)

50
40
30
20
10
0
Site of metastasis
Patients(%)
Lung Liver Peritoneum Lymph Bone Pleura Other
nodes
45
33
6
10
6
2
17
39
42
10
8
4
2
14
ML18147: similar patterns of PD in patients treated
with Avastin + CT vs CT beyond progression
(PD due to new lesions)
Chemotherapy

CT 117 82 46 13 5 2 2 1 0
Av + CT 109 91 52 14 5 2 1 0 0
9.3 11.6
HR (95% CI)=0.79 (0.59–1.06)
1.0
0.8
0.6
0.4
0.2
0.0
Time (months)OSestimate
0 6 12 18 24 30 36 42 48
10.0 11.0
HR (95% CI)=0.81 (0.67–0.97)
Liver-limited disease Non-liver-limited disease
Pts at risk:
ML18147: OS was similar in patients with liver-limited or non-
liver-limited disease at baseline
Chemotherapy
Chemotherapy
CT 292 210 115 38 19 5 1 1 0
Av + CT 300 237 136 50 24 11 3 1 0
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36 42 48
OSestimate
Time (months)

1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36 42 48
4.1 5.7 4.1 5.6
ML18147: PFS was similar in patients with liver-limited and
non-liver-limited disease at baseline
Liver-limited disease Non-liver-limited disease
CT 117 33 5 2 0 0 0 0 0
Av + CT 109 52 8 3 0 0 0 0 0
CT 292 86 15 4 4 0 0 0 0
Av + CT 300 137 37 9 5 2 0 0 0
PFSestimate
Pts at risk:
Time (months)
HR (95% CI)=0.68 (0.52–0.89) HR (95% CI)=0.68 (0.57–0.80)
Chemotherapy
Chemotherapy
1.0
0.8
0.6
0.4
0.2
0.0
Time (months)PFSestimate
0 6 12 18 24 30 36 42 48

SOFT: phase III trial of 1L Avastin +
mFOLFOX-6 vs Avastin + SOX
• Phase III
• Primary endpoint: non-inferiority in PFS
• Secondary endpoints: OS, RR, disease control rate (DCR), TTP, time to treatment
failure (TTF), resection rate (R0), safety
Previously untreated mCRC
patients
(n=512)
Avastin + mFOLFOX-6
Avastin + S-1/oxaliplatin (SOX)
R
Takahari, et al. ASCO 2013

Internal Use Only
SOFT: PFS with 1L Avastin + S-1/oxaliplatin (SOX) was non-inferior to 1L
Avastin + mFOLFOX6
0 6 12 18 24 30 36 42
1.0
0.6
0.2
0
PFSestimate
0.8
0.4
Time (months)
10.2 10.2
Avastin
+ mFOLFOX6
Avastin
+ SOX
Median, months
(95% CI)
10.2
(9.5‒11.3)
10.2
(9.4‒11.1)
HR
(95% CI)
1.021
(0.847‒1.232)
• Response rate was 62.7% with Avastin + mFOLFOX6 vs 61.5% with Avastin + SOX

Internal Use Only
0 6 12 18 24 30 36 42
1.0
0.6
0.2
0
OSestimate
0.8
0.4
Time (months)
SOFT: OS with 1L Avastin + S-1/oxaliplatin (SOX) and 1L Avastin +
mFOLFOX6 was similar
Avastin
+ mFOLFOX6
Avastin
+ SOX
Median, months
(95% CI)
30.9
(28.6‒33.1)
29.6
(25.8‒NR)
HR
(95% CI)
1.052
(0.805‒1.376)
29.6 30.9
Median follow-up duration: 23.4 (0.3‒37.8) months

SOFT: no new safety concerns
Grade 3–4 adverse event, % Avastin + mFOLFOX-6 Avastin + SOX
Leucopenia 8.4 2.4
Neutropenia 33.7 8.8
Anorexia 1.2 5.2
Diarrhoea 2.8 9.2

Key CRC data from ASCO 2013: FIRE-3, CAIRO3 and more

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