Ca colon

Key CRC data from ASCO 2013FIRE-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

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 + FOLFIRIITT 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 1.4PR 57.6 56.6SD 17.5 28.8PD 7.1 5.4Not 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)Heinemann, et al. ASCO 2013

• 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 risk297 100 19 10 5 3295 99 15 6 4

FIRE-3: PFS was similar with Avastin- and cetuximab-based therapy

PF

S e

stim

ate

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 risk297 218 111 60 29 9295 214 111 47 18 2

FIRE-3: OS (secondary endpoint) higher in FOLFIRI/cetuximab arm

OS

est

ima

te

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


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, %



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 between treatment arms

Adverse event, %

Cetuximab + FOLFIRI (n=297)Avastin + FOLFIRI

(n=295)p value (grade

≥3)Any grade Grade ≥3 Any grade Grade ≥3Any 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, %


(n=295)


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 0.007Significant differences in any-grade toxicity: *p<0.0001; ǂp=0.0003Red 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, %


(n=295)


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

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)

RAvastin +

XELOX(x6)

CR

PR

SD

Avastin + capecitabine

Observation Avastin + XELOX PD2PD1

PFS2PFS1

TTP2Arm A

Arm B

Avastin + XELOX PD2PD1

CAIRO3: study profile

Data cut-off 190413; median duration of follow-up 40 monthsKoopman, et al. ASCO 2013

558 patients enrolled

279 patientsobservation

279 patientsmaintenance

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 AvastinP

FS

1 es

timat

e

279 85 18 9 6 6 3Observation279 172 89 44 29 15 9Maintenance

*Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013

Maintenance ObservationMedian PFS1, months 8.5 4.1

Stratified HR (95% CI) 0.44 (0.36–0.53)p<0.00001

Adjusted* HR 0.41p <0.001

4.1 8.5

0 6 12 18 24 30 360.0

0.2

0.4

0.6

0.8

1.0

Time (months)

CAIRO3: PFS2 significantly improved with maintenance Avastin

Time (months)

PF

S2

estim

ate

0 6 12 18 24 30 360.0

0.2

0.4

0.6

0.8

1.0


10.5 11.8

Maintenance ObservationMedian PFS2, months 11.8 10.5

Stratified HR (95% CI) 0.81 (0.67–0.98)p=0.028

Adjusted* HR 0.77p=0.007


Time (months)

OS

est

ima

te

0 6 12 18 24 30 360.0

0.2

0.4

0.6

0.8

1.0


CAIRO3: OS significantly improved with maintenance Avastin (preliminary analysis)

Maintenance Observation

Median OS, months 21.7 18.2

Stratified HR (95% CI) 0.87 (0.71–1.06)p=0.156

Adjusted* HR 0.80p=0.035

18.2 21.7


CAIRO3: safety profile during observation/ maintenance

Koopman, et al. ASCO 2013

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%

New EPOC

• 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 andKRAS WT mCRC

(n=272)

CT alone12 weeks(n=134)

Cetuximab + CT12 weeks(n=137)

R

Surgery

Surgery

CT alone12 weeks(n=134)

Cetuximab + CT12 weeks(n=137)

New EPOC: significantly poorer PFS with cetuximab + CT compared to CT alone

Cetuximab + CT (n=116)

CT alone(n=117)

Median, months 14.1 20.5HR (95% CI)p value

1.49 (1.04–2.12)0.030

Patients at riskCT aIone 116 89 65 38 23 12 5 2 1 1 0Cetuximab + CT 117 87 54 24 15 5 3 2 1 0 0

PFS

estim

ate

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 reachedPrimrose, et al. ASCO 2013

39.1 NR

Patients at riskCT aIone 127 113 90 61 40 29 12 4 2 1 0Cetuximab + CT 127 99 81 55 38 22 7 2 1 0 0

New EPOC: numerically shorter OS with cetuximab + CT compared to CT alone

OS

estim

ate

1.0

0.75

0.5

0.25

0

Time (months)

New EPOC: safetyGrade ≥3 adverse event, %

CT alone(n=134)

Cetuximab + CT(n=137)

Pre-operative chemotherapyOverall 40.3 46.7Nausea/vomiting 3.0 4.4Skin rash 1.5 15.3Peripheral neuropathy 4.5 0.7Hypomagnesaemia 0 1.5Embolic event 4.5 5.8Post-operative chemotherapyOverall 21.2 27.9Nausea/vomiting 3.8 1.9Skin rash 0 7.7Peripheral neuropathy 1.9 3.8Hypomagnesaemia 0 0Embolic event 1.9 2.9

CT = FOLFOX4, XELOX or FOLFIRI Primrose, et al. ASCO 2013

Red box indicates a difference in incidence between treatment arms of ≥5%

CALGB 80405 QoL analysis

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 discretionNaughton, 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-C30Global health/quality of life p=0.164Physical functioning p=0.22Role functioning p=0.263Social functioning p=0.756Emotional functioning p=0.769Cognitive functioning p=0.785Dermatology-specific QoL (DSQL)Skin symptoms p<0.001Limitations 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

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 riskAvastin 131 40 14 8 6 5 3 2 1No Avastin 131 22 10 7 5 1 1 1 0

TT

P e

stim

ate

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 AvastinEvents, n 126 124Median PFS, months 9.5 8.5HR (95% CI)p value

0.75 (0.58‒0.96) 0.021

0

0.2

0.4

0.8

1.0

0.6

PF

S e

stim

ate

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 60Time (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 AvastinEvents, n 84 84Median OS, months 25.1 22.8HR (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 60Time (months)

640

0.2

0.4

0.8

1.0

0.6

OS

est

ima

te

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

Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%

EAGLE

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

PF

S e

stim

ate

Tamagawa, et al. ASCO 2013

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 + FOLFIRIAvastin 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)Median, months 17.4 17.6

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

PF

S e

stim

ate

0 6 12 18 24 30 36 42 48 54 60

0.8

0.4

Time (months)

17.4 17.6

NE = not evaluableTamagawa, et al. ASCO 2013

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)



Adverse event, %　 Grade ≥3 Any grade Grade ≥3 Any grade Grade ≥3 Any gradeWBC 16.2 64.1 15.0 67.2 17.3 61.1Neutropenia 44.9 64.9 48.3 67.0 41.6 63.2Haemoglobin 3.0 64.7 2.2 66.5 3.8 63.2PLT 0.8 35.1 0.6 34.6 1.1 35.7T-Bill 0.0 7.7 0.0 6.7 0.0 8.6AST 0.8 40.3 0.0 43.6 1.6 37.3ALT 0.5 25.2 0.0 25.1 1.1 25.4ALP 0.3 49.3 0.6 52.5 0.0 46.5Fatigue 9.9 60.3 8.3 58.7 11.4 62.2Anorexia 5.8 62.7 6.1 62.6 5.4 63.2Nausea 4.7 51.0 5.0 50.8 4.3 51.4Vomiting 3.3 22.2 2.8 19.6 3.8 24.9Diarrhoea 2.5 41.4 3.3 39.7 1.6 43.2Stomatitis 3.3 48.5 2.8 49.7 3.8 47.6Alopecia 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)



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

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

PF

S e

stim

ate

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

Median PFS, months 9.7 12.1

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 treatmentNo 444 0.7 0.039Yes 64 1.3

Performance status0 456 0.79 0.21–2 52 0.53

Site of primaryLeft 330 0.82 0.288Right 149 0.66

Liver only diseaseNo 402 0.74 0.293Yes 105 0.95

Type of metastasesMetachronous 103 0.92 0.356Synchronous 404 0.73

Resection of primaryNo 166 0.77 0.997Yes 341 0.77

Kohne scoreHigh 47 0.83 0.822Intermediate 224 0.72Low 213 0.81

Experimental better

Control better

0.5 1 1.52


TRIBE: Avastin + FOLFOXIRI improved PFS vs Avastin + FOLFIRI in all subgroups analysed by KRAS or BRAF status

Experimentalbetter

Controlbetter

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 + 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)

OS

est

imat

e

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 0FOLFIRI +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


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 monthsFalcone, et al. ASCO 2013

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



PEAK KRAS/NRAS analysis

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

OutcomePanitumumab +

FOLFOX6Avastin + 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)



0.84 (0.64‒1.11) 0.22


Avastin + mFOLFOX6

(n=82)

Events, n/N (%) 57/88 (65) 66/82 (80)



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)

PF

S e

stim

ate

PF

S e

stim

ate

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)


1.39 (0.73‒2.64) 0.32

1.0

0.6

0.2

0

PFS

estim

ate

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


Avastin + mFOLFOX6

(n=143)

Events, n/N (%) 52/142 (37) 78/143 (55)



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)

OS

est

ima

te

OS

est

ima

te

24.3 34.2 28.9 41.3

Schwartzberg , et al. ASCO 2013; data cut-off 3 January 2013


Avastin + mFOLFOX6

(n=82)

Events, n/N (%) 30/88 (34) 40/82 (49)



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 38 40 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 + FOLFOX6Primary 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 between treatment arms

• Biomarker subpopulations showed similar adverse event rates compared with the primary analysis population


PRIME KRAS/NRAS analysis

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; 0.072Median PFS (months) 9.6 8.0 0.80; 0.02WT KRAS exon 2/MT other RAS [new test]Median OS (months) 17.1 18.3 1.29; 0.305Median PFS (months) 7.3 8.0 1.28; 0.326WT RAS [new test]Median OS (months) 26.0 20.2 0.78; 0.043Median PFS (months) 10.1 7.9 0.72; 0.004MT RAS [new test]Median OS (months) 15.6 19.2 1.25; 0.034Median PFS (months) 7.3 8.7 1.31; 0.008

• 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)

PF

S e

stim

ate

7.3 8.0

PF

S e

stim

ate

Time (months)0 2 4 6 8 10 12 14 1618

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


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

0.00 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


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


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)

OS

est

ima

te

OS

est

ima

te

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

Median PFS (months) 10.8 9.2 0.68; 0.002

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

DREAM KRAS analysis

Patients with

previously untreated

mCRC (n=700)

Avastin* + mFOLFOX7

RAvastin*+ XELOX2

Avastin* + FOLFIRI

NO

PR

OG

RE

SS

ION

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 q3wTournigand, 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 riskAvastin 228 179 115 74 42 29 17 13 10 7 3 2 1Avastin + erlotinib 224 182 124 82 58 39 30 20 17 12 7 4 2

1.0

0.6

0.2

0

PF

S e

stim

ate

0 2 4 6 8 10 12 14 16 18 20 22 24

0.8

0.4

Time (months)

4.6 5.9

Tournigand, et al. ASCO 2013

DREAM: similar OS (from registration) with maintenance Avastin + erlotinib vs Avastin alone (ITT population)

Avastin(n=228)

Avastin + erlotinib(n=224)

Median OS, months 27.9 28.4

HR (95% CI)p value

0.89 (0.70‒1.12) 0.8857

Patients at riskAvastin 228 224 193 143 99 77 46 25 10 3 0Avastin + erlotinib 224 220 187 140 99 73 43 31 20 11 4

1.0

0.6

0.2

0

PF

S e

stim

ate

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

AvastinAvastin + erlotinib

WT KRAS, n 111 129


HR (95% CI)p value

0.86 (0.64‒1.16) 0.135


1.0

0.6

0.2

0

PF

S e

stim

ate

0 2 4 6 8 10 12 14 16 18 20 22 24

0.8

0.4

Time (months)

5.9 6.0


AvastinAvastin + erlotinib

MT KRAS, n 95 78


HR (95% CI)p value

0.77 (0.54‒1.08)0.124


1.0

0.6

0.2

0

PF

S e

stim

ate

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


AVEX age analysis

• 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 capecitabineSaunders, et al. ASCO 2013

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=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=53)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


OLIVIA

• 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

PFS

estim

ate

0 4 8 12 16 20 24 28 32

0.8

0.4

Pts at risk:39 37 26 16 541 38 35 27 21

2 1 0 012 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

712

4 2

23

80

60

40

20

10

0

Site of metastasis

Patie

nts

(%)

Lung Liver Peritoneum Lymph Bone Pleura Othernodes

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

Patie

nts

(%)

Lung Liver Peritoneum Lymph Bone Pleura Othernodes

45

33

610

62

17

3942

108

42

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 0Av + 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)O

S es

timat

e0 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

0.00 6 12 18 24 30 36 42 48

OS

estim

ate

Time (months)


1.0

0.8

0.6

0.4

0.2

0.00 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 0Av + 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

PFS

estim

ate

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)PF

S es

timat

e0 6 12 18 24 30 36 42 48


SOFT

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

PF

S e

stim

ate

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

OS

est

imat

e

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) monthsTakahari, et al. ASCO 2013

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



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