ca colon
TRANSCRIPT
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
Heinemann, et al. ASCO 2013
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)
Median, months 28.7 25.0
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
Heinemann, et al. ASCO 2013
FIRE-3: no difference in haematological toxicity between treatment arms
Heinemann, et al. ASCO 2013
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 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
Heinemann, et al. ASCO 2013
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
Heinemann, et al. ASCO 2013
Adverse event, %
Cetuximab + FOLFIRI (n=297)Avastin + FOLFIRI
(n=295)
p value (grade ≥3)Any grade Grade ≥3 Any grade Grade ≥3
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
Heinemann, et al. ASCO 2013
Significant differences in any-grade toxicity: *p<0.001; ǂp=0.046; §p=0.006
Adverse event, %
Cetuximab + FOLFIRI (n=297)Avastin + FOLFIRI
(n=295)
p value (grade ≥3)Any grade Grade ≥3 Any grade Grade ≥3
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
279 207 111 42 16 11 4Observation279 207 130 66 38 23 12Maintenance
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
*Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013
Time (months)
OS
est
ima
te
0 6 12 18 24 30 360.0
0.2
0.4
0.6
0.8
1.0
279 248 184 122 78 53 28Observation279 252 192 143 95 58 33Maintenance
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
*Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013
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
Koeberle, et al. ASCO 2013
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
Koeberle, et al. ASCO 2013
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
Koeberle, et al. ASCO 2013
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
Koeberle, et al. ASCO 2013
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 – – – – – –
Koeberle, et al. ASCO 2013
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)
Median, months 6.1 6.4
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
Tamagawa, et al. ASCO 2013
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)
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 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
Tamagawa, et al. ASCO 2013
Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%
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
Tamagawa, et al. ASCO 2013
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
• Primary endpoint: PFS
• 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
Falcone, et al. ASCO 2013
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
Falcone, et al. ASCO 2013
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
Falcone, et al. ASCO 2013
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
Stratified HR (95% CI)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 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
Falcone, et al. ASCO 2013
Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%
PEAK KRAS/NRAS analysis
Previously untreated, KRAS exon 2 WT mCRC
(n=285)
Panitumumab + mFOLFOX6 (n=142)
Avastin + mFOLFOX6 (n=143)
R
• Primary endpoint: PFS
• 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
Schwartzberg , et al. ASCO 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)
Median, months 10.9 10.1
Stratified HR (95% CI)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)
Median, months 13.0 10.1
Stratified HR (95% CI)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)
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)
Stratified HR (95% CI)p value
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
Panitumumab +mFOLFOX6 (n=142)
Avastin + mFOLFOX6
(n=143)
Events, n/N (%) 52/142 (37) 78/143 (55)
Median, months 34.2 24.3
Stratified HR (95% CI)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)
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
Panitumumab +mFOLFOX6 (n=88)
Avastin + mFOLFOX6
(n=82)
Events, n/N (%) 30/88 (34) 40/82 (49)
Median, months 41.3 28.9
Stratified HR (95% CI)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 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
Schwartzberg , et al. ASCO 2013
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
Schwartzberg , et al. ASCO 2013
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
• Primary endpoint: PFS
• 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
Oliner, et al. ASCO 2013
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
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
Oliner, et al. ASCO 2013
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
Oliner, et al. ASCO 2013
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
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)
OS
est
ima
te
OS
est
ima
te
Time (months)
PRIME: mutations in BRAF do not appear to be predictive for panitumumab treatment effect
Oliner, et al. ASCO 2013
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
Median PFS (months) 6.1 5.4 0.58; 0.116
MT RAS or MT BRAF
Median OS (months) 15.3 18.0 1.21; 0.064
Median PFS (months) 7.3 8.0 1.24; 0.027
WT KRAS exon 2/MT other RAS or MT BRAF
Median OS (months) 14.5 15.8 1.14; 0.508
Median PFS (months) 6.7 7.3 1.05; 0.797
PRIME: adverse events in panitumumab arm similar to those reported for patients with KRAS exon 2 WT mCRC
Oliner, et al. ASCO 2013
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)
Median PFS, months 4.6 5.9
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
Tournigand, et al. ASCO 2013
DREAM: similar PFS (from randomisation) with maintenance Avastin + erlotinib vs Avastin alone in KRAS WT mCRC
AvastinAvastin + erlotinib
WT KRAS, n 111 129
Median PFS, months 5.9 6.0
HR (95% CI)p value
0.86 (0.64‒1.16) 0.135
Patients at riskAvastin 111 91 60 42 25 19 11 9 7 5 3 2 1Avastin + erlotinib 129 105 74 51 35 23 18 13 11 7 4 3 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)
5.9 6.0
Tournigand, et al. ASCO 2013
AvastinAvastin + erlotinib
MT KRAS, n 95 78
Median PFS, months 4.4 4.7
HR (95% CI)p value
0.77 (0.54‒1.08)0.124
Patients at riskAvastin 95 76 47 27 17 10 6 4 3 2 0 0 0Avastin + erlotinib 78 61 38 25 18 11 8 6 6 5 3 1 0
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
Tournigand, et al. ASCO 2013
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
Tournigand, et al. ASCO 2013
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
Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%
AVEX age analysis
• Phase III
• Primary endpoint: PFS
• 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
Saunders, et al. ASCO 2013
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
Saunders, et al. ASCO 2013
AVEX age subgroup analysis: ORR numerically 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)
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
70–74 years 75–79 years ≥80 years
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 – – – – – –
Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%
Saunders, et al. ASCO 2013
70–74 years 75–79 years ≥80 years
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
Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%
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)
Gruenberger, et al. ASCO 2013
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)
Gruenberger, et al. ASCO 2013
OLIVIA: prolonged PFS in Avastin + FOLFOXIRI vs Avastin + mFOLFOX6 in 1L mCRC (ITT population)
mFOLFOX6 + Avastin
FOLFOXIRI + Avastin
Median, months 12.0 18.8
p-value p=0.0002
OLIVIA: no new safety concerns
Gruenberger, et al. ASCO 2013
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
Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%
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)
Greil, et al. ASCO 2013
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
Avastin + chemotherapy
Greil, et al. ASCO 2013
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
Avastin + chemotherapy
Chemotherapy
Avastin + 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)
Greil, et al. ASCO 2013
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
Avastin + chemotherapy
Chemotherapy
Avastin + 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
Greil, et al. ASCO 2013
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
Takahari, et al. ASCO 2013
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
Takahari, et al. ASCO 2013
Red box indicates a difference in incidence of grade ≥3 AE between treatment arms of ≥5%