1. Final results of the phase III, randomised, double-blind AVOREN trial of first-line bevacizumab + interferon-a2a in metastatic renal cell carcinoma
Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S on behalf of the AVOREN investigators

2. Disclosures
Honoraria from Antigenics, Bayer Healthcare, Genentech, GSK, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Wyeth
Consultant for Antigenics, Bayer Healthcare, Inate Pharma, F. Hoffmann-La Roche Ltd, Novartis, Wyeth

3. AVOREN study design Endpoints Treatment primary:* OS
IFNa + Bevacizumab (n=327)
Nephrectomised patients with advanced RCC (n=649)
Stratification:
Country
MSKCC risk group PD
1:1
IFNa + placebo (n=322) PD
Endpoints
primary:* OS
secondary: PFS, TTP, TTF, RR, safety
Treatment
bevacizumab/placebo 10mg/kg i.v. q2w
IFN 9MIU s.c. t.i.w. (maximum 52 weeks)
*PFS is the primary endpoint for regulatory approval in the USA
Escudier, et al. Lancet 2007

4. Summary of published AVOREN data
Final analysis of PFS performed at the time of the interim analysis
significant increase from 5.4 to 10.2 months when bevacizumab is combined with IFN (HR=0.63; p=0.0001)1
good safety profile
By reducing the IFN dose for safety issues
PFS benefit is maintained2
decreased incidence of grade 3/4 events2
1. Escudier, et al. Lancet 2007; 2. Melichar, et al. Ann Oncol 2008

5. Independent review of PFS and ORR
Investigator1
IRC2
IFN + Bevacizumab (n=327)
IFN + placebo (n=322)
IFN + Bevacizumab (n=288)
IFN + placebo (n=281)
ORR (%) 31 13 12
p value
<0.0001
Median PFS (months)
10.2
5.4
10.4
5.5
HR (95% CI)
0.63 (0.52–0.75)
0.57 (0.45–0.72)
1. Escudier, et al. Lancet 2007; 2. Roche, data on file

6. Objectives Final analysis of OS Clinical cut-off September 2008
Median follow-up: 22 months
Statistical considerations
required 445 events from 649 randomised patients
80% power to detect an improvement in OS from 13 to 17 months
corresponding to an HR of 0.76 at a two-sided overall significance level of 0.05

7. Final OS: unstratified and stratified analyses
Cox regression
p value HR
95% CI
Log-rank
Wilcoxon
Unstratified
0.91
0.76–1.10
0.3360
0.2046
Stratified*
0.86
0.72–1.04
0.1291
0.0969
*Stratified by Motzer score and region

8. Probability of survival
Final OS
1.0
0.8
0.6
0.4
0.2
Probability of survival
IFN + Bevacizumab (n=327)
IFN + placebo (n=322)
HR=0.86 (95% CI: 0.72–1.04)
p= (stratified*)
21.3
23.3
Time (months)
Patients at risk (n)
IFN + Bevacizumab
IFN + placebo
*Stratified by Motzer score and region

9. Multiple Cox regression analysis for OS
A multiple Cox regression model controls for several predetermined baseline prognostic factors that influence survival independent of treatment
Variables included in the analysis
gender, age, Motzer score, location of metastases (lung, bone, liver), body weight loss, number of sites, baseline SLD, region, baseline VEGF, and some lab values (albumin, creatinine, alkaline phosphatase, WBC count, platelets)
Adjustment for these factors resulted in an improved treatment effect
HR=0.78 (95% CI: 0.63–0.96); p=0.0219

10. Final OS in reduced-dose IFN population
1.0
0.8
0.6
0.4
0.2
Probability of survival
Bevacizumab + reduced-dose IFN (n=131)
Bevacizumab + IFN (n=327)
23.3
26.0
Time (months)
Patients at risk (n)
Bevacizumab + reduced-dose IFN
Bevacizumab + IFN

11. Censoring patients at time of crossover (n=13)
IFN + Bevacizumab
(n=327)
IFN + placebo
(n=322)
Patients with event, n (%)
220 (67.3)
224 (69.6)
Patients without events, n (%)
107 (32.7)
98 (30.4)
Median OS, months (95% CI)
23.3 (20–27)
20.8 (18–24)
HR (95% CI)
0.84 (0.70–1.02)
p value (Log-rank test)*
0.0766
Derived measure
*Stratified by Motzer score and region

12. Censoring crossover patients
1.0
0.8
0.6
0.4
0.2
Probability of survival
IFN + Bevacizumab (n=327)
IFN + placebo (n=322)
HR=0.84 (95% CI: 0.70–1.02)
p=0.0766*
20.8
23.3
Time (months)
Patients at risk (n)
Bevacizumab + IFN
IFN + placebo
*Stratified by Motzer score and region

13. Summary of subsequent medical therapies
Treatment, n (%)
IFN + Bevacizumab
(n=327)
IFN + placebo
(n=322)
Total patients with ≥1 treatment
180 (55)
202 (63)
VEGF inhibitors
Sunitinib
83 (25)
92 (29)
Sorafenib
60 (18)
50 (16)
Bevacizumab
10 (3)
12 (4)
Other*
7 (2)
6 (2)
mTOR inhibitors‡
14 (4)
Cytokines
32 (10)
52 (16)
Chemotherapy§
28 (9)
47 (15)
*Protein TKI, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib, angiogenesis inhibitors NOS, VEGF inhibitor NOS
‡Temsirolimus, everolimus (RAD001)
§Antimetabolites, vinca alkaloids and antineoplastic agents

14. Regional variation in subsequent treatment with TKIs
IFN + Bevacizumab
IFN + placebo
Therapy
Western Europe (n=180)
Eastern Europe and other (n=147)
Western Europe (n=177)
Eastern Europe and other (n=145)
TKIs, n (%)
Sunitinib
52 (29)
31 (21)
64 (36)
28 (19)
Sorafenib
51 (28)
9 (6)
48 (27)
2 (1)

15. Regional variation in OS
IFN + Bevacizumab
IFN + placebo
Western Europe (n=180)
Eastern Europe and other (n=147)
Western Europe (n=177)
Eastern Europe and other (n=145)
Events, n (%)
120 (67)
100 (68)
125 (71)
99 (68)
Median OS, months (95% CI)
24.5 (21–29)
23.1 (17–27)
23.7 (21–28)
17.1 (13–22)
HR (95% CI)*
0.93 (0.71–1.21)
0.92 (0.71–1.20)
p value (log-rank)*
0.5922
0.5336
*Stratified by Motzer score and region

16. OS by post-protocol therapies
IFN + Bevacizumab
vs IFN + placebo (n)
Median OS
IFN + Bevacizumab (months)
IFN + placebo (months)
HR (95% CI)
Subsequent TKI*‡
113 vs 120
38.6
33.6
0.80 (0.56–1.13)
Subsequent sunitinib
83 vs 92
43.6
39.7
0.88 (0.58–1.35)
Subsequent sorafenib
60 vs 50
30.7
0.73 (0.44–1.20)
*Subsequent therapy defined as any post-protocol therapy, any line (before or after PD)
‡TKIs include sunitinib, sorafenib, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib and unspecified protein TKI

17. Subgroup analysis of OS in AVOREN
Baseline risk factor
Total (n) HR HR
95% CI
All patients
649
0.86
0.72–1.04
Sex
Female
Male
192
457
0.90
0.84
0.64–1.27
0.66–1.05
Age (years)
<65
≥65
410
239
0.78
0.99
0.61–0.99
0.73–1.35
Motzer score
Favourable
Intermediate
Poor
180
366 55
0.86
0.83
0.57–1.30
0.65–1.06
0.47–1.59
Baseline VEGF > median No
Yes
192
0.74
0.88
0.50–1.10
0.62–1.24
Per cent body weight loss
10
>10
501 81
0.88
0.60
0.70–1.09
0.35–1.04

18. Subgroup analysis of OS in AVOREN (cont’d)
Baseline risk factor
Total (n) HR HR
95% CI
No. of metastatic sites 1 2
>2
152
242
252
0.81
1.02
0.74
0.52–1.27
0.73–1.41
0.55–0.99
Lung metastases No
Yes
173
473
1.10
0.77
0.73–1.66
0.61–0.96
Tumour in lung only No
Yes
565 81
0.88
0.68
0.72–1.08
0.36–1.28
Bone metastases No
Yes
521
125
0.87
0.88
0.70–1.09
0.58–1.32
Liver metastases No
Yes
508
138
0.76
1.30
0.62–0.95
0.85–1.98

19. OS in patients without liver metastases at baseline
Probability of survival
1.0
0.8
0.6
0.4
0.2
Median OS
IFN + Bevacizumab (n=258)
IFN + placebo (n=250)
HR=0.76 (95% CI: 0.62–0.95) p=0.0155*
21.4
27.5
Time (months)
Patients at risk (n)
Bevacizumab + IFN
IFN + placebo
*Stratified by Motzer score and region

20. Conclusions
Although not statistically significant, a trend towards improved OS was observed with bevacizumab + IFN combination. The results have been confounded by
post-protocol bevacizumab
subsequent therapies
Patients with bevacizumab + reduced doses of IFN had similar OS to the whole bevacizumab + IFN population
Treatment effect is significant when adjusted for prognostic factors
This analysis confirms the activity of this treatment in first line metastatic RCC with good or intermediate risk

21. Acknowledgements All patients who participated
All investigators, nurses and study coordinators
F. Hoffmann-La Roche Ltd