Bevacizumab plus Interferon-alpha versus Interferon-alpha Monotherapy in Patients with Metastatic Renal Cell Carcinoma:

Results of Overall Survival for CALGB 90206

Brian I. Rini1, Susan Halabi 2,3, Jonathan E. Rosenberg4, Walter M. Stadler5, Daniel A.Vaena6, James N. Atkins7, Joel Picus8, Piotr Czaykowski9, Janice

Dutcher10 and Eric J. Small4

1. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH2. Department of Biostatistics / Bioinformatics, Duke University Medical Center, Durham, NC3. CALGB Statistical Center, Durham, NC 4. University of California San Francisco, San Francisco, CA5. University of Chicago Medical Center, Chicago, IL6. University of Iowa, Iowa City, IA7. Southeast Cancer Control Consortium Inc.8. Washington University, St. Louis, MO9. University of Manitoba, Winnipeg, Manitoba; NCI Canada, Kingston, ON, Canada 10. New York Medical College, NY, NY; Eastern Cooperative Oncology Group, Boston, MA

Background

• Bevacizumab (BEV) plus interferon alpha (IFN) demonstrated a superior objective response rate and progression-free survival (PFS) versus IFN monotherapy in metastatic RCC patients in 2 phase III trials1,2

• The primary objective of CALGB 90206 was to compare overall survival (OS) for metastatic RCC patients receiving BEV plus IFN or IFN monotherapy

1. Escudier B et al. Lancet, 20072. Rini BI et al. JCO 2008

Study Schema

RANDOMIZE

IFNA 9 MU TIW

IFNA 9 MU TIW +

Bevacizumab 10 mg/kg IV

q d1 and d15

STRATIFY

• Patients stratified for nephrectomy status (yes/no) and MSKCC risk group (0 risk factors vs. 1-2 risk factors vs. 3 or more risk factors)*

Eligibility Criteria• Confirmed metastatic RCC with a

component of clear cell histology• Karnofsky PS ≥ 70%• Measurable or evaluable disease

(by RECIST)• No prior systemic treatment• Adequate end-organ function• No CNS metastases• BP < 160/90 with meds• No DVT within 1 year or arterial

thrombotic event within 6 months• Prior nephrectomy not required

* Motzer R et al., JCO 20(1), 2002

• The primary endpoint was OS, defined as the time from randomization to death due to any cause

• The trial was designed with 86% power to detect a hazard ratio (HR) of 0.76 (assumed median OS improvement 13 to 17 months), assuming a two-sided type I error of 0.05

• The primary analysis was an intent-to-treat approach using the stratified log-rank statistic, and the present analysis was based on the target number of 588 deaths

• Secondary endpoints: Progression-free survival (PFS), objective response rate (RECIST criteria), safety

Statistical Methods

Patient DispositionPatients consented

(n=732)

IFNA monotherapy (n=363)

Discontinued Treatment (n=346)

PD / Death (n=218)Toxicity (n=66)

Refused further tx (n=33)Other (n=24)

Lost to follow-up (n=4)D/C after achieving CR (n=1)

Analyzed (n=363)

Bevacizumab+ IFNA (n=369)

Discontinued Treatment (n=349)

PD / Death (n=200)Toxicity (n=80)

Refused further tx (n=40)Other (n=25)

Lost to follow-up (n=2)D/C after achieving CR (n=2)

Analyzed (n=369)

Never started tx (n=13)

Never started tx (n=3)

Baseline Demographics and Clinical Characteristics (n=732)Bevacizumab plus

IFN (n=369)IFN monotherapy

(n=363)

Sex – no. (%) Male Female

269 (73%)100 (27%)

239 (66%)124 (34%)

Median Age, years (inter-quartile range)

61 (56-70)

62 (55-70)

ECOG performance status – no. (%) 0 1 2

230 (62%)132 (36%)

7 (2%)

227 (62%)133 (37%)

3 (1%)

Previous nephrectomy – no. (%) 312 (85%) 308 (85%)

Previous radiation therapy – no. (%) 35 (9%) 38 (10%)

Common Sites of Metastases Lung Lymph node Bone Liver

252 (68%)130 (35%)104 (28%) 74 (20%)

254 (70%)129 (36%)109 (30%) 73 (20%)

Number of adverse risk factors 0 (favorable) 1-2 (intermediate) ≥ 3 (poor)

97 (26%)234 (64%) 38 (10%)

95 (26%)231 (64%) 37 (10%)

Time(months)

Ove

rall

Sur

viva

l (pr

obab

ility

) IFN BEV/IFNStratified log-rank p=0.069

Kaplan-Meier Overall Survival Curves by Treatment Arm

0 6 12 18 24 30 36 42 48 54 60

0.0

0.2

0.4

0.6

0.8

1.0

363 286 221 177 148 118 98 64 37 10 1369 314 242 190 160 139 116 94 42 17 2

IFNBEV/IFN

Number of Patients at Risk

---- BEV/IFN: Median OS 18.3 months

IFN: Median OS 17.4 months

Kaplan-Meier Overall Survival by Treatment Arm

Overall Survival by MSKCC Risk Status*

Median OS (months)

Risk Group %BEV/IFN IFN HR

Favorable (0 risk factors) 26 32.5 33.5 0.89

(p = 0.524)

Intermediate (1-2 risk factors) 64 17.7 16.1 0.87

(p = 0.174)

Poor (≥ 3 risk factors) 10 6.6 5.7 0.76

(p = 0.25)

* Motzer R et al., JCO 20(1), 2002

Second-line Therapy Received in Patients who Discontinued Protocol Therapy for Any Reason Other Than Death

Bevacizumab + IFN (n=351)

IFN monotherapy (n=350)

Percentage of patients receiving any second-line therapy

54% 62%

VEGF-targeted therapy 37% 46%

Bevacizumab 6% 14%

Chemotherapy 18% 14%

Investigational therapy 11% 18%

Cytokines 13% 14%

* Fifty-six percent of patients overall received at least one subsequent systemic therapy

Median OS (months) according to treatment arm and subsequent therapy

Bevacizumab + Interferon

Interferon Total(unstratified log-rank p comparing arms)

Stratified HR

Received 2nd-line

therapy

(n=408)

31.4 26.8 28.2(p=0.079)

0.80 (p=0.055)

Did not receive 2nd-line therapy

(n=324)

13.1 9.1 10.2(p=0.059)

0.82 (p=0.108)

Total 18.3 17.4 18.1 (p=0.097)

0.86 (p=0.069)

Variable

Received non protocol treatment* (n=408)

Did not receive non protocol treatment (n=324 )

p-value

Gender

Male

Female

70%

30%

79%

31% 0.687

Median Age, years

(inter-quartile range)

61

(55-69)

62

(56-71) 0.019

ECOG PS

0

1

2

67%

32%

1%

56%

42%

2%

0.012

Previous nephrectomy 88% 80% 0.004

Previous XRT 12% 8% 0.064

Sites of Metastases

Lung

Lymph node

Bone

Liver

70%

35%

29%

17%

68%

36%

29%

24%

0.572

0.756

0.935

0.020

MSKCC risk group

0 (favorable)

1-2 (intermediate)

≥ 3 (poor)

29%

64%

6%

22%

62%

15%

<.001

Baseline characteristics of patients according to subsequent therapy

* There was no difference in baseline characteristics for patient who received subsequent therapy by treatment assignment

Variable

NephrectomyYes (N = 620)No (N =112)

MSKCC0 (N = 192)1 (N = 465)2+ (N = 75)

Liver MetsYes (N = 147)No (N = 585)

Age< 44.8 (N = 363)>= 44.8 (N = 369)

GenderMale (N = 508)Female (N = 224)

TotalN = 732

Median BEV/IFN

20.2 (17.1, 25.0)15.7 (10.1, 20.6)

32.5 (21.6, 43.7)17.7 (15.6, 22.5)6.6 (5.9, 8.9)

15.8 (10.1, 21.0)20.3 (17.0, 24.3)

18.1 (14.9, 21.7)20.8 (16.4, 27.1)

18.7 (16.1, 24.3)17.6 (14.4, 24.0)

18.3 (16.5, 22.5)

Survival (months) IFN

18.8 (15.7, 23.5)9.4 (5.7, 16.1)

33.5 (24.3, 39.4)16.1 (13.4, 19.9)5.7 (4.4, 9.2)

9.4 (7.5, 17.1)19.2 (15.9, 21.7)

16.2 (13.7, 20.0)18.8 (13.8, 27.0)

18.6 (15.8, 24.3)14.1 (10.4, 20.0)

17.2 (14.4, 20.0)

p-value

0.28720.0381

0.51890.16880.2439

0.0830.1824

0.5980.6813

0.43450.0687

0.069

0 0.5 1 1.5 2

Forest Plot of Overall Survival in Select Subgroups

BEV/IFN better IFN better

Kaplan-Meier Progression-Free Survival by Treatment Arm

0 6 12 18 24 30 36 42 48

Time(months)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

ssio

n-F

ree S

urv

ival P

robabili

ty

IFNBEV/IFN, Stratified log-rank p<0.0001

363 145 77 47 36 30 7

369 218 129 84 55 37 26 20 10

IFN

BEV/IFN

Number of Patients at Risk

-- Median PFS 8.4 months Median PFS 4.9 months HR= 0.71 (95% CI=0.6-0.8)

Objective Response

Note: patients with measurable disease only

Bev + IFN (n=325) IFN (n=314)

Overall Response rate 25.5% [95% CI = 20.9-30.6]

13.1%[95% CI = 9.5-17.3]

CR 3.7% 1.9%

PR 23.4% 12.7%

p < 0.0001

Duration of response 11.9 months [95% CI = 8.3 – 14.8]

9.7 months[95% CI = 7.6 – 19.8]

p = 0.362

Adverse event

Bevacizumab + IFN

(n=366)

IFN

(n=352)

Any grade 3/4 adverse event 79% 61%

Fatigue/asthenia/malaise 37% 30%

Anorexia 17% 8%

Proteinuria 15% <1%

Hypertension 11% 0%

Hemorrhage 2% <1%

Venous thromboembolism 2% 1%

Gastrointestinal perforation <1% 0%

Arterial ischemia 1% 0%

Frequency of selected grade 3 or 4 AEs

Conclusions

• Overall survival is greater in patients with metastatic clear cell RCC receiving bevacizumab plus interferon as initial systemic therapy compared to interferon alone, but does not meet pre-defined criteria for significance

• Although the effect of bevacizumab plus IFN on OS is preserved regardless of subsequent treatment, the most robust OS is achieved in patients with favorable underlying disease biology who are able to receive subsequent therapy

• The combination of bevacizumab and IFN as initial therapy in metastatic RCC patients results in a significantly greater progression-free survival and objective response rate versus IFNA monotherapy

• Toxicity is greater in the combination therapy arm, including more fatigue, anorexia, hypertension and proteinuria

• The research for CALGB 90206 was supported, in part, by grants from the National Cancer Institute to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman) and the CALGB Statistical Center (Stephen George, PhD).

• Cancer Therapy Evaluation Program (CTEP)• Eastern Cooperative Oncology Group (ECOG)• National Cancer Institute Canada (NCIC)

• Genentech; Schering-Plough for drug supply through CTEP

• Patients, families and caregivers for the courage to participate in a randomized clinical trial

Acknowledgements

Wait til next year . . .