Rationale for VEGFR-targeted Therapy in RCC

Tim Eisen

EIKCS, Budapest, May 2013

Tim Eisen - Disclosures

Company Research

Support

Advisory Board Trial

Management

Group

Honoraria

Astra Zeneca + + +

Astellas + +

Aveo + + +

Bayer + + + +

GSK + + + +

Immatics +

Pfizer + + +

Roche + +

We need effective therapies in the adjuvant setting

– RCC recurs in ~20–60% of patients post-nephrectomy,1,2

– Incidence and time to recurrence depend on risk score 2,3

– Median time to recurrence

5–9 months in patients with pTxN+ tumours3

35–38 months in patients with pT1 tumours3

Adjuvant therapy: a key unmet need

0.9

27

39

64

2

70

7

0

10

20

30

40

50

60

70

80

pT1 pT2 pT3 pTxN+

Tumour type pre-nephrectomy*

Pro

po

rtio

n o

f p

atie

nts

wit

h r

ecurr

ence

(%

)

1. Lam JS et al. Curr Urol Rep 2005;6:7–18;

2. Eisen T et al. Eur Urol Suppl 2007;6:492–8; 3. Kassouf W et al. Can Urol Assoc J 2009;3:73–6.

*Kassouf et al reported data from multiple studies; within each tumour

type, each bar represents a different study

Metastases-free survival after resection

Leibovich BC et al. Cancer 2003;97:1663–71.

Angiogenesis is one of many steps

leading to metastasis……

Fidler & Ellis, Nature Medicine (2000)

Angiogenesis – Key Pathways

•Tumour growth requires angiogenesis

•Interacting network of signals

•Positive & negative regulators

•Signals from various cell types

•Signals to various cell types

•Endothelial cells proliferate, migrate &

form new vessels

•Pericytes stabilise vasculature

Ferrara & Kerbel, Nature 2005

Poorly understood VEGFR inhibitor effects

Direct effect on tumour

Immunomodulation

– Inflammation

– Tumour immunity

“Off target” effects of small molecules

Lessons from colorectal cancer

Results have been reported for two Phase III trials of adjuvant

bevacizumab in colorectal cancer:

Neither study met its primary endpoint

However are there still lessons that we can learn?

NSABP C-081

• mFOLFOX6

• mFOLFOX6 + bevacizumab

Bevacizumab administered 1 year

AVANT2

• FOLFOX4

• FOLFOX4 + bevacizumab

• XELOX + bevacizumab

Bevacizumab administered 48 wks

1. Allegra CJ et al. J Clin Oncol 2011, De Gramont A et al. Lancet Oncol 2012; .

AVANT – study design

Primary endpoint: DFS

Secondary endpoints: OS, safety De Gramont A et al. Lancet Oncology 2012.

Resected colon

cancer

(high-risk stage II

and stage III)

(n=3450)

FOLFOX4

(24 weeks)

FOLFOX4

(24 weeks)

Bevacizumab 5 mg/kg q2w with chemotherapy and 7.5

mg/kg q3w monotherapy

(48 weeks)

XELOX4

(24 weeks)

Bevacizumab 7.5 mg/kg q3w

(48 weeks)

Disease-free survival in AVANT

Disease-free survival

at 1 year

Disease-free survival

at 3 years

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Favours

bevacizumab addition

Favours

chemo only

Favours

bevacizumab addition

Favours

chemo only

FOLFOX4 + bevacizumab

XELOX + bevacizumab

De Gramont A et al. Lancet Oncol 2012.

Post-operative bevacizumab in

ovarian/peritoneal/fallopian tube cancer

Primary endpoint: Progression-free survival

Secondary endpoints: Overall survival, safety, QoL

+ Placebo

+ Bevacizumab (15 mg/kg)

Inclusion criteria:

• Patients with epithelial ovarian,

primary peritoneal or fallopian tube

cancer

• Disease stage after debulking surgery:

Stage III optimal or suboptimal;

Stage IV

• Less than 1–12 weeks since debulking

surgery

• No prior chemotherapy

RA

ND

OM

IZE

1:1

:1

+ Bevacizumab (15 mg/kg)

N = 1873

Placebo

Bevacizumab (15 mg/kg)

Placebo

Cytotoxic therapy

(6 cycles) Maintenance

therapy

(16 cycles) Carboplatin AUC 6

+ paclitaxel 175 mg/m2

Burger RA et al. J Clin Oncol 2010;28:abstract LBA1. QoL, quality of life.

Key findings in ovarian/peritoneal/fallopian

tube cancer

Three-arm Phase III study of 1st-line systemic therapy after debulking surgery in

advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer

– Regimen 1: Standard chemotherapy + placebo, then maintenance placebo

– Regimen 2: Standard chemotherapy + Bev, then maintenance placebo

– Regimen 3. Standard chemotherapy + Bev, then maintenance Bev

0

0.2

0.4

0.6

0.8

1.0

1.2

Significantly lower risk of

1st progression/death in patients with

maintenance bevacizumab (regimen 3 vs

regimen 1;

p < 0.0001)

Trend toward lower risk of 1st

progression/death with regimen 2 vs

regimen 1

Favours add-on bevacizumab Favours standard therapy

Burger RA et al. J Clin Oncol 2010;28.

Hazard ratio

Bev, bevacizumab

...but there are limitations to cross-study

and cross-tumour comparisons

Biology can vary considerably between tumour types

Outcome with one particular agent may not indicate outcome

with a different agent

CRC and ovarian cancer studies added bevacizumab to existing

adjuvant regimen

– In RCC, there is no approved adjuvant regimen; studies are

evaluating antiangiogenic agents as monotherapy

Adjuvant data in RCC are urgently needed and eagerly awaited!

Many questions to consider…

Do we need to inhibit VEGFR as potently in micrometastases as

strongly as in macrometastases?

Is long-term low dose VEGFR inhibition the way to go?

Novel immunotherapeutic options

Other modalities

MAMS vs traditional

Traditional Approach

Phase II

Phase III

T1

C T1

T2 T3

C T3

T4

C T4

Multi-arm, Multi-stage

T2 T3 T1 C T4

Phase II

Phase III