Giorgio Mustacchi

NSCLC: Targeting angiogenesis

NON-SMALL CELL LUNG CANCERNON-SMALL CELL LUNG CANCER

Fry WA, et al. Cancer. 1996;77:1953.

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NON-SMALL CELL LUNG CANCER NON-SMALL CELL LUNG CANCER Survival by stageSurvival by stage

Key targets for novel anticancer agents

Angiogenesis/ vasculature

G1

M

G0S

G2

Signal transduction

Cell cycle

Invasion

Metastasis Apoptosis

Extracellular

Intracellular

Rini BI, Small EJ. J Clin Oncol 23: 1028-1043, 2005.

Molecular-targeted agents under investigation in lung cancer

Phase I

Phase II

Phase III

Approved

AZD2171

Vandetanib

Motesanib

Sorafenib

Avastin

Sunitinib

VEGF TRAP

Vatalanib

Angiogenesis inhibitors

GefitinibTarceva

Bortezomib

Matuzumab

Cetuximab

Bexarotene

Imatinib

AZD6244

Tipifarnib

Talabostat

PF-3512676

Celecoxib

AS1404

Lapatinib

RAD001CP-751871

ABT-751

Panitumumab

EGFR/HER inhibitors

Other molecular-targeted therapies

HKI-272

1. Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191.

*Bevacizumab was given until disease progression or unacceptable toxicity.

After disease progression, patients in the control arm of AVF0757g had the option to receive single-agent bevacizumab 15 mg/kg Q3W.

Trial Phase Patients Treatment Arms*

AVF0757g[1] II 98

PC 6

Bevacizumab 7.5 mg/kg Q3W + PC 6

Bevacizumab 15 mg/kg Q3W + PC 6

Bevacizumab in Advanced NSCLC:Clinical Trial Evidence

In Squamous cell type life-threatening or fatal hemoptysis in 4/13 pts

Alan Sandler, M.D., Robert Gray, Ph.D., Michael C. Perry, M.D., Julie Brahmer, M.D., Joan H. Schiller, M.D., Afshin Dowlati, M.D., Rogerio Lilenbaum, M.D., and David H.

Johnson, M.D.

N Engl J MedVolume 355(24):2542-2550

December 14, 2006

Paclitaxel-Carboplatin +/- Bevacizumabin NSCLC

FDA Registrative ECOG Trial

Study design

• Randomized Phase III Open Label Multicenter Trial• Chemonaive pts, Stage III/IV NSCLC• PS < 2• Excluded: Squamous, CNS M1, hemoptysis• No Bevacizumab crossover permitted

Pacli/Carbo +/- Bevacizumab

E4599 Trial: Addition of Bevacizumab improves RR, PFS and Overall Survival

Months

Pro

bab

ilit

y

HR: 0.79 (95% CI: 0.67-0.92; P = .003)

10.3 12.3

Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

0

0.2

0.4

0.6

0.8

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0 12 36 48186 24 30 42

CPCP + bevacizumab

RR % Survival, %

P<.001 12 Months 24 Months

CP + bevacizumab

35 51 23

CP 15 44 15

Sandler A et al. N Engl J Med 2006;355:2542-2550

HR for Death (Subgroups Analysis)

Sandler A et al. N Engl J Med 2006;355:2542-2550

Causes of Death

(85.2%)(89.8%)

(4.5%)(0.6%)

Adverse Events, According to Treatment

Sandler A et al. N Engl J Med 2006;355:2542-2550

Adverse EventsAccording to Treatment and age </> 70

Ramalingam, JCO Jan 2008

PFS according to age </> 70

Ramalingam, JCO an 2008

In older pts Bevacizumab is more toxic

without > in survival

AVAil: 1°-Line Chemotherapy +/- Bevacizumab

AVAiL: Efficacy Results

Rack, WCLC 2007, Abs C1-06

Rack, WCLC 2007, Abs C1-06

The benefit is significant, but…

In ~ 60 % of NSCLC there is a contraindication :

» Age over 70» Squamous Cell Lung cancer» Anti-coagulation therapy» Brain metastasis» History of hemoptysis» PS > 1

Inhibitory spectrum of multi-kinasetargeting TKIs

1Wedge SR, et al. Cancer Res 2002;62:4645–55; 2Carlomagno F, et al. Cancer Res 2002;62:7284–90; 3Mendel DB, etal.ClinCancer Res 2003;9:327–37; 4Abrams TJ, et al. Mol Cancer Ther 2003;2:471–8; 5Wilhelm SM, et al. CancerRes2004;64:7099109; 6Carlomagno F, et al. J Natl Cancer Inst 2006;98:326–34

IC50 (nm)*

VEGFR-1 VEGFR-2 VEGFR-3 PDGFR EGFR RAF c-Kit RET

Vandetanib1,2

(ZD6474) – 40 110 – 500 – – 100

Sunitinib3,4

(SU11248) – 9 – 8 – – 10 –

Sorafenib5,6

(BAY43-9006) – 90 20 57 – 6 68 50

*Biochemical IC50 values were determined using slightly different methods between the studies. Cut-off of 1,000nM used

Sunitinib in platinum-failing NCSLC

Open Phase II trial

Median PSF

(weeks)

% RR

% SD

N = 63 12

(95% CI: 10 to 16.1)

11.1 28.6

Socinski, JCO Feb 2008

Median Overall Survival : 23.4 weeks (95% CI: 17 to 28.3)

Sorafenib vs Placeboin Heavily pretreated NCSLC

• Double blind controlled Phase II trial• PS < 2• At least 2 prior chemotherapy regimens (n= 342)

If Response after 2 months of Sorafenib (n=97; 28.3%)

Randomisation to Sorafenib or Placebo

Median PSF

(mos)

Stable DX

PD

Sorafenib 3.6 29% 46%

Placebo 1.9

(p=.01)

5%

(p=.002)

58%

Schiller, ASCO 2008, Abs 8014

Tumour cavitation with a multi-targeting TKI

Pretreatment After 6 weeks’ treatment with sorafenib 400mg b.i.d.

Image kindly provided by Dr M Reck, Hospital Grosshansdorf, Germany

Sorafenib: G 3 & 4 Toxicities

Hand-Foot Skin Reaction (15%); Fatigue (11%); INR abnormalities (3%)

Schiller, ASCO 2008, Abs 8014

2 G5 hemoptysis

Docetaxel +/- Vandetanib in pretreated NCSLC

• Double blind controlled Phase II trial vs Placebo• PS < 2

N = 127 Median PSF

(weeks)

Vandetanib 18.7

Placebo 12

HR 0.64

(p=.074)

Heymach, JCO 2007

Vandetanib +/- Carbo/Paclitaxel in 1st line NCSLC

• Randomized Phase II trial • PS < 2

N = 181 Median PSF

(weeks)

% RR

Vandetanib na 7

Van + CP 24 32

CP 23

HR 0.76

(p=.098)

25

Heymach, ASCO 2007, Abs 7544

Discontinued

MORE TOXIC

Tarceva and Avastin: targeting the tumour and the vasculature

Tumour

Tarceva AvastinInhibits tumour cell growth and blocks synthesis of angiogenic proteins (e.g. bFGF, VEGF, TGF-) by tumour cells

Inhibits endothelial cells from responding to the angiogenic protein VEGF

bFGFVEGFTGF-

Endothelial cells

Phase II study of Avastin with chemotherapy or Tarceva in advanced NSCLC

Previously treated advanced non-squamous NSCLC (n=120)

PD

PD Tarceva

PD Tarceva

• Randomised, multicentre study

• Primary endpoint: safety and preliminary efficacy (PFS)

• Secondary endpoints: objective RR (+ duration); duration of survival

Avastin 15mg/kg every 3 weeks; Tarceva 150mg/day orally;docetaxel 75mg/m2 and pemetrexed 500mg/m2 every 3 weeksPD = progressive disease Herbst R, et al. Eur J Cancer Suppl 2006;4:20 (Abs. 53)

Tarceva + Avastin (n=39)

Chemotherapy(n=41)

Chemotherapy+ Avastin

(n=40)

Phase II study of Avastin plus chemotherapy or Tarceva in advanced NSCLC: efficacy

Herbst R, et al. Eur J Cancer Suppl 2006;4:20 (Abs. 53)

PFS Overall survival

Pro

gre

ssio

n-fr

ee s

urvi

val r

ate 1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7 8

Progression-free survival (months)

Sur

viva

l rat

e

Duration of survival (months)

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

1.0

0.8

0.6

0.4

0.2

0

Avastin + Tarceva 4.4 33.6 Avastin + CT 4.8 30.5CT 3 21.5

Median 1-year(months) rate (%)

Avastin + Tarceva 13.7 57.1Avastin + CT 12.6 53.6CT 8.6 34.8

Median 6-month(months) rate (%)

• Double‑blind, randomised study • Primary endpoint = OS• Secondary endpoints: PFS, RR and duration, safety and

pharmacokinetics• Status: ongoing; planned n=650

OSI-3364g*No crossover permitted

Phase III study of Tarceva ± Avastin in the second-line setting

Previously treated advanced non-

squamous NSCLC

PD*

PDTarceva 150mg/day

+ placebo

Tarceva 150mg/day + Avastin 15mg/kg

every 3 weeks

Phase II study of first-line Tarceva + Avastin versus Avastin + chemotherapy

• Randomised, multicentre, open-label

• Primary endpoint: PFS

• Secondary endpoints: safety, QoL, OS, correlation of biomarkers and clinical characteristics with outcome– EGFR IHC and FISH, EGFR mutations, K-ras, pMAPK, pAKT, HER2

IHC and FISH, HER3, amphiregulin, TGF-, EGF, ICAM

• Status: planned; n=200

Tarceva 150mg + Avastin 15mg/kg every 3

weeks

Stage IIIB/IV enlarged non-squamous NSCLC,

unselectedChemotherapy + Avastin

BO20571

ATLAS: Tarceva + Avastin following the new standard of care in first-line treatment

Avastin +placebo

Chemotherapy naïve stage IIIB/IV non-squamous

NSCLC

Tarceva

Non-PD

AVG3671g (phase IIIb)Avastin 15mg/kg every 3 weeks; Tarceva 150mg/day*Either carboplatin/paclitaxel, carboplatin/gemcitabine or carboplatin/docetaxel

Off study

Avastin +Tarceva

PD

Off study

(n800)

PD

1:1Avastin plus

chemotherapy*

PD or significant

toxicity

• Primary endpoint = PFS

• Status: ongoing; planned n=1,150

Fry WA, et al. Cancer. 1996;77:1953.

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NSCLC: Survival by stageNSCLC: Survival by stageThe best treatment: NO SMOKINGThe best treatment: NO SMOKING