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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
1.0
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
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