outline - ucsf medical education · 11/21/2009 1 emerging novel targets for nsclc 11 th ucsf/ucd...
TRANSCRIPT
11/21/2009
1
Emerging Novel targets for NSCLC
11th UCSF/UCD Thoracic Oncology Conference11/21/2009
Sarita Dubey, M.D.,Medical Oncology
University of California, San Francisco
Targeted Therapy for Lung Cancer?
• Cytotoxic chemotherapy is non-specific
• Benefit of “one size fits all” chemotherapy approach has plateaued
– Several critical pathways involved in initiation and progression of lung cancer identified
– viable pharmacologic targets
BEZ 235
XL765
BEZ 235
ARRY
PF 00299804, HKI 272
XL647, BIBW 2992,
Outline
• EGFR
• Anti-angiogenic / vascular disrupting agents
• IGF-1R
• Others
11/21/2009
2
Outline
• EGFR
• Anti-angiogenic / vascular disrupting agents
• IGF-1R
• Others
EGFR resistance
Inhibition of EGFR by Gefitinib/erlotinib
T790M mutation reduces ATP affinity of gefitinib/erlotinib
MET amplification activated PI3K/Akt via ERBB3
Engelman & Janne, CCR 2008;14 Yun, PNAS 2008; 105
OTHERS;
Kras MT,
PI3KCA MT
MET & T790M account for 60-70%
2nd Generation EGFR TKIs
BIBW 2992 EGFR, HER2, Phase I NSCLC RR 20%
HKI 272 EGFR, HER2,HER3, T790M
Phase I40% SD
XL 674 EGFR, HER2, VEGFR2, T790M
Phase II29% RR
PF00299804 Irreversible Pan HERT790M
Phase IPR10%
Riley, T Thoracic Oncol 2008, 3
Janne, ASCO 2008,
Overcoming EGFR resistanceOther inhibitors
XL 880Eder ASCO 2007 #3526
MET, VEGFR
XL 184Salgia ASCO 2008, 3522
MET, VEGFR2, RET
XL 765Papadopoulos ASCO 2008, # 3510
PI3K, mTOR
BEZ 235Engelman, Nat Med 2008: 14
PI3K, mTOR
ARQ 197Yap, ASCO 2009, # 3523
MET
11/21/2009
3
The Ras-Raf-MEK-ERK pathway
B-Raf Mutations: malignant melanomas and papillary thyroid cancers, colon cancer
Ras Mutations: lung, colonand pancreatic cancers
Kras/BRaf mutations activate the MEK pathway
GDPGDPGDPGDP
GTPGTPGTPGTP RAS*RAS*RAS*RAS*
RafRafRafRaf
MEK1MEK1MEK1MEK1MEK2MEK2MEK2MEK2
ERK1ERK1ERK1ERK1ERK2ERK2ERK2ERK2
MEK PathwayMEK PathwayMEK PathwayMEK Pathway
GrowthGrowthGrowthGrowthFactorsFactorsFactorsFactors
Proliferation (Ki67) Cell death
(Caspase 3)
Migration
P
Approach to Kras Mutation
• Kras driven mice adenocarcinoma
Engelman, Nat Med, 2008; 14 : 1351
Combined inhibition of PI3K, mTOR, and MEK may efffectively treat Kras MT tumors
MEK1/2
ligand
RasRas
Raf
Erk1/2Erk1/2
PI3K
PKCNF-κBNF-κB
Akt
mTORX
XX
Outline
• EGFR
• Anti-angiogenic / vascular disrupting agents
• IGF-1R
• Others
Angiogenesisinhibitors
11/21/2009
4
Ligand sequestration: MAbs, soluble receptors
GRB2 SOS
ras
PLCγ
p85
Inhibition of tyrosine phosphorylation and downstream
signallinginhibition
Transcriptionfactor inhibition
Tyrosine kinase inhibition: TKIs
TKI = tyrosine kinase inhibitor
Receptor blocking:MAbs
Approaches to inhibition of VEGF signaling
BEV, VEGF-TRAP
GW786034, AZD2171, vatalanib
Anti-anigiogenesis Receptor TKI’sInhibitor VEGFR
1
VEGFR2
VEGFR3
PDGFR C-Kit FGFR Other
Vatalanib
(PTK787)+ + + + +
AZD2171+ + +
Pazopanib
(GW786034)+ + +
Sunitinib
(SU11248)+ + + +
AG013736+ + + + +
Sorafenib
(Bay 43-9006)+ + Raf
Zactima
(ZD6474)+ +
EGFR
RET
ESCAPE - Chemotherapy ± Sorafenib
♦ Stage IIIB/IV NSCLC
♦ PS 0-1
Stratification:Geographic regionECOG PS 0 vs 1
Squamous vsnon-squamous cell
Stage IIIb (with effusion) vs Stage IV
Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m2 d1 +
Sorafenib 400 mg bid d2-19, q3w(CPS)
Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m2 d1 + Placebo d2-19,
q3w (CPP)
Hanna, Chest Conference, 2008, Abstr # 13
Sorafenib
Placebo
ESCAPE - Chemotherapy ± SorafenibOverall Survival
HR = 1.16 95% CI: 0.95, 1.43P = 0.930
HR = 1.0995% CI: 0.93, 1.28P = 0.849
CPSMedian: 10.5 months95% CI: 9.2, 11.7
CPP Median: 10.7 months95% CI: 9.8, 11.8
Oct 2007 Sept 2008*
Hanna, Chest Conference, 2008, Abstr # 13Months
204 128 16
Sur
viva
l Pro
babi
lity
0.25
0.50
0.75
1.00
00
24Months
204 128 16
Sur
viva
l Pro
babi
lity
0.25
0.50
0.75
1.00
00
24
CPSMedian: 10.7 months95% CI: 9.3, 13.9
CPP Median: 10.6 months95% CI: 9.7, 12.0
11/21/2009
5
Many Targeted Therapies Failed to Show Additional Benefit when Combined with Platinum Based CT
Median Survival results in months Placebo Agent
INTACT-1 CG ± gefitinib 10.9 9.9/9.9 NSINTACT-2 CP ± gefitinib 9.9 9.8/8.7 NSTRIBUTE CP ± erlotinib 10.5 10.6 NSTALENT CG ± erlotinib 10.0 10.3 NSSPIRIT-1 VC ± bexarotene 9.9 8.7 NSSPIRIT-2 CP ± bexarotene 9.2 8.5 NSPaz-Ares et al. CG ± aprinocarsen 10.4 10.0 NSISIS-3521 CP ± aprinocarsen 9.7 10.0 NSAG-3340-017 CG ± prinomastat 10.8 11.5 NSBR.18 CG ± BMS-275291 9.2 8.6 NSStudy 5404 CP± panitumumab 8.0 8.5 NSBR.24 CbP ± cediranib Will not proceed to Phase III because of
toxicity
Courtesy: E. Vokes
CALGB 30607: Sunitinib as Maintenance Therapy in Non-progressing Advanced NSCLC Patients
(PI: Mark Socinski)
Continue until disease progression †
Planned follow-up:
1 year
Sunitinib 37.5 mg/day
Placebo
Randomization of responding
patients or patients with
stable diseasestratified by
prior treatment with/without bevacizumab
Patients with untreated
stage IIIB/IV NSCLC and
ECOG PS 0–1 Four cycles of platinum-based chemotherapy*
*Platinum-based regimen may include carboplatin/cis platin plus paclitaxel, docetaxel, vinorelbine or gemcitabine with or without bevacizu mab (bevacizumab discontinued after four cycles)
†At progression, patients receiving placebo may cros s over to the sunitinib arm
10 Endpoint - PFS
Vascular Disrupting Agents
Kelland. Curr Cancer Ther Rev. 2005;1:1-9.
VDA AntiangiogenicLarge established BVs Small new BVs
Central part of tumor Peripheral tumor
Apoptosis Inhibition of proliferation
VDA’s
Tubulin antagonists
• AVE8062A
• Combretastatin A4• ZD6126
Flavone acetic acids• ASA404 (DMXAA)
11/21/2009
6
ASA404: VDA
• Molecular target - unclear• Early phase : apoptosis of endothelial
cells • Late phase: may stimulate IκB kinase,
thereby releasing active NF-κB→ influence the organization of the
cytoskeleton causing loss of contact between adjacent cells, and increasing vascular permeability
Baguley. Lancet Oncol. 2003;4:141-148.
ASA404 with Paclitaxel/Carboplatin Advanced NSCLC
Phase II Extension
ASA404 1,800 mg/m2 + P/C
Response N = 29
PR 11 (37.9%)
SD 14 (48.3%)
Median TTP 5.5 mo
Median survival 14.9 mo
McKeage et al. IASLC 2007.
Ongoing studies with ASA 404
• ATTRACT I :– First line
• Carboplatin/taxol ± ASA404• ATTRACT 2
– Second line– Docetaxel ± ASA404
Outline
• EGFR
• Anti-angiogenic / vascular disrupting agents
• IGF-1R
• Others
11/21/2009
7
Targeting IGFR
InsR-A
IGF-II
Survival Proliferation Metastasis
InsR-B M6P/IGF-2RIGF-2RIGF-1R
Ins
IGF-IMoAbsIMC-A12AMG 479
CP-751,871R1507
TKI’s
OSI 906
XL228
EGF
HGF
EGFR
Courtesy: K. Reckamp
IGF-1R in lung cancer
• IGF1/ IGF2 and IGF-1R are overexpressed in NSCLC and correlate with decreased apoptosis (Pavelic 2005 ).
• More than 50% of squamous cell cancers of the lung have LOH or mutation of M6P/IGF-2R (Kong 2000). Loss of heterozygosity (LOH) of M6P/IGF-2R is associated with increased amount of IGF-2 protein and a higher proliferation index (Ki67).
• IGF level associated with worse prognosis in stage I NSCLC (Merrick ASCO 2007, Abst#7550)
MoAbs Targeting IGF-1RAgent Type of Antibody Studies
IMC- A12 Fully human bivalent MoAb
Phase II planned NSCLC
CP-751,871 Fully human MoAb Phase III planned NSCLCPhase II sarcoma
AMG 479 Fully human MoAb Phase IPhase II sarcoma
MK 0646 Fully human MoAb Phase II planned NSCLC
R1507 Fully human Phase II sarcoma
Inhibit binding of ligand to receptor, inhibit receptor activation, receptor internalization
2:1 randomization
PC: paclitaxel 200 mg/m 2, carboplatin (AUC=6)
PCI: paclitaxel 200 mg/m 2, carboplatin (AUC=6),
Step 1: CP-751,871 10 mg/kg
Step 2: CP-751,871 20 mg/kg
PCI
n=97
n=53
CP-751,871
Single agent
Optional upon progression
CP-751,871
Single agent
Phase II of CP-751,871(Figitumumab) with paclitaxel, carboplatin in first-line advanced
NSCLC
PCI: paclitaxel 200 mg/m 2, carboplatin (AUC=6) CP-751,871 20 mg/kg
Step 3: single-arm, post-study extension
in squamous
30 patients(14 evaluable) Karp, JCO 2009, 27:2516
11/21/2009
8
Phase II of Figitumumab with paclitaxel, carboplatin in first-line advanced NSCLC
Response rates
PCF (20mg/m2 dose) PCAdenoca 57% 25%
Squamous 78% 46%
NOS 50% 52%
•Karp , ASCO 2008, Abstr # 8015
Phase II of Figitumumab with paclitaxel, carboplatin in first-line advanced NSCLC
Progression Free Survival (PFS)
Pro
gres
sion
rat
e (%
)
100
80
60
40
20
0
Time (months)0 1 2 3 4 5 6 7 8 9 10 11
PC PCF 10 mg/kgPCF 20 mg/kg
Dose (PC + F mg/kg) 0 10 20Median PFS (months) 4.3 3.6 5.0
Hazard Ratio 1.37 0.80
All Histologies
Dose (PC + F mg/kg) 0 20Sample size (n) 13 9Median PFS (months) 4.3 5.6
Squamous Cell
NSCLCII/IIIA
Phase II
Cisplatindocetaxel q 21 days
x 3 cycles
Cisplatindocetaxel q 21 days x 3 cyclesMK0646 10mg/kg/wk
Study Design CALGB 30803
RANDOMIZE
Med-scopy/
EBUS
Tumor/blood
Biomarker analysis
PET/MRI
MK0646: 10mg/Kg once weekly beginning with first dose of chemotherapy and continuing until one week prior to surgery.
PI: Dubey
Outline
• EGFR
• Anti-angiogenic / vascular disrupting agents
• IGF-1R
• Others
11/21/2009
9
Toxicities of targeted agents
• Unique : quite different from cytotoxics
• Anti-angiogenic agents: hypertension, hemorrhage, poor wound healing, proteinuria
• IGFR inhibitors: hyperglycemia
• EGFR inhibitors: skin rash, transaminitis, interstitial lung disease
• Multi- TKI: QT prolongation,