11/21/2009

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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

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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

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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

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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

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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)

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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

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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

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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

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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,

sdubey@medicine.ucsf.edu