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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
11/21/2009
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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