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Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content.

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Presentation on theme: "Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content."— Presentation transcript:

1 Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.



4 Chemobiologic Treatment of Advanced Adenocarcinoma: Role of VEGF Inhibition Heather Wakelee, MD Assistant Professor of Medicine, Oncology Stanford University/Stanford Cancer Center

5 The Angiogenic Switch Small tumor Nonvascular Dormant Larger tumor Vascular Metastatic potential 1-2 mm Angiogenic Switch

6 VEGF: Targeted Approaches - Antibody Anti-receptor blocking antibodies Antiligand blocking antibodies Tyrosine kinase inhibitors Adapted from Noonberg and Benz. Drugs. 2000;59:753. Bevacizumab

7 Bevacizumab in Advanced NSCLC Phase III ECOG 4599 –878 patients: Carboplatin/Paclitaxel +/- Bevacizumab –PFS 6.2 vs 4.5 mo, response 35% vs 15% –MST 12.3 mo (10.3 mo control) Phase III AVAiL –1043 patients: Cisplatin/Gemcitabine +/- Bevacizumab –PFS HR 0.75, p.003 at 7.5 mg/kg 0.85, p.046 at 15 mg/kg –RR 32% vs 20% –MST 13.6m (7.5); 13.4m (15); 13.1m (plac), NS Johnson. JCO. 22: , 2004, Sandler. NEJM. 355: , 2006, Manegold. ASCO. 2007, abstr LBA 7514.

8 Bevacizumab in Special Populations Women – age/sex interaction Elderly – with caution Anti-coagulated – Safe Brain Metastases – Safe Squamous Histology – Not Safe

9 E4599: Age/Sex/Bevacizumab Interaction Eligible patients from E4599 (N=850) were divided into male and female cohorts by treatment (-/+ BEV) Separated into age groups of /= 60 yo Survival calculated for each cohort Known prognostic factors such as performance status, weight loss, and stage were also compared for each sex/age cohort using two-sided Fishers exact tests Wakelee et al. Lung Cancer 2012

10 Age/Sex/Bevacizumab Age 60 Cut-Point < 60 yo>/= 60 yo Women - BEV11.0 mo N= mo N=105 Women + BEV15.5 mo N= mo N=122 Men - BEV9.3 mo N= mo N=158 Men + BEV12.4 mo N= mo N=137 Wakelee et al. Lung Cancer 2012

11 Younger women (under 60) receiving bevacizumab experienced a more substantial survival benefit (bev = 15.5 mo; control = 11.0 mo).

12 Elderly on E4599 Elderly ( 70)Non-Elderly (< 70) PCPCBPCPCB CR+PR17%29%14%36% Median PFS4.9 m5.9 m P = m6.2 m P<0.001 Median survival 12.1 m11.3 m P = m12.8 m P = Ramalingam JCO 2008, 26:60 Grade 3/4 Toxicity 70 yrs < 70 yrsP Melena/GI Bleed3.5%0.9%0.005 Motor Neuropathy3.5%0.6%0.05 Related Deaths6.3%2.6%0.08 Proteinuria7.9%1.3%0.001 No added toxicity on MO19390 in those > 65, nor in AVAiL Laskin JTO 7:203, 2012

13 Bevacizumab Prognostic Factors: E4599 Baseline ICAM associated w/ RR and OS +/- bevacizumab Pts w/ low baseline ICAM: RR 32% vs 14%; P = 0.02 Pts w/ low baseline ICAM: 1 yr survival 65% vs 25%; better overall survival (P = ) Pts w/ high VEGF levels had better RR to bevacizumab, but no survival benefit Pts w/ stable E-selectin (baseline to wk 7) had better OS with bevacizumab (p = 0.05) Dowlatti Clin CA Res;2008;14:1407

14 ECOG 1505 Adj Chemo +/- Bevacizumab Accrual 1100+/1500 RANDOMIZERANDOMIZE STRATIFIED: -Stage (IB[4cm], II, IIIA-N2, IIIA- T3N1) -Histology -Gender -Chemo regimen Chemotherapy x 4 cycles ELIGIBLE: Resected IB-IIIA Lobectomy No prior chemo No planned XRT Chemotherapy x 4 cycles Plus Bevacizumab x 1 year Investigator choice of 4 chemo regimens Cis/Vinorelbine, Cis/Docetaxel, Cis/Gemcitabine, Cis/Pemetrexed


16 Promising Small Molecule Inhibitors of VEGFR and Their Targets InhibitorVEGFR-1VEGFR-2VEGFR-3PDGFRcKITEGFROther Sunitinib++-++-FGFR Vatalanib+++++-cFms Vandetanib-+++/--+ret Cediranib Pazopanib+++- Sorafenib-++++-Raf Axitinib Cabozantinib++++Met Motesanib+++++ BIBF FGFR

17 VEGFR TKIs and Toxicity InhibitorToxicity SunitinibAsthenia, rash, skin discoloration (yellow), hair depigmentation, neutropenia, hypertension, stomatitis, diarrhea, nausea/vomiting VatalanibFatigue, nausea/vomiting, dizziness, ataxia, transaminitis VandetanibDiarrhea, rash, hypertension (mild), proteinuria, QTc interval CediranibFatigue, nausea/vomiting, diarrhea PazopanibFatigue, hypertension, nausea/vomiting, anorexia, diarrhea, hair depigmentation, extrapyramidal disorder, transaminases SorafenibDiarrhea, fatigue, pancreatitis, hypertension, hand/foot syndrome AxitinibFatigue, hypertension, transaminitis, seizure, stomatitis, diarrhea, nausea/vomiting, anorexia, arthralgia, rare epistaxis/hemoptysis BIBF1120Nausea/vomiting, diarrhea, fatigue, abdominal pain, transaminitis

18 VEGFR-TKI Activity in NSCLC Vandetanib improved symptoms in combination with second- line chemotherapy –Improved PFS with docetaxel, but no FDA approval Cediranib w/ 1st-line chemo WAS promising (BR.24) –Phase III trial halted for toxicity Sorafenib single agent promising results, but toxic with carboplatin/paclitaxel (ESCAPE trial) Motesanib did not improve OS when added to carboplatin/paclitaxel (MONET1) Multiple ongoing trials with sunitinib, axitinib, vatalanib, pazopanib, BIBF1120, ABT869, others

19 Anti-VEGF Therapy in NSCLC: No Biomarkers, Small Steps Forward Bevacizumab increases RR and PFS when added to first- line chemotherapy for NSCLC, improved OS in 1/2 trials Okay w/ anti-coag, brain mets, caution in elderly No VEGFR-TKI to date has improved the efficacy of chemotherapy, including motesanib at ASCO 2011 VDA-ASA404 and decoy receptor, aflibercept, failed to improve outcomes when added to chemotherapy in NSCLC Single-agent promise seen with sorafenib, sunitinib and others, but no confirmatory phase III trial data yet Novel agents in development: other VDAs, other antibodies (ramucirumab - VEGFR-2 ab) Predictive and prognostic markers are in development to help guide patient selection, but none validated to date –ICAM, VEGF levels, VEGF polymorphisms, C/AFs…

20 Saturday, February 11, 2012 Hollywood, Florida Faculty Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD

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