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Chemobiologic Treatment of Advanced Adenocarcinoma: Role of VEGF Inhibition

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Chemobiologic Treatment of Advanced Adenocarcinoma: Role of VEGF Inhibition
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Chemobiologic Treatment of Advanced Adenocarcinoma: Role of VEGF Inhibition

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  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.

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

  3. Angiogenic Switch 1-2 mm The Angiogenic Switch • Small tumor • Nonvascular • “Dormant” • Larger tumor • Vascular • Metastatic potential

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

  5. 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. 22:2184-91, 2004, Sandler. NEJM. 355: 3542-52, 2006, Manegold. ASCO. 2007, abstr LBA 7514.

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

  7. 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 or >/= 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 Fisher’s exact tests Wakelee et al. Lung Cancer 2012

  8. Age/Sex/BevacizumabAge 60 Cut-Point Wakelee et al. Lung Cancer 2012

  9. Younger women (under 60) receiving bevacizumab experienced a more substantial survival benefit (bev = 15.5 mo; control = 11.0 mo). Wakelee et al. Lung Cancer 2012

  10. Elderly on E4599 No added toxicity on MO19390 in those > 65, nor in AVAiL Laskin JTO 7:203, 2012 Ramalingam JCO 2008, 26:60

  11. 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 = 0.00005) • 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

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

  13. VEGFR-TKIs

  14. Promising Small Molecule Inhibitors of VEGFR and Their Targets

  15. VEGFR TKIs and Toxicity

  16. 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

  17. 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…

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