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Chemobiologic Treatment of Advanced Adenocarcinoma:
Role of VEGF Inhibition
Heather Wakelee, MD
Assistant Professor of Medicine, Oncology
Stanford University/Stanford Cancer Center
The Angiogenic Switch
Small tumor• Nonvascular• “Dormant”
Larger tumor• Vascular• Metastatic potential
1-2 mm
Angiogenic
Switch
VEGF: Targeted Approaches - Antibody
Anti-receptorblockingantibodies
Antiligandblockingantibodies
Tyrosine kinase inhibitors
Adapted from Noonberg and Benz. Drugs. 2000;59:753.
Bevacizumab
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.
Bevacizumab in Special Populations
Women – age/sex interaction
Elderly – with caution
Anti-coagulated – Safe
Brain Metastases – Safe
Squamous Histology – Not Safe
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
Age/Sex/BevacizumabAge 60 Cut-Point
< 60 yo >/= 60 yo
Women - BEV 11.0 moN= 75
13.8 moN=105
Women + BEV 15.5 moN=85
12.8 moN=122
Men - BEV 9.3 moN=95
8.5 moN=158
Men + BEV 12.4 moN=73
11.0 moN=137
Wakelee et al. Lung Cancer 2012
Wakelee et al. Lung Cancer 2012
Younger women (under 60) receiving bevacizumab
experienced a more substantial survival benefit (bev = 15.5 mo;
control = 11.0 mo).
Elderly on E4599
Elderly (≥ 70) Non-Elderly (< 70)
PC PCB PC PCB
CR+PR 17% 29% 14% 36%
Median PFS 4.9 m 5.9 m
P = 0.063
4.4 m 6.2 m
P<0.001
Median survival
12.1 m 11.3 m
P = 0.4
9.6 m 12.8 m
P = 0.0027
Ramalingam JCO 2008, 26:60
Grade 3/4 Toxicity ≥ 70 yrs < 70 yrs P
Melena/GI Bleed 3.5% 0.9% 0.005
Motor Neuropathy 3.5% 0.6% 0.05
Related Deaths 6.3% 2.6% 0.08
Proteinuria 7.9% 1.3% 0.001
No added toxicity on MO19390 in those > 65, nor in AVAiL
Laskin JTO 7:203, 2012
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
ECOG 1505 Adj Chemo +/- Bevacizumab
Accrual 1100+/1500
RANDOM IZE
STRATIFIED:
-Stage (IB[≥4cm], II, IIIA-N2, IIIA-T3N1)-Histology-Gender-Chemo regimen
Chemotherapyx 4 cycles
ELIGIBLE:
Resected IB-IIIA
≥LobectomyNo prior chemoNo planned XRT
Chemotherapyx 4 cycles
PlusBevacizumab
x 1 year
•Investigator choice of 4 chemo regimens •Cis/Vinorelbine, Cis/Docetaxel, Cis/Gemcitabine, Cis/Pemetrexed
VEGFR-TKIs
Promising Small Molecule Inhibitors of VEGFR and Their Targets
Inhibitor VEGFR-1 VEGFR-2 VEGFR-3 PDGFR cKIT EGFR Other
Sunitinib + + - + + - FGFR
Vatalanib + + + + + - cFms
Vandetanib - + + +/- - + ret
Cediranib + ++ + + - -
Pazopanib + + + -
Sorafenib - + + + + - Raf
Axitinib + + + + + -
Cabozantinib + + + + Met
Motesanib + + + + +
BIBF1120 + + + + FGFR
VEGFR TKIs and Toxicity
Inhibitor Toxicity
Sunitinib Asthenia, rash, skin discoloration (yellow), hair depigmentation, neutropenia, hypertension, stomatitis, diarrhea, nausea/vomiting
Vatalanib Fatigue, nausea/vomiting, dizziness, ataxia, transaminitis
Vandetanib Diarrhea, rash, hypertension (mild), proteinuria, QTc interval
Cediranib Fatigue, nausea/vomiting, diarrhea
Pazopanib Fatigue, hypertension, nausea/vomiting, anorexia, diarrhea, hair depigmentation, extrapyramidal disorder, transaminases
Sorafenib Diarrhea, fatigue, pancreatitis, hypertension, hand/foot syndrome
Axitinib Fatigue, hypertension, transaminitis, seizure, stomatitis, diarrhea, nausea/vomiting, anorexia, arthralgia, rare epistaxis/hemoptysis
BIBF1120 Nausea/vomiting, diarrhea, fatigue, abdominal pain, transaminitis
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
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…
Saturday, February 11, 2012Hollywood, Florida
Faculty
Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD
Co-Chair and ModeratorNeil Love, MD
Chandra P Belani, MDJohn Heymach, MD, PhDPasi A Jänne, MD, PhD
Thomas J Lynch Jr, MDHeather Wakelee, MD
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