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

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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. 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.
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Chemobiologic Treatment of Advanced
AdenocarcinomaRole of VEGF Inhibition

• Heather Wakelee, MD
• Assistant Professor of Medicine, Oncology
• Stanford University/Stanford Cancer Center

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The Angiogenic Switch

• Small tumor
• Nonvascular
• Dormant

• Larger tumor
• Vascular
• Metastatic potential

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VEGF Targeted Approaches - Antibody
Bevacizumab
Antiligand blocking antibodies
Tyrosine kinase inhibitors
Anti-receptor blocking antibodies
Adapted from Noonberg and Benz. Drugs.
200059753.
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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. 222184-91, 2004, Sandler. NEJM.
355 3542-52, 2006, Manegold. ASCO. 2007, abstr
LBA 7514.
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Bevacizumab in Special Populations

• Women age/sex interaction
• Elderly with caution
• Anti-coagulated Safe
• Brain Metastases Safe
• Squamous Histology Not Safe

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E4599 Age/Sex/Bevacizumab Interaction

• Eligible patients from E4599 (N850) were divided
  into male and female cohorts by treatment (-/
  BEV)
• Separated into age groups of lt 60 or gt/ 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
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Age/Sex/BevacizumabAge 60 Cut-Point
lt 60 yo gt/ 60 yo
Women - BEV 11.0 mo N 75 13.8 mo N105
Women BEV 15.5 mo N85 12.8 mo N122
Men - BEV 9.3 mo N95 8.5 mo N158
Men BEV 12.4 mo N73 11.0 mo N137
Wakelee et al. Lung Cancer 2012
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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
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Elderly on E4599
Elderly ( 70) Elderly ( 70) Non-Elderly (lt 70) Non-Elderly (lt 70)
PC PCB PC PCB
CRPR 17 29 14 36
Median PFS 4.9 m 5.9 m P 0.063 4.4 m 6.2 m Plt0.001
Median survival 12.1 m 11.3 m P 0.4 9.6 m 12.8 m P 0.0027
Grade 3/4 Toxicity 70 yrs lt 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 gt 65, nor
in AVAiL
Laskin JTO 7203, 2012
Ramalingam JCO 2008, 2660
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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 Res2008141407
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ECOG 1505 Adj Chemo /- BevacizumabAccrual
1100/1500
RANDOM I Z E

• ELIGIBLE
• Resected IB-IIIA
• Lobectomy
• No prior chemo
• No planned XRT

STRATIFIED -Stage (IB4cm, 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

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VEGFR-TKIs
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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
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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
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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

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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

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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