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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