Randomized, Open Label, Phase III Trial

of Figitumumab in Combination with Paclitaxel and Carboplatin

versus Paclitaxel and Carboplatin in Patients

with Non-Small Cell Lung Cancer (NSCLC)J Jassem, CL Langer, DD Karp, T Mok,

S Novello, K Park, J Strausz, RJ Benner, S Green and A Gualberto

Abstract 7500

Medical University, Gdansk, Poland; Abramson Cancer Center, Philadelphia, PA;

MD Anderson Cancer Center, Houston, TX; Chinese University, Hong Kong, New Territories; University of Turin, Italy; Sungkyunkwan University, Seoul,

Korea; Koranyi Natl. Inst. for Pulmonology, Budapest, Hungary; Pfizer Oncology, New London, CT

Insulin Like Growth Factor 1 Receptor

• Central component of a signal transduction pathway that includes the IGF-1 and IGF-2 ligands and their binding proteins (IGFBPs 1 to 7)1

– IGFBPs regulate IGFs bioavailability and biological activity

• IGFs are survival factors for normal and cancer cells

– High circulating IGF-1 levels are associated with increased risk of cancer related death2

– Low circulating IGF-1 levels are associated with increased risk of heart failure and myocardial events3

1. Pollak M. Nat Rev Cancer 2008;8:915-928 2. Major JM et al. J Clin Endocrinol Metab. 2010;95:1054-9.3. Laughlin GA et al. J Clin Endocrinol Metab. 2004; 89:114-

20.

Figitumumab (CP-751,871)

Fully human IgG2 subtype monoclonal antibody against the IGF-1R with a T1/2 of approximately 28 days1

Well tolerated as a single agent and in combination with chemotherapy/targeted agents in early studies2

Phase I single-agent activity in Ewing’s sarcoma3

Phase II activity in first-line NSCLC in combination with paclitaxel/carboplatin4

1. Cohen et al. Clin Cancer Res 2005;11:2063-732. Gualberto A. Expert Opin Biol Ther 2010;10:575-853. Olmos et al. Lancet Oncol 2010;11:129-354. Karp et al. J Clin Oncol. 2009 27:2516-22

Study A1016: Phase III Study of Carboplatin

+ Paclitaxel +/- Figitumumab in 1st Line NSCLC

of non-adenocarcinoma histologyTrial Design Endpoints Stratification Started

Global, multi-center, randomized, open-label

Primary: OSSecondary: PFS, ORR, safety, QoL, biomarkers, pharmacoeconomics

• Gender• Histology (Sq vs non-Sq)• Prior Adj Chemo (Y/N)

2Q08

Key Entry Criteria

● Histology other than Adenocarcinoma

● Brain mets allowed

● Adjuvant >12 month prior

RRAANNDDOOMMIIZZEE

RRAANNDDOOMMIIZZEE

N=820

Figitumumab (20 mg/kg)Paclitaxel

Carboplatin

Paclitaxel Carboplatin

N = 410

N = 410

Rationale for Studying Figitumumab

in Non-Adenocarcinoma Histologies

• High IGF-1R expression in squamous cell carcinoma1,2

• High activity of the paclitaxel, carboplatin and figitumumab combination in squamous cell carcinoma

ORR = 64%, N=42, single arm phase 2 study3

• No significant difference in the toxicity of figitumumab in squamous cell carcinoma vs other histologies3

• No regulatory requirement for the combination of paclitaxel, carboplatin and figitumumab with bevacizumab in non-adenocarcinoma histologies

1. Gualberto et al. J Clin Oncol 27:15s, 2009 (suppl; abstr 8091)

2. Dziadziuszko et al. J Clin Oncol 28; 2174-80, 2010 3. Karp et al. J Clin Oncol 27:15s, 2009 (suppl; abstr 8072)

Baseline Patient CharacteristicsVariable PCF (N=342) PC (N=339)

Gender Male Female

76%23%

77%23%

Age Median 62 years 62 years

Histology Squamous Adenosquamous Large Cell Other

86%4%8%1%

85%6%8%2%

ECOG 0 1

33% 66%

34% 64%

Prior Adjuvant Chemo

5% 4%

Variable PCF (N=342) PC (N=339)

Smoking Status Current Smoker Ex Smoker Never Smoker

42%49%10%

42%49%10%

Region Eastern Europe North America Western Europe Other

42%23%16%19%

42%17%20%20%

Race White Asian Black Other

77% 16%3%4%

80% 17%1%2%

HbA1c >6.5% 15% 12%

History of Diabetes

15% 10%

Baseline Patient Characteristics (cont.)

Most Frequent Grade 3-5 Adverse Events

(>5% for PCF)

Variable PCF (N=338)

PC (N=333)

Neutropenia 19% 18%

Hyperglycemia* 13% 1%

Asthenia 8% 5%

Thrombocytopenia 8% 6%

Peripheral neuropathy

7% 7%

Anorexia 7% 2%

Anemia 6% 7%

Fatigue 6% 4 %

Pneumonia 6% 3%

Dehydration 6% 1%

*Glucose levels in grade 3 hyperglycemia: 251–500 mg/dL; grade 4 >500 mg/dL

AEs with the Largest Difference between Study Arms

All Grades & (Grades 3-5)

PCF (N=338) PC (N=333)

Anorexia 39% (7%) 23% (2%)

Nausea 39% (4%) 30% (1%)

Fatigue 32% (6%) 25% (4%)

Diarrhea 30% (4%) 12% (1%)

Vomiting 25% (3%) 13% (1%)

Hyperglycemia 23% (13%) 5% (1%)

Asthenia 22% (8%) 18% (5%)

Weight loss 19% (3%) 8% (<1%)

Dehydration 12% (6%) 3% (1%)

Grade 5 PCF (N=338) PC (N=333)

Infection 3.5% 0.6%

Cardiovascular 3% 1.2%

Overall Survival

PC

mOS = 10.3 mo

PCF

mOS = 8.5 mo

Months

% P

rob

ab

ilit

y o

f S

urv

ival

HR (95%CI):1.23 (1.0,1.5), p=0.051

Event Total

PCF 184 342

PC 165 339

Overall Survival by Subsets: HR 95% CIClinical Parameters did not Provide Positive

SubsetsFavors PCF Favors PC

Overall

Stage IIIB

Current SmokerNever or Ex Smoker

Stage IV

Non-squamousSquamous

FemaleMale

ECOG PS 0

ECOG PS 1

0.6 1.0 1.6 2.7

HR

12

10

8

6

4

2

0

Free IGF-1 quartiles; Study 1002

PFS

(m

on

ths)

1st 2nd 3rd 4th (>0.9 ng/mL)

PC PC + F 10 mg/kg

PC + F 20 mg/kg

P=0.0533 P=0.0009

Phase 2 Biomarker Analysis Suggested a Free Plasma (unbound to IGFBPs) IGF-1/Treatment

Interaction

4 m

on

ths

Hixon et al. J Clin Oncol. 27:15s, 2009 (abstr 3539)

OS of PCF improved at high Free IGF-1

levels in the Phase 3 Study (1016)

Free IGF-1 Criterion (ng/mL)

0.6 0.7 0.8 0.9 1.0 1.1 1.2 0.8

1.0

1.2

1.4

Free IGF-1 Criterion (ng/mL)

0.4 0.6 0.8 1.0 1.2

12

10

8

6

PCF

PC

Median OS aboveFree IGF-1 Criterion

Hazard Ratio above

Free IGF-1 Criterion

Hazard

Rati

o P

CF/P

C

Med

ian

OS

(m

on

ths)

(pre-treatment) (pre-treatment)

PC mOS = 10.3 mo

PCF mOS = 7.0 mo

1.0

0.8

0.6

0.4

0.2

0.0

Su

rviv

al p

rob

ab

ilit

y

Event Total

PCF 109 185

PC 75 139

Censored

0 5 10 15 20

Median OS at Free IGF-1 <1.0 ng/ml Favored PC

N=324 (Provision of samples for pharmacodynamics was optional)

Time (months)

HR (95% CI): 1.40 (1.0, 1.9)

PCF mOS = 10.2 mo

PCmOS = 7.0 mo

1.0

0.8

0.6

0.4

0.2

0.0

Su

rviv

al p

rob

ab

ilit

y

Event Total

PCF 44 86

PC 19 39

Censored

0 5 10 15 20Time (months)

Median OS at Free IGF-1 1.0 ng/ml Favored PCF

N=125 (Provision of samples for pharmacodynamics was optional)

HR (95% CI): 0.97 (0.6, 1.7)*

* Additional follow up is necessary

Grade 5 AEs by Free IGF-1Higher PCF Grade 5 Toxicity at Low Free IGF-1

Arm PCF PC

Free IGF1 (ng/mL) <1 ≥1 <1 ≥1

Patients (N) 184 86 138 38

Infection 5% 3% - 3%

Hemorrhage/hemoptysis

4% 2% 2% 3%

Cardiovascular/ cardiopulmonary failure

4% 1% 2% -

Renal failure 1% 1% - -

Respiratory failure 2% 1% - -

Death, health deterioration

3% 3% 5% 5%

Other 1% 1% 2% -

Grade 5 AEs within the First 60 days

Low Free IGF-1 Defines Early Grade 5 PCF Toxicity

Arm PCF (N=270) PC (N=176)

Free IGF-1 (ng/mL) <1 ≥1 <1 ≥1

Patients (N) 184 86 138 38

Organ failure 3.8% - 0.7% -- Cardiovascular (CV failure, MI) 2.7% - 0.7% -

- Respiratory 0.5% - - -

- Renal 0.5% - - -

Infection (Pneumonia/Sepsis)

2.7% 2.3% - 2.6%

Hemorrhage/Hemoptysis 1.6% 2.3% 1.4% 2.6%

Other 0.5% - 2.2% 2.6%

8.6% 4.6% 4.3% 7.8%Percentage of pts

Study 1016 Status

• Closed to new accrual on Sept 28, 2009 due to an imbalance in deaths related to therapy by investigator: 8 (PCF) vs 0 (PC)

– SAEs in the PCF arm included asthenia, dehydration, hyperglycemia and hemoptysis

– More cardiac events (all grades) noted on PCF (15 vs 5)

• Closed permanently to new accrual on Dec 21, 2009 (N=681) after a planned interim analysis at 225 events due to a survival HR that crossed the pre-specified futility boundary

• Biomarker analysis continues to design future studies

Conclusions

• Addition of figitumumab to standard chemotherapy did not increase overall survival in advanced non-adenocarcinoma NSCLC

• Potential benefit of figitumumab may be compromised by its side effects

• Risk/benefit of figitumumab in addition to standard chemotherapy appears to be related to the levels of circulating free IGF-1

• Additional research is necessary to verify the potential of benefit in patients with high free IGF-1

Acknowledgements

• 1016 Study Investigators and Clinical Site Personnel

• 1016 Study Team and Colleagues• M Hixon, PhD (Brown University) for free IGF-1

data• Our Patients and their Families