randomized, open label, phase iii trial of figitumumab in combination with paclitaxel and...

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