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