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Abstract 7500

Abstract 7500. 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).

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Abstract 7500

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  1. Abstract 7500 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 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

  2. 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 • Pollak M. Nat Rev Cancer 2008;8:915-928 • Major JM et al. J Clin Endocrinol Metab. 2010;95:1054-9. • Laughlin GA et al. J Clin Endocrinol Metab. 2004; 89:114-20.

  3. Figitumumab(CP-751,871) Fully human IgG2 subtype monoclonal antibody against the IGF-1R with a T1/2 of approximately28 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 • Cohen et al. Clin Cancer Res 2005;11:2063-73 • Gualberto A. Expert Opin Biol Ther 2010;10:575-85 • Olmos et al. Lancet Oncol 2010;11:129-35 • Karp et al. J Clin Oncol. 2009 27:2516-22

  4. Study A1016: Phase III Study of Carboplatin + Paclitaxel +/- Figitumumab in 1st Line NSCLC of non-adenocarcinoma histology RANDOMIZE Figitumumab (20 mg/kg) Paclitaxel Carboplatin Key Entry Criteria • Histology other than Adenocarcinoma • Brain mets allowed • Adjuvant >12 month prior N = 410 Paclitaxel Carboplatin N = 410 N=820

  5. Rationale for Studying Figitumumab in Non-Adenocarcinoma Histologies • High IGF-1R expression in squamous cell carcinoma1,2 • High activity of the paclitaxel, carboplatinand 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 • Gualberto et al. J Clin Oncol 27:15s, 2009 (suppl; abstr 8091) • Dziadziuszko et al. J Clin Oncol 28; 2174-80, 2010 • Karp et al. J Clin Oncol 27:15s, 2009 (suppl; abstr 8072)

  6. Baseline Patient Characteristics

  7. Baseline PatientCharacteristics (cont.)

  8. Most Frequent Grade 3-5 Adverse Events (>5% for PCF) *Glucose levels in grade 3 hyperglycemia: 251–500 mg/dL; grade 4 >500 mg/dL

  9. AEs with the Largest Difference between Study Arms

  10. Overall Survival PC mOS = 10.3 mo % Probability of Survival PCF mOS = 8.5 mo HR (95%CI):1.23 (1.0,1.5), p=0.051 Months

  11. Overall Survival by Subsets: HR 95% CI Clinical Parameters did not Provide Positive Subsets Favors PCF Favors PC Overall Never or Ex Smoker Current Smoker Stage IIIB Stage IV Non-squamous Squamous ECOG PS 0 ECOG PS 1 Female Male 0.6 1.0 1.6 2.7 HR

  12. Phase 2 Biomarker Analysis Suggested a Free Plasma (unbound to IGFBPs) IGF-1/Treatment Interaction Free IGF-1 quartiles; Study 1002 12 10 8 6 4 2 0 PC P=0.0533 P=0.0009 PC + F 10mg/kg PC + F 20 mg/kg PFS (months) 4 months 1st 2nd 3rd 4th (>0.9 ng/mL) Hixon et al. J Clin Oncol. 27:15s, 2009 (abstr 3539)

  13. OS of PCF improved at high Free IGF-1levels in the Phase 3 Study (1016) Median OS above Free IGF-1 Criterion Hazard Ratio above Free IGF-1 Criterion 12 1.4 PCF 1.2 10 Hazard Ratio PCF/PC Median OS (months) 1.0 8 PC 0.8 6 0.6 0.7 0.8 0.9 1.0 1.1 1.2 0.4 0.6 0.81.0 1.2 Free IGF - 1 Criterion (ng/mL) Free IGF - 1 Criterion (ng/mL) (pre-treatment) (pre-treatment)

  14. Median OS at Free IGF-1 <1.0 ng/ml Favored PC 1.0 0.8 0.6 0.4 0.2 0.0 PC mOS = 10.3 mo HR (95% CI): 1.40 (1.0, 1.9) Survival probability PCF mOS = 7.0 mo N=324 (Provision of samples for pharmacodynamics was optional) 0 5 10 15 20 Time (months)

  15. Median OS at Free IGF-1 1.0 ng/ml Favored PCF 1.0 0.8 0.6 0.4 0.2 0.0 PCF mOS = 10.2 mo HR (95% CI): 0.97 (0.6, 1.7)* Survival probability PC mOS = 7.0 mo N=125 (Provision of samples for pharmacodynamics was optional) 0 5 10 15 20 Time (months) * Additional follow up is necessary

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

  17. Grade 5 AEs within the First 60 daysLow Free IGF-1 Defines Early Grade 5 PCF Toxicity Percentage of pts 8.6% 4.6% 4.3% 7.8%

  18. 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

  19. 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

  20. 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

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