1 / 20

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).

hope
Download Presentation

Abstract 7500

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related