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Efficacy and Safety of Conatumumab Plus AMG 479 in Patients With Advanced Sarcoma

This study investigates the efficacy and safety of combining Conatumumab and AMG 479 in patients with advanced sarcoma. Results show promising outcomes and manageable side effects.

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Efficacy and Safety of Conatumumab Plus AMG 479 in Patients With Advanced Sarcoma

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  1. Efficacy and Safety of Conatumumab Plus AMG 479 in Patients With Advanced Sarcoma S Chawla,1 AC Lockhart,2 N Azad,3 E Elez,4 F Galimi,5 N Baker,6 YJ Hei,5 H Kindler7 1Sarcoma Oncology Center, Santa Monica, CA, USA 2Washington University School of Medicine, St. Louis, MO, USA 3John Hopkins Medical Center, Baltimore, MD, USA 4Vall d’Hebron University Hospital, Barcelona, Spain 5Amgen Inc, Thousand Oaks, CA, USA 6Amgen Limited, Uxbridge, UK 7University of Chicago Cancer Research Center, Chicago, IL, USA Abstract: 890126

  2. INTRODUCTIONAMG 479 Mechanism of Action • AMG 479 is an investigational, fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF1R) • Binds to IGF1R and prevents binding of its ligands, IGF-1 and IGF-21

  3. Conatumumab is an investigational, fully human monoclonal antibody against human death receptor 5 (DR5) Binds to DR5, activates caspases, and induces apoptosis2 INTRODUCTION (continued)Conatumumab Mechanism of Action

  4. INTRODUCTION (continued) • IGF1R inhibition and DR5 stimulation inhibit the growth of sarcoma cells3,4 • In preclinical models, activation of IGF1R can lead to resistance to DR5-induced apoptosis5 • Combining AMG 479 with conatumumab may prevent DR5 agonist-resistant cells from escaping apoptosis • A multicenter, open-label, phase 1b/2 study was conducted to investigate the efficacy and safety of conatumumab plus AMG 479 in patients with advanced solid tumors (phase 1b) and advanced non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer, ovarian cancer, or sarcoma (phase 2) • Among 4 patients with soft tissue sarcoma in the phase 1b study, 1 had stable disease (SD) for 24 weeks and 1 had SD after > 1 year on treatment6 • Here we present the results for sarcoma patients enrolled in the phase 2 study

  5. PHASE 2 STUDY OBJECTIVE • To estimate the efficacy of conatumumab in combination with AMG 479 as measured by the objective response rate (ORR)

  6. METHODSPhase 2 Study Schema Planned N = 15 per cohort CONTINUATION OF TREATMENT Sarcoma AMG 479 18 mg/kg Conatumumab 15 mg/kg LONG-TERM FOLLOW-UP NSCLC (squamous) AMG 479 18 mg/kg Conatumumab 15 mg/kg • KEY ELIGIBILITY • Confirmed locally advanced or metastatic disease • Measureable disease • ≥ 16 years old • ECOG PS of 0 or 1 • Adequate organ function • Informed consent • No uncontrolled CNS disease • No anti-cancer therapy ≤ 28 days before enrollment • No prior treatment with DR agonists nor IGF1R antagonists E N R O L L M E N T NSCLC (non-squamous) AMG 479 18 mg/kg Conatumumab 15 mg/kg Pancreatic AMG 479 18 mg/kg Conatumumab 15 mg/kg Ovarian AMG 479 18 mg/kg Conatumumab 15 mg/kg Sarcoma AMG 479 18 mg/kg Conatumumab 15 mg/kg aIf eligible. Two interim analyses of safety data were conducted after at least 15 patients and then 45 patients were enrolled and had completed 1 cycle of treatment. CRC AMG 479 18 mg/kg Conatumumab 15 mg/kg Every 3 weeks for ≤ 24 months

  7. METHODS (continued)Study Design • Multicenter, open-label, phase 1b/2 study of conatumumab in combination with AMG 479 • In the phase 1 study, the planned maximum target dose of conatumumab (15 mg/kg every 3 weeks) was determined to be safe and well tolerated (as determined by the incidence of dose-limiting toxicities) • The phase 2 study was opened for enrollment after the maximum target dose of conatumumab was determined • Patients received AMG 479 (18 mg/kg) followed by conatumumab (15 mg/kg) IV every 3 weeks for up to 24 months or until disease progression, intolerable adverse event, death, withdrawal of consent, or administrative decision • Tumors were imaged by CT or MRI every 6 weeks for 6 months and every 8 weeks thereafter

  8. METHODS (continued)Endpoints • Primary: ORR • Confirmed complete response (CR) plus partial response (PR) by RECIST v1.0 per investigator review • Secondary: time to response, duration of response, progression-free survival, incidence of adverse events and laboratory abnormalities, incidence of anti-conatumumab or anti-AMG 479 antibody formation, and PK (Cmax and Cmin for conatumumab and AMG 479)

  9. RESULTSPatient Disposition • Median number of infusions per patient = 2 (range, 1 to 7) aIncludes sarcoma (n = 16), squamous NSCLC (n = 4), non-squamous NSCLC (n = 11), CRC (n = 16), pancreatic cancer (n = 16), and ovarian cancer (n = 7). bDiscontinued AMG 479 and conatumumab, 1 due to grade 3 gastrointestinal hemorrhage (not attributed to study drugs); and 1 due to grade 3 constipation, somnolence, and peripheral motor neuropathy (not attributed to study drugs). cDiscontinued conatumumab. dDiscontinued AMG 479.

  10. RESULTS (continued) Patient Demographics aSafety analysis set. Two patients, 1 with sarcoma and 1 with squamous NSCLC, did not receive study drugs.

  11. RESULTS (continued)Baseline Disease • Prior treatment • Surgery, 14 (93%) • Radiotherapy, 11 (73%) • Chemotherapy, 15 (100%) Safety analysis set.

  12. RESULTS (continued)Tumor Response aA best overall response of SD required a radiologically determined response of SD or better no earlier than study day 35.

  13. RESULTSProlonged SD • Two other patients had SD at the week-6 assessment • All 5 SD patients had multiple lines of prior anticancer therapy, which failed

  14. RESULTS (continued)Safety • There were no grade 4 or grade 5 AEs • There were no grade ≥ 3 conatumumab- or AMG 479-related AEs Safety analysis set. aIn at least 2 patients. AE, adverse event.

  15. CONCLUSIONS • In this diverse and heavily pre-treated population of sarcoma patients: • Conatumumab plus AMG 479 was well tolerated • Prolonged SD (18 to 46+ weeks) was observed in 3 patients • Further study of this drug combination may be warranted

  16. REFERENCES • Beltran PJ, et al. Mol Cancer Ther. 2009;8:1095-1105. • Kaplan-Lefko PJ, et al. Cancer Biol Ther. 2010;9:618-631. • Ashkenazi A and Herbst RS. J Clin Invest. 2008;118:1979-1990. • Olmos D, et al. Cancer J. 2010;16:183-94. • Amgen data on file. • Chawla SP, et al. J Clin Oncol. 2010;28:abstr 3102.

  17. ACKNOWLEDGEMENTS • This trial was sponsored by Amgen Inc., ClinicalTrials.gov ID: NCT00819169 • Kathryn Boorer from Amgen Inc. provided writing assistance

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