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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 Kindler 7. 1 Sarcoma Oncology Center, Santa Monica, CA, USA

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efficacy and safety of conatumumab plus amg 479 in patients with advanced sarcoma

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

introduction amg 479 mechanism of action
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
introduction continued conatumumab mechanism of action
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
introduction continued
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
phase 2 study objective
PHASE 2 STUDY OBJECTIVE
  • To estimate the efficacy of conatumumab in combination with AMG 479 as measured by the objective response rate (ORR)
methods phase 2 study schema
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

methods continued study design
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
methods continued endpoints
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)
results patient disposition
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.

results continued patient demographics
RESULTS (continued) Patient Demographics

aSafety analysis set. Two patients, 1 with sarcoma and 1 with squamous NSCLC, did not receive study drugs.

results continued baseline disease
RESULTS (continued)Baseline Disease
  • Prior treatment
    • Surgery, 14 (93%)
    • Radiotherapy, 11 (73%)
    • Chemotherapy, 15 (100%)

Safety analysis set.

results continued tumor response
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.

results prolonged sd
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
results continued safety
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.

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