CTOS 2010

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, USA2Washington University School of Medicine, St. Louis, MO, USA3John Hopkins Medical Center, Baltimore, MD, USA4Vall d’Hebron University Hospital, Barcelona, Spain5Amgen Inc, Thousand Oaks, CA, USA6Amgen Limited, Uxbridge, UK7University of Chicago Cancer Research Center, Chicago, IL, USA

Abstract: 890126

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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

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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

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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

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PHASE 2 STUDY OBJECTIVE

• To estimate the efficacy of conatumumab in combination with AMG 479 as measured by the objective response rate (ORR)

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METHODSPhase 2 Study Schema

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.

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

SarcomaAMG 479 18 mg/kg

Conatumumab 15 mg/kg

NSCLC (squamous)AMG 479 18 mg/kg

Conatumumab 15 mg/kg

SarcomaAMG 479 18 mg/kg

Conatumumab 15 mg/kg

NSCLC (non-squamous)AMG 479 18 mg/kg

Conatumumab 15 mg/kg

PancreaticAMG 479 18 mg/kg

Conatumumab 15 mg/kg

OvarianAMG 479 18 mg/kg

Conatumumab 15 mg/kg

CRCAMG 479 18 mg/kg

Conatumumab 15 mg/kg

ENROLLMENT

Planned N = 15 per cohort

Every 3 weeks for ≤ 24 months

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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

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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)

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n (%) Sarcoma Patients All Patientsa

Patients enrolled 16 70

Patients who received conatumumab 15 (94) 68 (97)and AMG 479

Patients who discontinued 12 (75) 50 (71)conatumumab and AMG 479

Ineligibility determined 0 (0) 1 (1)

Adverse event 2 (13)b 4 (6)c 3 (4)d

Full consent withdrawn 0 (0) 3 (4)

Lost to follow-up 0 (0) 1 (1)

Death 0 (0) 1 (1)

Partial consent withdrawn 0 (0) 1 (1)

Other 0 (0) 1 (1)

Disease progression 10 (63) 38 (54)c 39 (56)

RESULTSPatient Disposition

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.

• Median number of infusions per patient = 2 (range, 1 to 7)

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Sarcoma All Patients(N = 15)a (N = 68)a

Sex - n (%)

Male 5 (33) 35 (51)

Female 10 (67) 33 (49)

Race/ethnicity - n (%)

White or Caucasian 14 (93) 58 (85)

Black or African American 0 (0) 5 (7)

Hispanic or Latino 1 (7) 2 (3)

Asian 0 (0) 3 (4)

Age (years) at randomization

Median (range) 54.0 (29 to 65) 58.5 (29 to 83)

Age group at randomization - n (%)

< 65 years 14 (93) 47 (69)

≥ 65 years 1 (7) 21 (31)

≥ 75 years 0 (0) 4 (6)

RESULTS (continued)

Patient Demographics

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

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RESULTS (continued)

Baseline Disease

Safety analysis set.

• Prior treatment– Surgery, 14 (93%)

– Radiotherapy, 11 (73%)

– Chemotherapy, 15 (100%)

Sarcoman (%) (N = 15)

Bone sarcoma 3 (20)Ewing 1 (7)Fibrosarcoma 1 (7)Osteosarcoma 1 (7)

Soft tissue sarcoma 12 (80)Leiomyosarcoma 5 (33)Synovial sarcoma 2 (13)Myxoid liposarcoma 1 (7)Low grade myofibroblastic sarcoma 1 (7)Connective tissue sarcoma 1 (7)Malignant peripheral nerve sheath sarcoma 1 (7)Undifferentiated pleomorphic sarcoma 1 (7)

Disease stage at enrollmentStage III 1 (7)Stage IIIA 0 (0)Stage IV 14 (93)

ECOG performance status at screening - n (%)0 6 (40)1 9 (60)

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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.

Sarcoman (%) (N = 15)

Patients with measurable disease at baseline 15

Number of objective responders 0 (0)

Best overall response assessmenta

Confirmed CR 0 (0)Confirmed PR 0 (0)SD 5 (33)Progressive disease 10 (67)

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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

Tumor Type Duration of SD

38-year-old Synovial sarcoma 46 weeksHispanic female Still on treatment

58-year-old Leiomyosarcoma 41 weekswhite female

51-year-old Neurofibrosarcoma 18 weekswhite male

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Sarcoman (%) (N = 15)

Patients reporting at least 1 AEa 11 (73)Pyrexia 4 (27)Back pain 4 (27)Chills 3 (20)Nausea 3 (20)Fatigue 2 (13)Vomiting 2 (13)Abdominal pain upper 2 (13)Rash 2 (13)

Grade 3 AEs 3 (20)Abdominal pain upper 1 (7)Constipation 1 (7)Gastrointestinal hemorrhage 1 (7)Peripheral motor neuropathy 1 (7)Somnolence 1 (7)

Patients with conatumumab-or AMG 479-related AEs 8 (53)

RESULTS (continued)

Safety

Safety analysis set. aIn at least 2 patients. AE, adverse event.

• There were no grade 4 or grade 5 AEs

• There were no grade ≥ 3 conatumumab- or AMG 479-related AEs

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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

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REFERENCES

1. Beltran PJ, et al. Mol Cancer Ther. 2009;8:1095-1105.

2. Kaplan-Lefko PJ, et al. Cancer Biol Ther. 2010;9:618-631.

3. Ashkenazi A and Herbst RS. J Clin Invest. 2008;118:1979-1990.

4. Olmos D, et al. Cancer J. 2010;16:183-94.

5. Amgen data on file.

6. Chawla SP, et al. J Clin Oncol. 2010;28:abstr 3102.

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ACKNOWLEDGEMENTS

• This trial was sponsored by Amgen Inc., ClinicalTrials.gov ID: NCT00819169

• Kathryn Boorer from Amgen Inc. provided writing assistance