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

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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 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 dHebron 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
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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 gt 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
Planned N 15 per cohort
CONTINUATION OF TREATMENT
Sarcoma AMG 479 18 mg/kg Conatumumab 15 mg/kg
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

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
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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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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.
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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

• Prior treatment
• Surgery, 14 (93)
• Radiotherapy, 11 (73)
• Chemotherapy, 15 (100)

Safety analysis set.
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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.
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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

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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.
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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.
   200981095-1105.
2. Kaplan-Lefko PJ, et al. Cancer Biol Ther.
   20109618-631.
3. Ashkenazi A and Herbst RS. J Clin Invest.
   20081181979-1990.
4. Olmos D, et al. Cancer J. 201016183-94.
5. Amgen data on file.
6. Chawla SP, et al. J Clin Oncol. 201028abstr
   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