A Phase 1b Study of Demcizumab plus and in Patients with 1st line Non-Squamous Non-Small Cell Lung Cancer (NSCLC). 1 McKeage M, 2 Kotasek D, 3 Millward M, 4 Markman B, 5 Jameson M, 6 Hidalgo M, 7 D Harris, 8 Stagg R, 8 Dupont J, 9 Hughes B. 1University of Auckland, Auckland, New Zealand; 2 Adelaide Cancer Centre, Adelaide, Australia; 3 Sir Charles Gairdner Hospital, Perth, Australia; 4 Monash Medical Centre, Monash University, Melbourne, Australia; 5 Waikato Hospital, Hamilton, New Zealand; 6 CNIO-CIOCC-START, Madrid, Spain; 7 Christchurch Hospital, Christchurch, New Zealand; 8 OncoMed Pharmaceutical, Redwood City, CA; and 9 The Royal Brisbane and Woman’s Hospital, Brisbane, Australia.

BACKGROUND RESULTS

There is accumulating evidence that the cell types within tumors are Adverse Events (All Grades) Occurring in > 15% of Patients Related Grade 3-5 Adverse Events > 10% by Dose Cohort (mg/kg) Two Patients Who Received 5mg/kg Q3wk are Progression Free > 16 months heterogeneous and that a subset of the cells retain the property to self- Study Design by Dose Cohort (mg/kg) (N = 20) renew and give rise to more differentiated progeny. These cells, called (N = 20) cancer stem cells (CSCs) or tumor initiating cells drive tumor growth and Pemetrexed, Dose Level – mg/kg 5 2.5 5 Total Patient Case: Carboplatin Prior to Risk After Risk After Risk metastasis and are more resistant to and radiotherapy than + Dose Level – mg/kg 5 2.5 5 Total (%) Mitigation Mitigation Mitigation Demcizumab * Prior to Risk After Risk After Risk the remaining tumor cells. The ability to characterize the CSCs through Mitigation Mitigation Mitigation N 6 6 8 20 • 62 yo male with Stage IV non-squamous (adenocarcinoma) NSCLC. Demcizumab surface markers and functional limiting tumor dilution assays, using First-line Stage IIIb/VI 5 mg/kg** Maintenance N 6 6 8 20 Hypertension 2 4 3 4 (20%) minimally passaged human tumors, has enabled the identification of novel Non-Squamous Until • Disease in left lung, mediastinum, pleural effusion, pericardial effusion, and bone. NSCLC agents that specifically target the CSC population. One pathway which 2.5 mg/kg*** Disease Progression Nausea 5 6 8 19 (95%) Neutropenia 2 1 4 3 (15%) appears critical for the CSCs is the Notch pathway. The pathway is • Treated with demcizumab at 5mg/kg Q3wk (for 2 cycles) and carboplatin + pemetrexed (for 6 cycles) 5 mg/kg*** Alanine Aminotransferse 3 0 0 2 (10%) comprised of 4 Notch receptors (1-4) and 5 ligands, Jagged (1-2) and delta- Vomiting 3 6 8 17 (85%) increased like ligand (DLL1, 3 and 4). The DLL4 ligand contributes to CSC self- Expansion Cohort • xx Fatigue 3 6 7 16 (80%) renewal and vascular development. Demcizumab is a humanized IgG2 antibody that blocks DLL4. In minimally passaged human tumor xenografts, * Once every 21 days for 6 cycles ** Prior to Risk Mitigation *** After Risk Mitigation Constipation 3 3 6 12 (60%) demcizumab was observed to have activity against a variety of tumors RECIST 1.1 - Best Overall Response Anemia 2 2 6 10 (50%) including colorectal cancer, breast cancer, lung cancer, , (N = 20) Patient Demographics and ovarian cancer. The impact of treatment on the frequency Hypertension 2 4 3 9 (45%) of tumorigenicity was assessed using a limiting dilution assay. In several Dose Cohort – mg/kg* 5 2.5 5 Total Dose Level - 5 2.5 5 Total models, using different chemotherapeutic agents, while the chemotherapy Prior to Risk After Risk After Risk Diarrhea 3 2 4 9 (45%) Prior to Risk After Risk After Risk Mitigation Mitigation Mitigation mg/kg Mitigation Mitigation Mitigation alone decreased tumor volume, the frequency of tumor initiating cells was N 6 6 8 20 increased in the residual tumor. In contrast, demcizumab alone decreased Dyspnea 3 1 4 8 (40%) Partial Response 2 4 1 7 (35%) the frequency of CSCs and the greatest reduction was observed when Median age (years) 66.5 59.5 65.0 64.0 Neutropenia 3 1 4 8 (40%) demcizumab was combined with chemotherapy. The single agent Phase Stable Disease 2 2 5 9 (45%) Male/Female 2/4 2/4 2/6 6/14 1a study of demcizumab has been completed. Reduction in tumor size was Decreased appetite 2 2 4 8 (40%) observed in various tumor types including NSCLC. Prior Surgery 0 0 1 1 Progressive 0 0 1 1 (5%) Headache 2 3 2 7 (35%) Disease METHODS Prior Neoadjuvant/Adjuvant Therapy 0 0 0 0 Thrombocytopenia 3 2 2 7 (35%) This was an open-label Phase 1b dose escalation study of demcizumab Not Evaluable 2 0 1 3 (15%) plus pemetrexed and carboplatin in chemotherapy naïve patients with stage Cough 1 1 3 5 (25%) IIIb/IV non-squamous NSCLC. Prior to enrollment, patients underwent Prior Radiotherapy 2 1 5 8 Platelet Count Decreased 0 0 4 4 (20% screening to determine study eligibility. * Once every 3 weeks Aspartate Aminotransferase 3 1 0 4 (20%) The study endpoints included determining the: increased Day 0 Day 480 • Safety profile Pharmacokinetics (n = 10)* % Change in Tumor Size

• Maximum tolerated dose (MTD) Gastroesphogeal reflux 1 3 0 4 (20%) (RECIST Response)** Progression free for 16+ months since last treatment. • Immunogenicity 50 • Pharmacokinetics 40 • Antitumor activity

• Biomarkers of Notch signaling and CSCs in blood Related Adverse Events (All Grades) > 10% by Dose Cohort (mg/kg) 30 (N = 20)1, 2 20 Conclusions Treatment regimen once every 21 days for 6 cycles: 10 • Carboplatin (area under the concentration-time curve, 6 mg/mL x min) 1 2 5 2.5 5 Total 0 • Pemetrexed 500 mg/m Dose Level – mg/kg 1 • Demcizumab is a first-in-class anti-DLL4 humanized with a dual Prior to Risk After Risk After Risk • Folic acid, vitamin B12 and dexamethasone Mitigation Mitigation Mitigation -10 mechanism of action; i.e., anti- and anti-angiogenic effects 1 Progressive disease due to a new lesion • Demcizumab – The subjects in the first cohort received demcizumab N 6 6 8 20 -20 5 mg/kg once every 3 weeks. Dosing of subjects in this cohort was paused • This is an ongoing Phase 1b dose escalation study of demcizumab, a cancer stem -30 due to emerging evidence of cardiotoxicity secondary to demcizumab in Fatigue 3 3 3 9 (45%) cell targeting monoclonal antibody, plus pemetrexed and carboplatin in -40 other ongoing studies. The protocol was subsequently amended to include % Tumor Size in Change chemotherapy naïve stage IIIb/IV NSCLC patients Hypertension 2 4 3 9 (45%) a risk mitigation plan to enhance the therapeutic index of demcizumab in an -50 effort to maximize efficacy and manage tolerability. The risk mitigation plan Nausea 1 2 5 8 (40%) -60 • The demcizumab 2.5 and 5 mg/kg once every 3 week dose cohorts were deemed to included intermittent dosing and cardiac monitoring using B-type natriuretic Neutropenia 2 1 4 7 (35%) -70 have an acceptable safety profile by the DSMB and enrollment is continuing at 5 mg/kg once peptide (BNP) testing and echocardiography, In addition, a every 3 weeks. cardioprotective medication (i.e, an angiotensin -converting enzyme inhibitor 5.0* 2.5* 5.0* Vomiting 1 2 2 5 (25%) or carvedilol) was administered to patients with rising BNPs. Upon review Dose (mg/kg) Decreased appetite 2 0 2 4 (20%) • Concomitant pemetrexed and carboplatin did not appear to influence the of the 5 mg/kg data from the 1st cohort of patients, only limited evidence of pharmacokinetics of demcizumab cardiotoxicity was observed. However, in order to proceed cautiously, Diarrhea 2 0 1 3(15%) 1 Progression due to new lesion subjects in the 2nd cohort were treated with demcizumab 2.5 mg/kg once * Once every 3 weeks • Demcizumab was well tolerated. The most common drug related toxicities every 3 weeks. Subsequently subjects in cohort 3 were once again treated Anemia 1 0 2 3(15%) with 5 mg/kg once every 3 weeks. were fatigue and hypertension. The hypertension was managed with anti-hypertensives. BNP Increased 1 0 2 3 (15%) Deaths on Study

Maintenance therapy: • There were no significant declines in the left ventricular ejection fraction and no cases of Dyspnea 3 0 0 3 (15%) (N = 20) Demcizumab once every 3 weeks. congestive heart failure indicating that the risk mitigation plan was effective. Dose Level- mg/kg 5 2.5 5 Total Aspartate Aminotransferase 3 0 0 3 (15%) A DSMB reviewed the data from each dose cohort after the last subject in • Seven of 16 (44%) evaluable patents had a RECIST partial response and 2 patients in the increased that cohort has been on study for 56 days to decide whether it was safe to * Pharmacokinetic samples were collected pre- and 5-min post-dose on Days 21 and 63. Concentration Deaths 0 1* 0 1 demcizumab 5 mg/kg dose cohort have been progression free for 16+ months. proceed to the next dose cohort. Data through September 5, 2012 are data are shown as symbols; Lines are the 5th, 50th and 95th percentiles of simulated concentration Alanine Aminotransferase 3 0 0 3 (15%) based on the population analysis of data combined from 4 studies (1380 samples from 80 patients).. increased presented. An expansion cohort of six additional patients will be enrolled at • Disease control (i.e., SD + PR) achieved in 16/17 (94%) patients. the maximum tolerated dose of demcizumab. • t ½ from Phase 1a study = 16 hours 1. Events considered to be possibly related to demcizumab. 2. No cases of congestive heart failure. * Cerebral vascular accident considered to be unrelated to demcizumab. • Pemetrexed & carboplatin did not influence the demcizumab pharmacokinetics • These data suggest that demcizumab warrants further development in the treatment of

NSCLC.