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

Background AEs (All Grades) in >20% of Patients Pharmacokinetics %ChangeinRECISTTargetLesionSize% Change in RECIST Target Lesion Size Three Patients at DEM 5 mg/kg Q3W by Dose Level (mg/kg) Progression Free > 480 Days There is accumulating evidence that the cell types within tumors are heterogeneous •To assess the impact of pemetrexedand carboplatinon demcizumabPK, plasma 100 and that a subset of the cells retain the property to self-renew and give rise to more Dose Level – mg/kg 5 2.5 5 5 7.5 Total (%) samples were collected pre- and post-infusion on Study Days 21 and 63, and Pt 1: Stage IV NSCLC (adenocarcinoma) differentiated progeny. These cells, called cancer stem cells (CSCs) or tumor Expansion analyzed for demcizumab concentration. 80 initiating cells drive tumor growth and metastasis and are more resistant to N6686430 •Disease in left lung, mediastinum, pleural & pericardial effusions, bone •Treated with DEM at 5mg/kg Q3W & carboplatin+ pemetrexed and radiotherapy than the remaining tumor cells. The ability to Nausea 5 6 8 6 3 28 (93%) •Demcizumabclears slowly in patients with a population mean half-life of 16 days. 60 characterize the CSCs through surface markers and functional limiting tumor dilution (3 cycles), then carboplatin + pemetrexed 3 cycles off study assays, using minimally passaged human tumors, has enabled the identification of Vomiting 3 6 8 3 2 22 (73%) •Pemetrexedand carboplatindid not significantly alter the PK of demcizumab in •Progression free >480 days 40 novel agents that specifically target the CSC population. One pathway which patients. •Investigator noted tumor decreased >12 months after completing all therapy Fatigue 3 6 7 4 1 21 (70%) appears critical for the CSCs is the Notch pathway. The pathway is comprised of 4 20 Notch receptors (1-4) and 5 ligands, Jagged (1-2) and delta-like ligand (DLL1, 3 and Constipation 3 3 6 5 1 18 (60%) Day 0 Day 480 4). The DLL4 ligand contributes to CSC self-renewal and vascular development. Representative Pharmacokinetic Data Demcizumab is a humanized IgG2 antibody that blocks DLL4. In minimally Anemia 2 2 6 4 2 16 (53%) 0 5Q3W 5Q3W 5Q3W 2.5Q3 5Q3W 5Q3W 5Q3W 7.5Q3W 2.5Q3 5Q3W 5Q3W 5Q3W 5Q3W 5Q3W 2.5Q3W 2.5Q3W2.5Q3W 5Q3W 5Q3W 5Q3W 5Q3W 2.5Q3W 5Q3W ppgassaged human tumor xenografts, demcizumab was observed to have activity Size ge Tumor in Diarrhea 3 2 6 2 2 15 (50%) n against a variety of tumors including colorectal cancer, breast cancer, lung cancer, -20 , and ovarian cancer. The impact of treatment on the Dyspnea 3 1 7 3 0 14 (47%) frequency of tumorigenicity was assessed using a limiting dilution assay. In several % Cha -40 models, using different chemotherapeutic agents, while the chemotherapy alone Hypertension 2 4 4 1 0 11 (37%) decreased tumor volume, the frequency of tumor initiating cells was increased in the Neutropenia 3 1 3 3 1 11 (37%) -60 residual tumor. In contrast, demcizumab alone decreased the frequency of CSCs Pt 2: Stage IV NSCLC (adenocarcinoma) and the greatest reduction was observed when demcizumab was combined with Thrombocytopenia 3 2 2 4 0 11 (37%) •Disease in left and right lungs & pleural effusion chemotherapy. -80 Decreased appetite 2 2 4 1 1 10 (33%) •Treated with DEM at 5mg/kg Q3W & carboplatin+ pemetrexed (6 cycles) Methods Cough 1 1 4 3 1 10 (33%) -100 •Progression free >569 days Alanine aminotranferase 300 4 2 9 (30%) This was an open-label Phase 1b dose escalation study of demcizumab plus increased RECIST Best Overall Response pemetrexed and carboplatin in chemotherapy naïve patients with stage IIIb or IV Edema 0 0 8 1 0 9 (30%) NSCLC. Prior to enrollment, patients underwent screening to determine study (n= 30) Aspartate Aminotransferse 311 1 1 7 (23%) eligibility. The study endpoints included the determination of the safety profile, Dose Level - mg/kg 5 2.5 5 5 7.5 Total increased maximum tolerated dose (MTD), immunogenicity, pharmacokinetics, antitumor Grey lines: expected range (5th, 50th, 95th percentiles) of concentration-time profiles based on Expansion (23 Evaluable) activity and biomarkers of Notch signaling and CSCs in blood. Patients received Phase 1a population PK analysis; symbols: observed individual data in this study by nominal time. BNP increased 1 0 5 1 0 7 (23%) Partial Response 2 4 2 1 0 9 (39%) demcizumab (2.5 or 5 mg/kg), pemetrexed 500 mg/m2 and carboplatin (AUC = 6) every 3 weeks for 6 cycles followed by maintenance DEM (first 4 cohorts) or Headache 2 3 2 0 0 7 (23%) Reversible Cardiopulmonary Toxicity* StableDisease 2 2 4 2 1 11 (48%) demcizumab (7.5 mg/kg), pemetrexed 500 mg/m2 and carboplatin (AUC = 6) every 3 Progressive Disease 0 0 1 2 0 3 (13%) weeks for 4 cycles followed by pemetrexed every 3 weeks (5th cohort) until disease (Grade 3) Pt 3: Treated with DEM 5 mg/kg Q3W & carboplatin + pemetrexed (1 cycle), progression. Folic acid, vitamin B12 and dexamethasone were administered as Related AEs (All Grades) >15% of Pts Not Evaluable 2 0 1 1 3 7 then carboplatin + pemetrexed followed by pemetrexed maintenance off study pemetrexed pre-medication. Dosing of subjects in the 1st cohort was paused due to Dose Level- mg/kg 5 2.5 5 5 7.5 Total emerging evidence of cardiotoxicity secondary to demcizumab in other ongoing by Dose Level (mg/kg) Expansion studies. The protocol was subsequently amended to include a risk mitigation plan N6686430 Duration on Study & Summary which included cardiac monitoring using B-type natriuretic peptide (BNP) testing Pulmonary HTN 002**0 02 (7%) Dose Level – mg/kg 5 2.5 5 5 7.5 Total (%) and echocardiography. In addition, a cardioprotective medication (i.,e, an (Reversible) Expansion Median Progression Free Survival (mPFS) •Thisis an ongoing Phase 1b dose escalation study of demcizumab,a angiotensin-converting enzyme inhibitor or carvediolol) was administered to patients Congestive heart failure 001**0 01 (3%) targeting , plus pemetrexed and with rising BNPs. As reversible cardiopulmonary toxicity occurred in 2 patients in N 6 6 8 6 4 30 (Revers ible ) carboplatin in chemotherapy naïve stage IIIb/IV NSCLC patients. the 3rd cohort receiving 5 mg/kg who were dosed for more than 168 days, the subjects in the 5th and subsequent cohorts will receive truncated dosing of Nausea 1 2 6 5 2 16 (53%) Right-sided 001**0 01 (3%) •Demcizumab, pemetrexedand carboplatinwere generally well tolerated with demcizumab (i.e. 7.5 mg/kg for only 4 courses or 63 days of therapy). A DSMB heart failure (Reversible) nausea, fatigue and hypertension being the most common drug related reviewed the data from each dose cohort after the last subject in that cohort had Fatigue 3 3 5 3 1 15 (50%) * Occurred following > 160 days of treatment and reversible following the discontinuation of demcizumab and medical management toxicities. The hypertension was managed with anti-hypertensives. Two cases been on study for 56 days to decide whether it was safe to proceed to the next dose ** Events occurred in the same two patients of reversible Grade 3 pulmonary hypertension and heart failure occurred in cohort. Data through June 20, 2013 are presented. A randomized Phase 2 trial in Hypertension 2 4 4 1 0 11 (37%) patients receiving 5 mg/kg for greater than 160 days. 1st line non-squamous NSCLC is planned for 2014. Truncated Dosing Vomiting 1 2 3 3 1 10 (33%) mPFS •Patients are being followed with cardiac monitoring using B-typenatriuretic Patient Demographics •As reversible cardiopulmonary toxicity occurred in 2 patients in the • 7.5 mg/kg: NA Days peptide (BNP) testing and echocardiography. BNP appears to be an early Neutropenia 2 1 3 2 0 8 (27%) 3rd cohort receiving 5 mg/kg once every 3 weeks who were dosed • 5 mg/kg: 160 Days indicator of demcizumab induced cardiotoxicity. In addition, a for more than 160 days, the subjects subsequently enrolled in the • 2.5 mg/kg: 126 Days cardioprotective medication (i.e, an angiotensin-converting enzyme inhibitor (n=30) Edema 0 0 7 1 0 8 (27%) or carvidiolol) was administered to patients with an elevated BNP. trial will receive truncated dosing of DEM (i.e. 63 days of therapy). Dose Level – mg/kg 5 2.5 5 5 7.5 Total BNP Increased 1 0 5 1 0 7 (23%) rd •Utilizinga truncated treatment approach for demcizumab(i.e. 63days of EiExpansion • Three patients in the 3 cohort had their DEM dosing truncated after these cardiopulmonary events occurred; i.e., their last dose therapy) appears to prevent the onset of late cardiopulmonary toxicity. N6686430Anemia 1 0 3 1 1 6 (20%) Truncated DEM dosing at 7.5 mg/kg Q3W is ongoing. was administered on Day 63. In addition, 4 patients in the 7.5 Median age (years) 66.5 59.5 65.0 60.5 59.5 62.5 Alanine Aminotransferse 3003 06 (20%) mg/kg truncated cohort (with DEM administered through Day 63). •Concomitantpemetrexedand carboplatindid not appear to influence the increased pharmacokinetics of demcizumab. Male/Female 2/4 2/4 2/6 3/3 2/2 11/19 •These 7 patients, who received truncated dosing of DEM, had been Decreased appetite 2 0 2 1 0 5 (17%) on study for 175, 154, 99, 85, 48, 22 and 17 days at the time of the •Nine of the 23 (39%) evaluable patients had a RECIST partial response and Prior Surgery 0 0 1 2 0 3 Diarrhea 2 0 1 1 1 5 (17%) data cut-off and none of them had developed clinically evident 11 (48%) had stable disease. TheKaplain-Meier estimated median progression free survival (mPFS) for the 5 mg/kg cohorts (N=20) was 160 Prior Neo-adjuvant/ 00 0 0 0 0 cardiopulmonary toxicity. Adjuvant Therapy Dyspnea 3 0 1 1 0 5 (17%) days at the time of the data cut. The blue bars represent the time on study. The green bars represent patients who discontinued the study without progression and have remained progression- •Four of these 7 patients had a response assessment and 1 had a st Aspartate Aminotransferse 3011 05 (17%) free off study. These four patients received 1-6 courses of demcizumab, carboplatin and pemetrexed on study and then received some additional carboplatin •A randomized Phase 2 trial of demcizumabin 1line non-squamous NSCLC Prior Radiotherapy 2 1 5 2 1 11 PR and 3 had SD. and pemetrexed off-study increased is planned for 2014. 2013 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference, Boston, 21 October 2013