An Open-label, Randomized, Parallel-Group Trial of Zalutumumab, a Human Monoclonal Anti–EGF Receptor Antibody, in Combination With Best Supportive Care, Versus Best Supportive Care, in Patients With Noncurable Squamous Cell Carcinoma of the Head and Neck Who Have Failed Standard Platinum-Based Chemotherapy J-P. Machiels, S. Subramanian, A. Ruzsa, G. Repassy, I. Lifrenko, A. Flygare, P. Sørensen, E. Ehrnrooth, O. Baadsgaard, P. M. Clement on behalf of the Hx-EGFr-202 Study Investigators Good Morning everybody, My name is Mohamed Abdulla, I am a professor of clinical oncology, cairo University. In the next few minutes we are going to explore a phase III trial of Zalutumumab, which is a fully humanized antibody developed to target epidermal growth factor receptor particularly among patients with squamous cell carcinoma of the head & neck.

Recurrent or Metastatic Head and Neck Cancer EGFr overexpression is associated with a poor outcome in SCCHN Platinum/5FU + cetuximab is an established first-line palliative treatment (median survival 10 months) No standard of care in patients that have failed platinum-based CT Cetuximab monotherapy is approved in US in this indication No randomized controlled trials have demonstrated that anti-EGFr monoclonal antibodies improve survival or PFS in platinum failures As we know, EGFR overexpression in squamous cell carcinoma of the head & neck is associated with advanced disease stage at presentation as well as higher potential for distant spread. Targeting EGFR plus conventional platinum based chemotherapy is the treatment of choice for those patients as a first line therapy, however there is no standard of care for subsequent relapse except for using Cetuximab as a monotherapy. SCCHN = squamous cell carcinoma of the head and neck; EGFr = epidermal growth factor receptor; RR = response rate; DCR = disease control rate; TTP = time-to-progression 2

Zalutumumab: a New EGFr-targeted Monoclonal Antibody High-affinity Human IgG1 antibody Effectively Blocks EGFr signaling Down-modulates EGFr levels Induces ADCC at low antibody concentrations Encouraging biological activity in Phase I/II dose escalation study1 Zalutumumab is a Human IgG1 antibody that is effectively down-modulating EGFR levels. Most interestingly that it induces antibody-dependant cell mediated cytotoxicity even at low antibody concentrations. IgG = immunoglobulin G; EGF = epidermal growth factor; ADCC = antibody-dependent cell-mediated cytotoxicity; SCCHN = squamous cell carcinoma of the head and neck PR = partial response; SD = stable disease; MTD = median time-to-death 1. Bastholt et al. Radiother Oncol 2007

Hx-EGFr-202: Study Design Open-label, parallel group: zalutumumab + BSC vs BSC with optional methotrexate (MTX) Primary endpoint: OS Interim and final analysis after 116 and 231 deaths Significance level at 0.0294 for both analyses Overall 80% power to detect a 50% increase in OS from 4 to 6 months Key secondary endpoint: PFS Other secondary endpoints Objective tumor response as assessed by IRC according to RECIST QoL: EORTC QLQ-C30 and H&N 35 Safety The study had compared Zalutumumab plus BSC versus BSC with optional methotrexate among squamous cell carcinoma of the head and neck not amenable for cure after failing first line platinum based therapy where OS & PFS were the 1ry & 2nd endpoints. Also OAR, QoL and Safety were among the 2nd end points. BSC = best supportive care; MTX = methotrexate ; ECOG = Eastern Cooperative Oncology Group; PS = performance status ; OS = overall survival; IRC = Independent Review Committee ( board-certified radiologists) ; RECIST = Response Evaluation Criteria In Solid Tumors ; EORTC = European Organisation for Research and Treatment of Cancer; Quality of Life Questionnaire Core 30; H&N 35 = Head and Neck 35

Main Inclusion/exclusion Criteria Inclusion criteria SCC of the oral cavity, oropharynx, hypopharynx or larynx, considered incurable with standard therapy IRC confirmed PD according to RECIST During or within 6 months after failure or intolerance to platinum-based chemotherapy Measurable disease ECOG performance status ≤2 Exclusion criteria Three or more prior CT regimens other than platinum-based CT Prior treatment with EGFr antibodies and/or EGFr small molecule inhibitors The study had included patients with advanced disease considered neither for cure nor for platinum based therapy and essentially not heavily pre-treated and naïve for similar class of targeted therapies. SCC = squamous cell carcinoma; PD = progressive disease; RECIST = Response Evaluation Criteria In Solid Tumors ; IRC = Independent Review Committee; ECOG = Eastern Cooperative Oncology Group; CT = chemotherapy; EGFr = epidermal growth factor receptor

Study Schema 286 patients were stratified according to ECOG PS to receive either BSC with optional methotrexate and Zalutumumab plus BSC. The randomization was 2:1. ECOG = Eastern Cooperative Oncology Group ; PS = performance status; BSC = best supportive care; OS = overall survival; MTX = methotrexate; CT = computed tomography ; MRI = magnetic resonance imaging

Zalutumumab Dose-titration to Rash Skin rash is correlated to survival in trials evaluating EGFr-targeted therapies1 As we know, cutaneous manifestations are the main side effects with anti-EGFR antibodies. The dose schedule started at 8 mg/kg BWT and increased by 4 mg/kg BWT till reaching a total of 16 mg/kg BWT guided by the dermatologic grade of toxicity till documented disease progression. EGFr = epidermal growth factor receptor 1. Bonner et al. Lancet Oncol 2010

Baseline Characteristics Zalutumumab + BSC without MTX (n=191) BSC with optional MTX (n=95) Age, years, median (range) 57 (29–81) 58 (28–78) Males, % 88% 87% ECOG PS 0–1/2, % 82% / 18% 83% / 17% Duration of disease, months, median (range) 18.9 (3–251) 19.6 (2–176) Primary tumor location, % Oral cavity Oropharynx Hypopharynx Larynx Other 34% 28% 18% 19% 2% 25% 27% 20% Distant metastasis, % 65% 66% Patient’s characteristics were well balanced between the 2 arms of the study. ECOG = Eastern Cooperative Oncology Group; PS = performance status; BSC = best supportive care; MTX = methotrexate

Prior Anticancer Therapies Zalutumumab + BSC without MTX (n=191) BSC with optional MTX (n=95) Prior therapies, n (%) Radiation alone 80 (42%) 37 (39%) Surgery 104 (54%) 53 (56%) Curative chemoradiation therapy Adjuvant CT Concurrent CRT Induction CT 3 (2%) 72 (38%) 30 (16%) 1 (1%) 38 (40%) 16 (17%) Palliative chemotherapy 159 (83%) 79 (83%) And hereby the prior therapeutic modalities. CRT = combined chemo–radiotherapy ; BSC = best supportive care; MTX = methotrexate

Zalutumumab and other Anti-cancer Therapies During Study Zalutumumab + BSC without MTX (n=191) BSC with optional MTX (n=95) Zalutumumab infusions, median (range) 15 (0–101) – MTX as part of BSC, n (%) 74 (78%) Taxanes 13 (7%) 11 (12%) Platinum compounds 9 (5%) 13 (14%) MTX after zalutumumab 16 (8%) – Pyrimidine analogues 5 (3%) 7 (7%) EGFr monoclonal antibodies 3 (2%) 5 (5%) Other 10 (5%) 10 (11%) 56 and 46 patients were excluded from both arms upon receiving other anti-neoplastic therapies during the study period. ECOG = Eastern Cooperative Oncology Group; PS = performance status; BSC = best supportive care; MTX = methotrexate; EGFr = epidermal growth factor receptor

Overall Survival Higher OAS rates were documented among patients received Zalutumumab however not reaching statistical significance and hence the study failed to significantly affect the 1ry end point. BSC = best supportive care; MTX = methotrexate; Z =zalutumumab; EGFr = epidermal growth factor receptor

Overall Survival by ECOG PS Also higher OAS rates were reported in Zalutumumab arm for patients with ECOG PS 0-1 as compared to patients with higher scores.. ECOG = Eastern Cooperative Oncology Group; PS = performance status; BSC = best supportive care; Z = zalutumumab

Overall Survival in Subgroups Further analysis indicated that most of patients are likely to benefit of drug therapy in terms of OAS with questionable benefit for female sex, primary laryngeal origin of disease as well as lower expression of EGFR. PS = performance status; EGFr = epidermal growth factor receptor; BSC = best supportive care

Progression-free Survival (IRC) In contrast to OAS, Zalutumumab therapy resulted in significant improvement in PFS when compared to BSC alone. IRC = Independent Review Committee; BSC = best supportive care; Z = zalutumumab; PFS = progression-free survival

Progression-free Survival in Sub-groups And this improvement was validated in all patients subgroups. PS = performance status; PFS = progression-free survival; BSC = best supportive care

Response and Disease Control Rates (IRC) Zalutumumab + BSC without MTX (n=191) BSC with optional MTX (n=95) Overall response rate, n (%) Complete response, n Partial response, n Duration of response, months, median (range) Disease control rate, n (%) 12 (6%) 2 10 5.5 (1.5–11.5) 91 (48%) 1 (1%) – 1 7.4 26 (27%) Moreover, patients in the investigational arm had shown higher overall as well as disease control rates. BSC = best supportive care ; MTX = methotrexate

Most Common Adverse Events* Zalutumumab + BSC without MTX (n=189) BSC with optional MTX (n=94) All N (%) Grade 3–4 Skin rash # 174 (92%) 39 (21%) ** - Anemia 47 (25%) 11 (6%) 18 (19%) 5 (5%) Pyrexia 42 (22%) 12 (13%) Headache 33 (17%) 5 (3%) 6 (6%) 1 (1%) Weight decreased 31 (16%) 4 (2%) 8 (9%) 2 (2%) Diarrhea 24 (13%) 4 (4%) Hypomagnesemia 22 (12%) Pneumonia 18 (10%) 9 (5%) Bronchitis 15 ( 8%) 3 (2%) Stomatitis 12 (6%) 11 (12%) Apart from cutaneous manifestations, other adverse events were not much different among both study groups. ** = No Grade 4 *Adverse events reported with a > 5% higher incidence in one of the treatment arms, # pre-dosing skin-examination according to modified CTCAE criteria, BSC = best supportive care

Conclusions The OS analysis favoured the zalutumumab arm, although the prespecified criteria for significance was not met (p= 0.065) Median OS 6.7 vs 5.2 months This is the first controlled study to show that an EGFr-targeted antibody induces a clinically meaningful improvement in PFS in patients who have failed platinum-based chemotherapy (p=0.001) 26-week PFS rate 20% vs. 7.3% The safety profile observed for zalutumumab, individually dose- titrated to rash, was as expected In conclusion; the use of Zalutumumab is associated with OAS improvement although not of statistical significance. Moreover, it is the first controlled study to show a clinically meaningful improvement in PFS in patients not considered for cure. BSC = best supportive care; MTX = methotrexate; OS = overall survival; PFS = progression-free survival; EGFr = epidermal growth factor receptor

Acknowledgments Belgium: J-P. Machiels J-L. Canon, L. Duck, J. Vermorken, P. Clement, S. Rottey Hungary: T. Pinter, G. Repassy, J. Szanto, K. Hideghety, A. Ruzsa, M. Wenczl, Z. Kotai, N. Bittner Poland: K. Skladowski, W. Rogowski, M. Mazurkiewicz, M. Pysz, P. Koralewski Russia: M. Byakhov, D. Udovitsa, O. Gladkov, S. Subramanian, S. Emelyanov, M. Matrosova, I. Reshetov, S. Orlov, V. Borisov, I. Lifrenko, L. Kuzina, I. Pimenov, V. Popov, V. Medvedev Brazil: S. Sutmoller, A. Wainstein F. Martinelli de Olivera, H. Pinczowski, A. Fulhaber Estonia: Dr. Niin France: M. Degardin, J. Guigay, F. Peyrade Lithuania: E. Aleknavicius, A. Cesas Sweden: E.Brun, T.Björk Serbia: M. Kreacic, D. Jovanovic, N. Jovic Spain: R.Hitt, J-A. Virzuela; F.Herrero, A.Lopez-Pousa, J.Pradera UK: C.Nutting, N.Slevin, C.Coyle, M.Robinson, C.Kelly, G.Robertson, C.Bramner,P.Jankowska, M.Rolles, H. Al Booz Canada: E. Chen, E. Winquist, J. Laskin, D. Hao, N. Chua Independent Data Monitoring Committee: J.B. Sørensen, B. Nilsson, T.Menné Independent Review Committee: R. J. Homer, A. L. Weber, M. Rothman Genmab Study Team Study funded by Genmab