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

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

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

1. Bastholt et al. Radiother Oncol 2007

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

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

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

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

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

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

1. Bonner et al. Lancet Oncol 2010

EGFr = epidermal growth factor receptor

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%25%2%

Distant metastasis, % 65% 66%

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%)

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%)

ECOG = Eastern Cooperative Oncology Group; PS = performance status; BSC = best supportive care; MTX = methotrexate; EGFr = epidermal growth factor receptor

Overall Survival

BSC = best supportive care; MTX = methotrexate; Z =zalutumumab; EGFr = epidermal growth factor receptor

Overall Survival by ECOG PS

ECOG = Eastern Cooperative Oncology Group; PS = performance status; BSC = best supportive care; Z = zalutumumab

Overall Survival in Subgroups

PS = performance status; EGFr = epidermal growth factor receptor; BSC = best supportive care

Progression-free Survival (IRC)

IRC = Independent Review Committee; BSC = best supportive care; Z = zalutumumab; PFS = progression-free survival

Progression-free Survival in Sub-groups

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%)

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 N (%)

All N (%)

Grade 3–4 N (%)

Skin rash # 174 (92%) 39 (21%) ** - -

Anemia 47 (25%) 11 (6%) 18 (19%) 5 (5%)

Pyrexia 42 (22%) 0 12 (13%) 0

Headache 33 (17%) 5 (3%) 6 (6%) 1 (1%)

Weight decreased 31 (16%) 4 (2%) 8 (9%) 2 (2%)

Diarrhea 24 (13%) 0 4 (4%) 1 (1%)

Hypomagnesemia 22 (12%) 5 (3%) 2 (2%) 0

Pneumonia 18 (10%) 9 (5%) 4 (4%) 2 (2%)

Bronchitis 15 ( 8%) 3 (2%) 2 (2%) 1 (1%)

Stomatitis 12 (6%) 0 11 (12%) 1 (1%)

*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

** = No Grade 4

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

BSC = best supportive care; MTX = methotrexate; OS = overall survival; PFS = progression-free survival; EGFr = epidermal growth factor receptor

Acknowledgments

Independent Data Monitoring Committee: J.B. Sørensen, B. Nilsson, T.MennéIndependent Review Committee: R. J. Homer, A. L. Weber, M. Rothman

Genmab Study TeamStudy funded by Genmab

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. WainsteinF. 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