1. 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.

2. 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

3. 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

4. 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 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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