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An Open-label, Randomized, Parallel-Group Trial of Zalutumumab, a Human Monoclonal Anti–EGF Receptor Antibody, in Combination With Best Supportive Care,

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Presentation on theme: "An Open-label, Randomized, Parallel-Group Trial of Zalutumumab, a Human Monoclonal Anti–EGF Receptor Antibody, in Combination With Best Supportive Care,"— Presentation transcript:

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

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 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

3 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 study 1 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

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 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 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 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 therapies 1 1. Bonner et al. Lancet Oncol 2010 EGFr = epidermal growth factor receptor

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% 25% 2% Distant metastasis, %65%66% 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%) Surgery104 (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 chemotherapy159 (83%)79 (83%) 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%) Taxanes13 (7%)11 (12%) Platinum compounds9 (5%)13 (14%) MTX after zalutumumab16 (8%)– Pyrimidine analogues5 (3%)7 (7%) EGFr monoclonal antibodies3 (2%)5 (5%) Other10 (5%)10 (11%) ECOG = Eastern Cooperative Oncology Group; PS = performance status; BSC = best supportive care; MTX = methotrexate; EGFr = epidermal growth factor receptor

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

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

13 Overall Survival in Subgroups PS = performance status; EGFr = epidermal growth factor receptor; BSC = best supportive care

14 Progression-free Survival (IRC) IRC = Independent Review Committee; BSC = best supportive care; Z = zalutumumab; PFS = progression-free survival

15 Progression-free Survival in Sub-groups 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%) (1.5–11.5) 91 (48%) 1 (1%) – (27%) 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 N (%) All N (%) Grade 3–4 N (%) Skin rash #174 (92%)39 (21%) **-- Anemia47 (25%)11 (6%)18 (19%)5 (5%) Pyrexia42 (22%)012 (13%)0 Headache33 (17%)5 (3%)6 (6%)1 (1%) Weight decreased31 (16%)4 (2%)8 (9%)2 (2%) Diarrhea24 (13%)04 (4%)1 (1%) Hypomagnesemia22 (12%)5 (3%)2 (2%)0 Pneumonia18 (10%)9 (5%)4 (4%)2 (2%) Bronchitis15 ( 8%)3 (2%)2 (2%)1 (1%) Stomatitis12 (6%)011 (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

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

19 Acknowledgments 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


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