Targeted Therapy in Head & Neck Cancer Anti-EGFR Treatment Jan B. Vermorken, MD, PhD University Hospital Antwerp Edegem, Belgium

Nucleus Anti-receptor Antibodies ± Toxins Tyrosine Kinase Inhibitors Hormone Agonists/ Antagonists Farnesyl Transferase Inhibitors Apoptosis Agonists Antisense Angiogenesis Inhibitors (Angiostatin, Endostatin & Anti-VEGF) Metalloproteinase Inhibitors Matrix Degradation (Collagenases, Gelatinases & Stromelysins) Immune System Activation (Vaccines, Monoclonal antibodies) Tumor Cell Growth Factor Receptors Intracellular Signaling Molecules Overview: Targeted Therapies Antimetabolites Microtubule inhibitors

EGF TGF  Amphiregulin  -cellulin HB-EGF Epiregulin Heregulins NRG2 NRG3 Heregulins  -cellulin Cysteine-rich domains Tyrosine kinase domain ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4 C-terminus The EGFR (ErbB) family and ligands

EGFR Expression in Human Tumors NSCLC40-80% Prostate40-80% Head & Neck90-100% Gastric33-74% Breast14-91% Colorectal75-89% Pancreatic30-95% Ovarian35-77% Bladder31-72% Glioma 40-63% Invasion Metastasis Late-stage disease Chemotherapy resistance Poor outcome EGFR expressionHigh expression generally associated with

Prognostic significance of EGFR expression in SCCHN High levels of EGFR and TGF  result in reduced disease-free and overall survival EGFR TGF  Low Medium High p= Proportion surviving with NED Years after surgery p= Low Medium High Proportion surviving with NED Years after surgery Grandis et al, 1998

Anti-EGFR Therapies Signal transduction Signal transduction Cell death MAbsTKIs Toxin conjugates Antisense Protein synthesis KK KK Ligand KK TKI KK Ligand

Synergistic Effects of Cetuximab + Cisplatin on Human Epidermoid Cancer Cell Line A Tumor size (cm 3 ) Cetuximab Cisplatin Days Days Survival (%) Control Cetuximab Cisplatin Cetuximab + cisplatin Fan Z et al,

Cetuximab + Radiation – Synergistic Effects on Human Epidermoid Cancer Cell Xenografts Saleh et al., Control 10 Gy Cetuximab Cetuximab + 10 Gy Time (days) Percent of original tumor

Anti-EGFR Agents in Phase III Evaluation AgentDrug typeStatusTumor type CetuximabEGFR mAblaunchedCRC phase IIIpancreatic, H&N, NSCLC PanitumumabEGFR mAbphase IIICRC and lung phase Ihead and neck GefinitibEGFR-TKIlaunchedNSCLC phase IIIhead and neck ErlotinibEGFR-TKIphase IIINSCLC, pancreatic phase IIhead and neck LapatinibEGFR-TKI /phase IIIbreast and renal ERBB²-TKIphase IIhead and neck

Cetuximab (Erbitux) – Summary of Clinical Studies in Head and Neck Cancer DiseaseType of studyTreatmentReference R/M SCCHNphase IIErbituxTrigo2004* Pt-refractory+ platinumBaselga 2005 Herbst 2005 R/M SCCHNphase I/IIIPt-based CTBurtness 2002 Pt-sensitive+ ErbituxHumblet 2004 Vermorken 2006 LA-SCCHNphase IIIRT + ErbituxBonner 2004 vs RT * Updated Vermorken et al, 2006

Disease progression Patients with recurrent and/or metastatic SCCHN that had progressed on platinum-based therapy ERBITUX 400 mg/m 2 followed by 250 mg/m 2 weekly Best supportive care or single agent/ combination chemo- or radiotherapy ERBITUX 400 mg/m 2 followed by 250 mg/m 2 weekly + Cisplatin/carboplatin Stable disease or response ERBITUX 400 mg/m 2 followed by 250 mg/m 2 x 4 cycles + Cisplatin 75 or 100 mg/m 2 q 3 weeks ERBITUX + cisplatin/carboplatin until disease progression ERBITUX alone until disease progression Trigo Baselga Herbst León Study Designs

Tumor Response TreatmentN CR+PR (%) [95% CI] CR+PR+NC (%) [95% CI] ERBITUX monotherapy % [7-21]46% [36-56] ERBITUX + cisplatin or carboplatin % [5-18]53% [43-63] ERBITUX + cisplatin % [5-19]56% [44-67] Retrospective analysis 4 All patients1513% [1-7]15% [10-22] Patients with CT only430% [0-8]9% [3-22] 1 Trigo/Vermorken et al 2004/2006, 2 Baselga et al 2005, 3 Herbst et al 2005, 4 León et al 2005

Overall Survival and Time to Progression TreatmentN Median OS months [95% CI] Median TTP months [95% CI] ERBITUX monotherapy [ ]2.3 [ ] ERBITUX + cisplatin or carboplatin [ ]2.8 [ ] ERBITUX + cisplatin [ ]2.2 [ ] Retrospective analysis 4 All patients [ ]N/A Patients with CT only433.5 [ ] N/A 1 Trigo/Vermorken et al 2004/2006, 2 Baselga et al 2005, 3 Herbst et al 2005, 4 León et al 2005

Cetuximab (Erbitux) in Platinum-Sensitive R/M SCCHN AuthorType ofNo. ofTreatmentRR (CR)MS (year)studyptsarms%mo BurtnessPh III60Pt + Erbitux26(2)9.3 (2002/200463Pt + placebo108.0 HumbletPh I/II27PF + Erbitux33(4)10.6 (2004) 26CF + Erbitux38(4)8.5 VermorkenPh III222Pt/5FU + ErbituxTETE (2006)220Pt/5FUTETE

Cetuximab (Erbitux): Grade 3-4 adverse toxicity CategoryERBITUX 1 ERBITUX + CDDP/carbo (n=96) 2 ERBITUX + CDDP (n=79) 3 Alone (n=103) + platinum (n=53) Any Fatigue Nausea/vomiting Mucositis Skin reactions Hypersensitivity Respiratory 34% 16% 3% 1% 15% 45% 21% 6% 0% 4% 0% 23% 43% 19% 6% 2% 3% 0% 13% N/A 18% 6% N/A 4% N/A 22% 1 Trigo et al 2004, 2 Baselga et al 2005, 3 Herbst et al 2005

Studies with other EGFR Inhibitors in SCCHN Phase I and II studies DoseStudyPtsRR Agent(s) mgPhaseN %Reference Gefitinib500 qdII4711Cohen, 2003 Gefitinib250 qdII563.5Kane, Gefitinib qdI1822Wirth, 2005 Celecoxib bid Erlotinib150 qdII1154.3Soulieres, 2004 Erlotinib150 qdI101/9Mauer, Bevacizumab5, 10, 15/kgII4511Vokes, 2005* iv q 3 wks ASCO 2004 (abstract 1 #5586, 2 #5539), * ASCO 2005 (#5504)

Stratify by  Karnofsky score: vs  Regional Nodes: N0 and N+  Tumor stage: AJCC T1-3 and T4  RT fractionation * : Concomitant boost Once daily Twice daily Arm 2 (Erbitux + RT) ERBITUX initial dose (Week 1), ERBITUX + RT (Weeks 2–8) ** Arm 1 (RT) Radiation therapy * Investigators’ choice ; ** UAB regimen, Robert F:JCO RANDOMIZERANDOMIZE Bonner J et al. New. Engl J Med [Submitted] A Phase III Study of RT ± ERBITUX N = 424

Patient Characteristics 56 (34–81)58 (35–83)Median age (range) Primary tumor site (%) Oropharynx Hypopharynx Larynx 81 / 1979 / 21Male / Female (%) ERBITUX + RTRT Bonner J et al. New. Engl J Med [Submitted] Patients (n)213211

A Phase III Study of RT ± ERBITUX Months Locoregional Control Probability ERBITUX + RT RT ERBITUX + RT m 69% 56% RT m 59% 48% Events Median 1-Year 2-Year Log rank p 0.02

A Phase III Study of RT ± ERBITUX Months Probability Survival ERBITUX + RT RT ERBITUX + RT m 62% 57% RT m 55% 44% Events Median 2-Year 3-Year Log rank p

Grade 3/4 acute toxicity TypeRT (%) Erbitux + RT (%) Skin1834 Mucosal5254 Dysphagia3025 Xerostomia 3 4 Fatigue 5 4 Infusion reaction— 3 Acute toxicity acceptable (skin, infusion reactions, no additional mucositis) Bonner J et al. New. Engl J Med [Submitted]

1.0 Probability Months Hazard ratio = 0.62; p=0.13 Patients Laryngectomies RT 93 8 ERBITUX + RT A Phase III Study: ERBITUX and larynx preservation Bonner et al. J Clin Oncol, ASCO Annual Meeting Proceedings 2005; 23:Abstract Updated information presented at ASCO (poster)

A Phase III Study: ERBITUX and Wound Healing Subgroup of n=39 patients undergoing neck dissections No significant prolongation in key parameters in the RT alone and ERBITUX + RT groups, respectively: –average length of hospital stay following dissection (2.1 days vs 2.8 days) –average time until neck drain removal (3.3 days vs 3.1 days) ERBITUX does not significantly affect wound healing following neck dissection Harari et al. Int J Radiat Oncol Biol Phys 2003; 57: S245-S246

Anti-EGFR Treatment in H&N Cancer Conclusions (1) Synergism with platinum compounds and RT Survival benefit in R/M SCCHN? Survival benefit in LA-SCCHN! (one trial) EGFR inhibitors + RT could replace RT alone for the treatment of intermediate risk LA-SCCHN EGFR inhibitors + RT offers an alternative for patients with high-risk LA-SCCHN* who are unable to tolerate concurrent CT and RT * Stage III, IV disease, excluding T1-2N1 and T3N0

Anti-EGFR Treatment in H&N Cancer Conclusions (2) Future need of clinical trials Chemoradiation vs EGFR inhibitors + RT Chemoradiation + EGFR inhibitors Induction CT  CRT + EGFR inhibitors Induction CT + EGFR inhibitors Interaction of EGFR inhibitors – other CT agents Interaction of EGFR inhibitors – other biologicals