Targeted Therapy in Head & Neck Cancer Anti-EGFR Treatment

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

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

3. The EGFR (ErbB) family and ligands EGF TGFa Amphiregulin b-cellulin HB-EGF Epiregulin NRG2 NRG3 Heregulins b-cellulin Heregulins Cysteine-rich domains 100 100 100 44 82 33 36 59 24 48 79 28 Tyrosine kinase domain C-terminus ErbB-1Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4

4. NSCLC 40-80% Prostate 40-80% Head & Neck 90-100% Gastric 33-74% Breast 14-91% Colorectal 75-89% Pancreatic 30-95% Ovarian 35-77% Bladder 31-72% Glioma 40-63% Invasion Metastasis Late-stage disease Chemotherapy resistance Poor outcome EGFR Expression in Human Tumors EGFR expression High expression generallyassociated with

5. EGFR TGFa 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 Low Low Medium Medium Proportion surviving with NED Proportion surviving with NED High High p=0.0001 p=0.0001 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years after surgery Years after surgery Prognostic significance of EGFR expression in SCCHN High levels of EGFR and TGF result in reduced disease-free and overall survival Grandis et al, 1998

6. Anti-EGFR Therapies Toxin conjugates MAbs TKIs Antisense Ligand Ligand Ligand Ligand TKI K K K K K K K K Proteinsynthesis Signal transduction Signal transduction Cell death

7. Synergistic Effects of Cetuximab + Cisplatin on Human Epidermoid Cancer Cell Line A431 Cetuximab Cisplatin 100 50 0 6 4 2 0 Control Tumor size (cm3) Survival (%) Cetuximab Cisplatin Cetuximab + cisplatin 0 5 15 25 35 0 20 40 60 80 180 Days Days Fan Z et al, 1993

8. Cetuximab + Radiation – Synergistic Effects on Human Epidermoid Cancer Cell Xenografts 400 300 200 100 0 Control 10 Gy Cetuximab Cetuximab + 10 Gy Percent of original tumor 0 10 50 100 150 200 250 Time (days) Saleh et al., 1999

9. Anti-EGFR Agents in Phase III Evaluation Agent Drug type Status Tumor type Cetuximab EGFR mAb launched CRC phase III pancreatic, H&N, NSCLC Panitumumab EGFR mAb phase III CRC and lung phase I head and neck Gefinitib EGFR-TKI launched NSCLC phase III head and neck Erlotinib EGFR-TKI phase III NSCLC, pancreatic phase II head and neck Lapatinib EGFR-TKI / phase III breast and renal ERBB²-TKI phase II head and neck

10. Cetuximab (Erbitux) – Summary of Clinical Studies in Head and Neck Cancer Disease Type of study Treatment Reference R/M SCCHN phase II Erbitux Trigo2004* Pt-refractory + platinum Baselga 2005 Herbst 2005 R/M SCCHN phase I/III Pt-based CT Burtness 2002 Pt-sensitive + Erbitux Humblet 2004 Vermorken 2006 LA-SCCHN phase III RT + Erbitux Bonner 2004 vs RT * Updated Vermorken et al, 2006

11. Study Designs Patients with recurrent and/or metastatic SCCHN that had progressed on platinum-based therapy Trigo Baselga León Herbst ERBITUX 400 mg/m2 followed by 250 mg/m2 weekly + Cisplatin/carboplatin ERBITUX 400 mg/m2 followed by 250 mg/m2 x 4 cycles + Cisplatin 75 or 100 mg/m2 q 3 weeks Best supportive care or single agent/ combination chemo- or radiotherapy ERBITUX 400 mg/m2 followed by 250 mg/m2 weekly Disease progression Stable disease or response ERBITUX + cisplatin/carboplatin until disease progression ERBITUX alone until disease progression

12. Tumor Response 1 Trigo/Vermorken et al 2004/2006, 2 Baselga et al 2005, 3 Herbst et al 2005, 4 León et al 2005

13. Overall Survival and Time to Progression 1 Trigo/Vermorken et al 2004/2006, 2 Baselga et al 2005, 3 Herbst et al 2005, 4 León et al 2005

14. Cetuximab (Erbitux) in Platinum-Sensitive R/M SCCHN Author Type of No. of Treatment RR (CR) MS (year) study pts arms % mo Burtness Ph III 60 Pt + Erbitux 26 (2) 9.3 (2002/2004 63 Pt + placebo 10 8.0 Humblet Ph I/II 27 PF + Erbitux 33 (4) 10.6 (2004) 26 CF + Erbitux 38 (4) 8.5 Vermorken Ph III 222 Pt/5FU + Erbitux TE TE (2006) 220 Pt/5FU TE TE

15. Cetuximab (Erbitux): Grade 3-4 adverse toxicity 1 Trigo et al 2004, 2 Baselga et al 2005, 3 Herbst et al 2005

16. Studies with other EGFR Inhibitors in SCCHNPhase I and II studies Dose Study Pts RR Agent(s) mg Phase N % Reference Gefitinib 500 qd II 47 11 Cohen, 2003 Gefitinib 250 qd II 56 3.5 Kane, 20041 Gefitinib+ 250-500 qd I 18 22 Wirth, 2005 Celecoxib 200-400 bid Erlotinib 150 qd II 115 4.3 Soulieres, 2004 Erlotinib 150 qd I 10 1/9 Mauer, 20042 Bevacizumab 5, 10, 15/kg II 45 11 Vokes, 2005* iv q 3 wks ASCO 2004 (abstract 1#5586, 2#5539), * ASCO 2005 (#5504)

17. Patient Characteristics RT ERBITUX + RT Patients (n) 213 211 Median age (range) 58 (35–83) 56 (34–81) Male / Female (%) 79 / 21 81 / 19 631324 561727 Primary tumor site (%)OropharynxHypopharynxLarynx Bonner J et al. New. Engl J Med [Submitted]

18. 1.0 0.9 0.8 0.7 0.6 0.5 Events Median 1-Year 2-Year RT 105 19 m 59% 48% ERBITUX + RT 90 36 m 69% 56% 0.4 0.3 0.2 0.1 0.0 36 12 18 24 30 42 6 A Phase III Study of RT ± ERBITUX Locoregional Control ERBITUX + RT Probability RT Log rank p 0.02 0 Months

19. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 A Phase III Study of RT ± ERBITUX Survival ERBITUX + RT Probability Events Median 2-Year 3-Year RT 117 28 m 55% 44% ERBITUX + RT 93 54 m 62% 57% RT Log rank p 0.02 6 24 30 36 42 60 12 0 18 48 54 12 0 18 Months

20. Grade 3/4 acute toxicity • Acute toxicity acceptable (skin, infusion reactions, no additional mucositis) Bonner J et al. New. Engl J Med [Submitted]

21. A Phase III Study: ERBITUX and larynx preservation 1.0 0.9 0.8 0.7 0.6 RT ERBITUX + RT Probability 0.5 Patients 78 93 0.4 Laryngectomies 12 8 0.3 0.2 0.1 Hazard ratio = 0.62; p=0.13 0.0 0 6 12 18 24 30 36 42 48 54 60 Months Bonner et al. J Clin Oncol, ASCO Annual Meeting Proceedings 2005; 23:Abstract 5533. Updated information presented at ASCO (poster)

22. 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

23. Anti-EGFR Treatment in H&N CancerConclusions (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

24. Anti-EGFR Treatment in H&N CancerConclusions (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