Is targeted therapy ready for the adjuvant setting ? Emile E. Voest Department of Medical Oncology

1. Is targeted therapy ready for the adjuvant setting ? Emile E. Voest Department of Medical Oncology UMC Utrecht

2. When are new agents ready to be incorporated in adjuvant regimens ? “Failure to appreciate the problems surrounding the assessment of the respons of a group of patients to adjuvant chemotherapy is the source of some of the current disillusionment with the positive, but less than dramatic results achieved with adjuvant chemotherapy in common tumors, such as breast and colorectal cancer.” “The selection of an adjuvant treatment program for a particular patient Is based on response rates in separate groups of patients with advanced cancer of the same histologic type” Vincent T. DeVita, Jr , 1993

3. Targeted therapy has proven efficacy in : • Breast cancer: • tamoxifen • aromatase inhibitors • trastuzumab • Prostate cancer: • LH/RH agonists • Colorectal cancer: • cetuximab • bevacizumab

4. Re-discovery of a target ? HER2 (ERBB2) mutations in 120 patients with lungcancer 4 % of all tumors had mutations within the kinase domain 10 % had mutations in adenocarcinoma Mutations occurred in ex-smokers EGFR (HER1) mutations 2 % of all tumors had mutations within kinase domain 4 % had mutations in adenocarcinoma Mutations occurred in never-smokers Stephens et al. Nature 2004;431:525-526

5. Mutational analysis of the EGFR Never smokers: 7 of 15 lungcancer patients had a mutation in EGFR Smokers : 4 of 81 lungcancer patients had a mutation in EGFR Response to gefitinib: 7 of 10 patients had a mutation Refractory to gefitinib: 0 of 8 patients had a mutation Resonse to erlotinib: 5 of 7 patients had a mutation Refractory to erlotinib: 0 of 10 patients had a mutation Pao W, PNAS 2004; 101:13306-13311

6. Mutational analysis of the EGFR Adenocarcinoma : 15 of 70 (21%)patients had a mutation in EGFR 9 of 45 (20%) women 7 of 74 (9%) men Other NSCLC : 1 of 49 (2%) patients had a mutation in EGFR Japanese patients had 15 of 58 (26%) mutations 14 of 41 (32%) adenocarcinoma US patients had 1 of 61 (2%) mutations 1 of 29 (3%) had adenocarcinoma Paez et al. Science 2004; 304:1458-1461 Also Lynch et al. NEJM 2004;350: 2129-2139

7. What is the definition of “targeted therapy” Targeted therapy is a form of treatment that is designed to specifically inhibit molecules that provide advantageous growth signals to cancer cells Current targets: Receptor tyrosine kinases VEGFR inhibitors EGFR inhibitors Endothelin receptors KIT BCR/ABL PDGFR Growth factors VEGF Estrogen Androgen Transcription factors

8. Vascularization is required to convert an in-situ carcinoma into a rapidly growing malignancy Premalignant stage Malignant tumor Tumorgrowth Vascularinvasion Dormantmicrometastasis Overtmetastasis (Avascular tumor) (Angiogenicswitch) (Vascularizedtumor) (Tumor cellintravasation) (Seeding indistant organs) (Secondary angiogenesis) Stages at which angiogenesis plays a role in tumor progression Adapted from Poon RT, et al. J Clin Oncol. 2001;19:1207–25

9. Tumor characteristics and environment promote VEGF expression Hypoxia PDGF IGF-1 EGF IL-8 Binding and activation of VEGFR VEGF release bFGF COX-2 NO Oncogenes P– – P Increased expression (MMP, tPA, uPA, uPAr, eNOS, etc.) – P P– Survival Proliferation Migration Permeability ANGIOGENESIS PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1IL-8 = insulin-like growth factor 8

10. Colorectal cancer 75-82% Lung cancer (NSCLC) 40-91% Head & neck cancer 90-100% Gastric cancer 33-74% Ovarian cancer 35-70% EGFR expression in human cancer

11. EGF TGFalpha Amphiregulin Betacellulin Epiregulin No known ligand Epiregulin Neuregulins HER 2 ErbB2 Neu Her 3 and 4 ErbB3 ErbB4 HER 1 EGFR ErbB1

12. The importance of EGFR as a target

13. Kinase inhibitor Activation of EGFR plays an essential role in cellular survival and proliferation programs

14. Anti-vascular therapies Phase III study of bevacizumab (Avastin) in combination with standard chemotherapy for advanced colorectal cancer IFL/Placebo IFL/BV p value n=412 n=403 Median survival 15.6 20.3 0.00003 PFS 6.24 10.6 <0.00001 Objective responses 35% 45% 0.0029 Duration of response 7.1 10.4 0.0014 Hurwitz H, et al. N Engl J Med 2004;350:2335–42

15. Phase II study with SU 11248 in patients with metastatic renal cell cancer SU 11248 is an oral multi-targeted tyrosine kinase inhibitor of PDGFR, KIT, VEGFR2 and VEGFR3 63 patients included 21 patients (33%) had a partial respons according to RECIST criteria 23 patients (37%) had stable disease lasting more than 3 months Median time to progression 8.3 months Grade 3 or 4 toxicity included: Fatigue/asthenia 8 % Lymphopenia 30% 2 patients had a decreased LVEF (>20%) and were taken off study Grade 1 or 2 toxicity included: Nausea 56% Diarrhea 51% Stomatitis 44% Fatigue/astenia 78% Motzer RJ et al. ASCO 2004, abstract 4500

16. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2.Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH • J Clin Oncol. 2004 Mar 1;22(5):785-94 • Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1.Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. • J Clin Oncol. 2004 Mar 1;22(5):777-84 Two negative studies ?? 1073 and 1039 patients were entered in both trials, respectively

17. Mutations in EGFR predict respons to treatment and differ in ethnic backgrounds Paez et al. Science 2004; 304:1497-1500 Lynch et al. New Engl J Med 2004;350:2129-2139

18. Frequency of involvement of KIT exon 11 codons by mutations in 322 gastrointestinal stromal tumors Corless, C. L. et al. J Clin Oncol; 22:3813-3825 2004

19. Immunohistochemistry for KIT in gastrointestinal stromal tumors (GISTs) harboring KIT versus PDGFRA mutations Corless, C. L. et al. J Clin Oncol; 22:3813-3825 2004

20. Predictive value of mutations in the treatment of GIST with imatinib KIT mutations in sporadic GIST exon 11 best respons to imatinib exon 9 intermediate respons exon 13 & 17 sensitive in vitro, clinical responses observed PDGFRalpha mutations in sporadic GIST exon 12 sensitive in vitro, responses observed exon 18 D842V poor respons, other mutations sensitive wild type poor response

21. Anti-vascular treatment: macroscopic versus microscopic disease Is the effect of bevacizumab in the adjuvant setting the same as in advanced disease ? • In advanced disease bevacizumab has little effect as single agent • possibly as a result of local production of large amounts • of growthfactors • In combination with chemotherapy there is a clear additive effect • of bevacizumab likely by reducing the hydrostatic pressure in the • tumor • In microscopic disease bevacizumab may be effective a single agent • and may not have an additive effect to chemotherapy

22. Adjuvant clinical trials with targeted therapy • Bevacizumab in colorectal cancer • Adjuvant study in high risk stage II and stage III colorectal cancer • Patient accrual: 3450 patients (1150 per arm) • FOLFOX-4 • FOLFOX-4 plus bevacizumab • Xeloda plus bevacizumab

23. Adjuvant clinical trials with targeted therapy • Cetuximab (anti-EGFR antibody) in colorectal cancer • Patient accrual: 4800 (800 per arm) • 6 arms: • FOLFOX q 2 weeks, 12 cycles • FOLFIRI q 2 weeks, 12 cycles • FOLFOX q 2 weeks, 6 cycles, FOLFIRI q 2 weeks, 6 cycles • FOLFOX q 2 weeks plus cetuximab • FOLFIRI q 2 weeks plus cetuximab • FOLFOX/FOLFIRI q 2 weeks plus cetuximab at least 1 positive lymphnode, no rectal cancers

25. Conclusion Early incorporation of targeted therapy in the adjuvant setting without specific knowledge of the mechanism of action may lead to ineffective use of potentially very effective new agnets