Is targeted therapy ready for the adjuvant setting ?

Emile E. Voest Department of Medical Oncology UMC Utrecht

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

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

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

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

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

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

Vascularization is required to convert an in-situ carcinoma into a rapidly growing malignancy

Premalignant stage (Avascular tumor) Malignant tumor (Angiogenic switch) Tumor growth (Vascularized tumor) Vascular invasion (Tumor cell intravasation) Dormant micrometastasis (Seeding in distant organs) Overt metastasis (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

Tumor characteristics and environment promote VEGF expression

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

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

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

The importance of EGFR as a target

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

Anti-vascular therapies

Phase III study of bevacizumab (Avastin) in combination with standard chemotherapy for advanced colorectal cancer Median survival PFS Objective responses Duration of response IFL/Placebo n=412 15.6

6.24

35% 7.1

IFL/BV n=403 20.3

10.6

45% 10.4

p value 0.00003

<0.00001

0.0029

0.0014

Hurwitz H, et al. N Engl J Med 2004;350:2335 –42

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 Lymphopenia 8 % 30% 2 patients had a decreased LVEF (>20%) and were taken off study Grade 1 or 2 toxicity included: Nausea 56% Diarrhea Stomatitis Fatigue/astenia 51% 44% 78% Motzer RJ et al. ASCO 2004, abstract 4500

Two negative studies ??

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 1073 and 1039 patients were entered in both trials, respectively

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

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

Copyright © American Society of Clinical Oncology

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

Copyright © American Society of Clinical Oncology

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

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

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

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

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