Is targeted therapy ready for the adjuvant setting ?

Emile E. Voest

Department of Medical OncologyUMC Utrecht

“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 chemotherapyin common tumors, such as breast and colorectal cancer.”

“The selection of an adjuvant treatment program for a particular patientIs based on response rates in separate groups of patients withadvanced cancer of the same histologic type”

Vincent T. DeVita, Jr , 1993

When are new agents ready to be incorporated in adjuvant regimens ?

Targeted therapy has proven efficacy in :

Breast cancer:tamoxifenaromatase inhibitorstrastuzumab

Prostate cancer:LH/RH agonists

Colorectal cancer:cetuximabbevacizumab

Stephens et al. Nature 2004;431:525-526

HER2 (ERBB2) mutations in 120 patients with lungcancer

4 % of all tumors had mutations within the kinase domain10 % had mutations in adenocarcinoma

Mutations occurred in ex-smokers

EGFR (HER1) mutations

2 % of all tumors had mutations within kinase domain4 % had mutations in adenocarcinoma

Mutations occurred in never-smokers

Re-discovery of a target ?

Pao W, PNAS 2004; 101:13306-13311

Never smokers: 7 of 15 lungcancer patients had a mutation in EGFRSmokers : 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

Mutational analysis of the EGFR

Paez et al. Science 2004; 304:1458-1461Also Lynch et al. NEJM 2004;350: 2129-2139

Adenocarcinoma : 15 of 70 (21%)patients had a mutation in EGFR9 of 45 (20%) women7 of 74 (9%) men

Other NSCLC : 1 of 49 (2%) patients had a mutation in EGFR

Japanese patients had 15 of 58 (26%) mutations14 of 41 (32%) adenocarcinoma

US patients had 1 of 61 (2%) mutations1 of 29 (3%) had adenocarcinoma

Mutational analysis of the EGFR

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 inhibitorsEGFR inhibitorsEndothelin receptorsKITBCR/ABLPDGFR

Growth factorsVEGFEstrogenAndrogen

Transcription factors

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

Adapted from Poon RT, et al. J Clin Oncol. 2001;19:1207–25

Stages at which angiogenesis plays a role in tumor progression

Premalignantstage

Malignanttumor

Tumorgrowth

Vascularinvasion

Dormantmicrometastasis

Overtmetastasis

(Avasculartumor)

(Angiogenicswitch)

(Vascularizedtumor)

(Tumor cellintravasation)

(Seeding indistant organs)

(Secondaryangiogenesis)

Tumor characteristics and environment

promote VEGF expression

EGF

Hypoxia PDGF

IL-8

bFGF

COX-2NO

Oncogenes

VEGF releaseBinding and activationof VEGFR

ProliferationSurvival Migration

ANGIOGENESISPermeability

Increased expression(MMP, tPA, uPA, uPAr,

eNOS, etc.)

– P

– P

P–

P–

PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1IL-8 = insulin-like growth factor 8

IGF-1

EGFR expression in human cancer

40-91%40-91%Lung cancer (NSCLC)Lung cancer (NSCLC)

90-100%90-100%Head & neck cancer Head & neck cancer

35-70%35-70%Ovarian cancerOvarian cancer

33-74%33-74%Gastric cancerGastric cancer

75-82%75-82%Colorectal cancerColorectal cancer

HER 1EGFRErbB1

HER 2ErbB2Neu

Her 3 and 4ErbB3 ErbB4

EGFTGFalpha

AmphiregulinBetacellulinEpiregulin

EpiregulinNeuregulins

No known ligand

The importance of EGFR as a target

EGFR activation

Angiogenesis

Cell proliferation

M

G1

S

G2

Survival/protection from apoptosisDedifferentiation

Metastasis: cell migration and

invasion

Gene activation

Signalling cascade••••

••••

Kinase inhibitor

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

Anti-vascular therapies

Phase III study of bevacizumab (Avastin) in combination with standard chemotherapy for advanced colorectal cancer

IFL/Placebo IFL/BV p valuen=412 n=403

Median survival 15.6 20.3 0.00003PFS 6.24 10.6 <0.00001Objective responses 35% 45% 0.0029Duration of response 7.1 10.4 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 inhibitorof PDGFR, KIT, VEGFR2 and VEGFR3

63 patients included21 patients (33%) had a partial respons according to RECIST criteria23 patients (37%) had stable disease lasting more than 3 monthsMedian 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 studyGrade 1 or 2 toxicity included:Nausea 56%Diarrhea 51%Stomatitis 44%Fatigue/astenia 78% Motzer RJ et al. ASCO 2004, abstract 4500

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

Paez et al. Science 2004; 304:1497-1500Lynch et al. New Engl J Med 2004;350:2129-2139

Mutations in EGFR predict respons to treatment and differ in ethnic backgrounds

Copyright © American Society of Clinical Oncology

Corless, C. L. et al. J Clin Oncol; 22:3813-3825 2004

Frequency of involvement of KIT exon 11 codons by mutations in 322 gastrointestinal stromal tumors

Copyright © American Society of Clinical Oncology

Corless, C. L. et al. J Clin Oncol; 22:3813-3825 2004

Immunohistochemistry for KIT in gastrointestinal stromal tumors (GISTs) harboring KIT versus PDGFRA mutations

KIT mutations in sporadic GIST

exon 11 best respons to imatinibexon 9 intermediate responsexon 13 & 17sensitive in vitro, clinical responses observed

PDGFRalpha mutations in sporadic GIST

exon 12 sensitive in vitro, responses observedexon 18 D842V poor respons, other mutations sensitivewild type poor response

Predictive value of mutations in the treatment of GIST with imatinib

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 settingwithout specific knowledge of the mechanism of action may lead to ineffective use of potentially very effective new agnets