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