Is targeted therapy ready for the adjuvant setting ?

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Is targeted therapy ready for the adjuvant
setting ? Emile E. Voest Department of Medical
Oncology UMC Utrecht
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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
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Targeted therapy has proven efficacy in Breast
cancer tamoxifen aromatase inhibitors trastuzu
mab Prostate cancer LH/RH agonists Colorectal
cancer cetuximab bevacizumab
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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 2004431525-526
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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 10113306-13311
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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 3041458-1461 Also
Lynch et al. NEJM 2004350 2129-2139
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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
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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.
200119120725
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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
Proliferation
Survival
Migration
Permeability
ANGIOGENESIS
PDGF platelet-derived growth factor IGF-1
insulin-like growth factor 1IL-8 insulin-like
growth factor 8
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EGFR expression in human cancer
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The importance of EGFR as a target
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Activation of EGFR plays an essential role in
cellular survival and proliferation programs
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Anti-vascular therapies
Phase III study of bevacizumab (Avastin) in
combination with standard chemotherapy for
advanced colorectal cancer IFL/Placebo IFL/BV
p value n412 n403 Median
survival 15.6 20.3 0.00003 PFS 6.24 10.6 lt
0.00001 Objective responses 35 45 0.0029 Dura
tion of response 7.1 10.4 0.0014
Hurwitz H, et al. N Engl J Med 2004350233542
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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 (gt20) and were
taken off study Grade 1 or 2 toxicity
included Nausea 56 Diarrhea 51 Stomatitis 4
4 Fatigue/astenia 78
Motzer RJ et al. ASCO 2004, abstract 4500
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Two negative studies ??
1073 and 1039 patients were entered in both
trials, respectively
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Mutations in EGFR predict respons to treatment
and differ in ethnic backgrounds
Paez et al. Science 2004 3041497-1500 Lynch et
al. New Engl J Med 20043502129-2139
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Frequency of involvement of KIT exon 11 codons by
mutations in 322 gastrointestinal stromal tumors
Corless, C. L. et al. J Clin Oncol 223813-3825
2004
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Immunohistochemistry for KIT in gastrointestinal
stromal tumors (GISTs) harboring KIT versus
PDGFRA mutations
Corless, C. L. et al. J Clin Oncol 223813-3825
2004
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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
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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

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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

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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
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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