Transcript Document

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
Malignant
tumor
Tumor
growth
Vascular
invasion
Dormant
micrometastasis
Overt
metastasis
(Avascular
tumor)
(Angiogenic
switch)
(Vascularized
tumor)
(Tumor cell
intravasation)
(Seeding in
distant 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
Tumor characteristics and environment promote
VEGF expression
Hypoxia
EGF
PDGF
IGF-1
IL-8
Binding and activation
of VEGFR
VEGF release
bFGF
COX-2
NO
Oncogenes
Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
P–
P–
–P
–P
Survival Proliferation
Migration
Permeability
ANGIOGENESIS
PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1
IL-8 = insulin-like growth factor 8
EGFR expression in human cancer
Colorectal cancer
75-82%
Lung cancer (NSCLC)
40-91%
Head & neck cancer
90100%
Gastric cancer
33-74%
Ovarian cancer
35-70%
EGF
TGFalpha
Amphiregulin
Betacellulin
Epiregulin
HER 1
EGFR
ErbB1
No known ligand
HER 2
ErbB2
Neu
Epiregulin
Neuregulins
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
IFL/Placebo
n=412
Median survival
15.6
PFS
6.24
Objective responses
35%
Duration of response
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
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
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
best respons to imatinib
exon 9
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