these abstracts are from the SAME SOURCE and look
at ERBITUX ....
aacr.org
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B106
Cetuximab Improves Locoregional Control and Survival of Locoregionally Advanced Head and Neck Cancer:
Independent Review of Mature Data with a Median Follow-up of 45 Months.
J A. Bonner,1 P M. Harari,2 J Giralt,3 N
Azarnia,4 R B. Cohen,5 C Jones,6 R Sur,7 D Raben,8 J Baselga,3 S Spencer,1 N Amellal,
9 E Rowinsky,4 K K. Ang.10 Univ of AL at Bham (UAB),1 Birmingham, AL, Univ of
WI,2 Madison, WI, Hosp Vall d'Hebron,3 Barcelona, Spain, Spain, ImClone Systems,4
Branchburg, NJ, Fox Chase Cancer Center,5 Philadelphia, PA, Sutter Cancer Center,6
Sacramento, CA, Johannesburg Hospital,7 South Africa, Africa, South Africa, Univ of
Colorado,8 Aurora, CO, Merck KGaA,9 Paris, France, France, MD Anderson Cancer
Center,10 Houston, TX.
Introduction:
This phase III trial was undertaken to determine whether the epidermal growth factor receptor blocking IgG1 antibody cetuximab improves locoregional disease control (LRC) and survival when added to radiotherapy (RT) in locoregionally
advanced squamous cell carcinoma of the head and neck (SCCHN).
This report summarizes mature study results, including a determination of the primary endpoint, LRC,
by an Independent Clinical Review Committee (ICRC).
Methods:
Patients with locoregionally advanced SCCHN with measurable disease were randomized to treatment with
either definitive RT alone or definitive RT plus weekly cetuximab, at an initial dose of 400 mg/m2 followed by 250 mg/m2 for the duration of RT.
The patients were stratified according to Karnofsky performance status, tumor stage,
nodal involvement, and RT fractionation regimen.
To ensure consistency and objectivity, the investigator generated data pertaining to LRC were submitted for blinded review by an ICRC, utilizing uniform guidelines developed prospectively.
Results:
424 total patients underwent randomization to
RT plus cetuximab (211)
or RT alone (213).
The median age of the patients was 57,
of whom 80% were male,
68 percent had Karnofsky performance
status of 90-100%;
and 60%, 25%, and 15% had oropharyngeal, laryngeal, and hypopharyngeal primary tumors, respectively.
The treatment arms were well balanced with regard to relevant demographic and stratification factors.
The addition of cetuximab to RT significantly improved both LRC and survival.
The median durations of LRC were 24.4 and 14.9 months (log-rank p=0.005), favoring RT plus cetuximab.
The addition of cetuximab to RT reduced the risk of locoregional failure by 32% (hazard ratio
= 0.68).
At 2 years, 50% and 41% of patients in the RT plus cetuximab and RT arms had LRC, respectively.
The median survival times were 49 and 29 months [median follow- up, 45 months], favoring RT plus cetuximab.
There was a 26% reduction in the risk of mortality (hazard ratio = 0.74, log-rank p = 0.03). The 3-year survival rates were 56% and 45% in favor of RT plus cetuximab.
Except for acneiform rashes and infusion
reactions the incidence of grade 3 or 4 toxicity did not differ between the arms.
Conclusions:
An independent review of mature data from a randomized study has confirmed that the addition of cetuximab to definitive RT improves LRC and survival in patients with locoregionally advanced SCCHN. This clinical benefit was achieved with
minimal augmentation of the toxicities of definitive radiotherapy. These results confirm an earlier report after a median follow-up of 28 months (Proc ASCO 22(14S), #5507,
489s, 2004). The regimen of cetuximab and RT represents a unique, new therapeutic option for treating locoregional SCCHN and a platform for additional efforts aimed at
further improvements in outcome.
===========================================================
A103
Increased Anti-tumor Efficacy of Cetuximab (Erbitux) with Chemotherapy
in Human Non-small Cell Lung Cancer (NSCLC) Xenografts Harboring Mutations
in the Epidermal Growth Factor Receptor (EGFR). Philipp Steiner, Christopher
Joynes, Francine Carrick, Bridget Finnerty, Erik Corcoran, Chris Damoci, Jessica
Kearney, Robin Rolser, Cindy Wang, Jacqueline Doody, Yaron Hadari, James R. Tonra,
Daniel J. Hicklin. ImClone Systems, Inc., New York, NY.
Targeting EGFR is a validated approach for the treatment of cancer. Cetuximab is a
monoclonal IgG1 antibody that blocks intracellular signaling through binding to EGFR.
Consequently, tumor growth is inhibited by cetuximab in various preclinical models.
Recently, several mutations were identified in the kinase domain of EGFR which can
modulate clinical response of NSCLC patients to EGFR inhibitors.
Therefore, we determined
the efficacy of cetuximab in NSCLC xenograft tumor models utilizing lines
that are either wild-type (wt) or have mutations in EGFR. We found that cetuximab exhibited
strong anti-tumor activity in EGFR(wt)-expressing A549, NCI-H292 (H292) and
H358 xenografts. Xenograft tumors from H1975 cell lines which harbor the L858R
and T790M EGFR mutations were equally susceptible to cetuximab treatment while
growth of H1650 tumors containing del746-750 mutation was moderately inhibited.
To establish treatment protocols causing tumor regression rather than tumor stasis cetuximab
was combined with various cytotoxic agents in the H292 and H1975 models.
Using H292 xenografts we found that cetuximab and docetaxel combination therapy
was more efficacious than cetuximab and docetaxel alone. Nine out of 10 mice showed
regressions in the combination group while only 1/10 regressions was found for both
cetuximab and docetaxel monotherapy. Furthermore, cisplatin augmented efficacy of
cetuximab with six out of 10 regressions found in the combination group while no tumor
regression was observed in the cisplatin group and one in the cetuximab group.
Increased efficacy of cetuximab combination treatments was also observed with gemcitabine,
carboplatin or pemetrexed but with fewer regressions compared to above
cetuximab and docetaxel or cisplatin combination treatments.
In the H1975 model,
gemcitabine strongly increased efficacy of cetuximab. All 12 tumors in the combination
group regressed while there were four regressions in the cetuximab and one
regression in the gemcitabine monotherapy groups. However, all 12 tumors relapsed
25 days after ending treatment. Docetaxel combined with cetuximab was more efficacious
than single treatments with 10/12 regressions compared to 2/12 regressions
for cetuximab and no regression for docetaxel monotherapies. Cisplatin, carboplatin
and pemetrexed did not augment efficacy of cetuximab in the H1975 model.
In summary,cetuximab treatment was active as monotherapy in NSCLC models with wt and
mutated EGFR expression. Combining cetuximab with gemcitabine or docetaxel further
increased efficacy of cetuximab in a tumor model harboring mutated EGFR. These
findings may be of importance for the clinical management of patients with chemo-refractory
NSCLC.
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A107
Combined Anti-EGFR Blockade: A Phase I Pharmacokinetic and Molecular
Pharmacodynamic Study of Cetuximab (Erbitux) and Gefitinib (Iressa) in
Patients with Advanced Colorectal, Head and Neck and Non-small Cell Lung
Cancer Expressing the EGFR.
Josep Tabernero,1 Patrick Schffski,2 Fredi Rojo,1 Ernst
de Bruijn,2 Francisco J. Ramos,1 Herlinde Dumez,2 Teresa Macarulla,1 Hans Prenen,2
Esther Casado,1 Gunther Guetens,2 Vicen Peralta,1 Jos Jimnez,1 Josep M. del Campo,1
Neus Gascon,3 Rosana Cajal,4 Erika Martinelli,1 Enric Jimnez,3 Allan T. Van Oosterom,2
Jose Baselga.1 Vall d'Hebron University Hospital,1 Barcelona, Spain, University Hospital
Gasthuisberg,2 Leuven, Belgium, Merck Farma y Qumica,3 Barcelona, Spain, Astra
Zeneca,4 Madrid, Spain.
Background:
The Epidermal Growth Factor Receptor (EGFR) plays a critical role in the
growth and survival of epithelial tumors. The monoclonal antibody (MAb) Cetuximab
(C) and the tyrosine kinase inhibitor (TKI) Gefitinib (G) are two anti-EGFR agents with
different mechanisms of action. We had previously shown a synergistic effect combining
the two agents, both in in vitro models and in xenografts, with superior inhibition
of EGFR, MAPK and Akt activation, as well as greater inhibition of cell proliferation
and vascularization and enhanced apoptosis than either treatment alone, resulting in
the regression of large tumors (Matar et al, Clin Cancer Res 2004). This phase I study
aims to explore safety, pharmacokinetics (PK) and molecular pharmacodynamic (PD)
changes in skin and tumor at different doses of C/G to define the recommended dose
(RD) for further development of this combination. Methods: Patients (pts) with advanced
colorectal (CRC), head and neck (HNC) and non-small cell lung cancer (NSCLC)
were treated at the RD of weekly iv C (loading dose 400 mg/m2 / continuation dose
250 mg/m2) and oral daily G (250 mg/d) as single agents (5 pts each) and in successive
cohorts of combined C/G (3-6 pts each): C (320/200) / G (100), C (400/250) / G (100),
C (400/250) / G (250), C (320/200) / G (500) and C (400/250) / G (500) (ongoing). Dose
escalation depended on dose limiting toxicity (DLT) rate during the first 4-week period.
Pre- and on-treatment steady-state (14 days) skin and tumor biopsies were obtained
from each pt and have been evaluated by immunohistochemistry (IHC) for total (t) and
phospho (p)-EGFR, p-MAPK, p-Akt, proliferation (Ki67) and p27 expression. Results:
29 patients have been treated so far: 16 CRC, 12 HNC & 1 NSCLC; median KI 90 %
(70-100); median age 60 years (38-80); 20 males, 9 females. Grade 3 adverse events
occurred in 5 pts: 1 pt with G alone with dyspnea and reversible interstitial lung disease;
and 3 pts with C/G comprising abdominal pain, venous thrombosis and reversible
deafness. There were 1 CR (HNC), 4 PRs (CRC) & 3 SD >6 weeks (2 HNC, 1 NSCLC) in
the C/G cohorts; 1 PR (CRC) in the C cohort and 3 SD (3 HNC) in the G cohort. Preliminary
PD studies show superior inhibition of p-EGFR, p-MAPK and p-Akt (p=0.05)
and reduction of proliferation (p=0.024) in the tumors of patients treated with C/G
compared with the single agent cohorts. Preliminary PK studies have shown no PK
interactions with the 2 drugs. Conclusions: This combination of an anti-EGFR MAb (C)
and a TKI (G) is feasible at the RD of both agents. Our findings suggest encouraging
clinical activity and superior PD signaling inhibition with the combination without any
significant PK interaction. Combined anti-EGFR therapy deserves further evaluation.
========================================================
A121
ErbB /HER Pathway Profiling in Formalin-Fixed Paraffin Embedded Preclinical
Xenograft Models Using Multiplexed Proximity Based Assays.
Rajiv Dua,
Yining Shi, Liching Cao, Ali Mukherjee, Yuping Tan, Herjit Pannu, Jagrup Pannu, Laura
Jarvis, Ahmed Chenna, Sharat Singh. Monogram Biosciences, S. San Francisco, CA.
The EGFR, ErbB2 , ErbB3 and ErbB4 are members of the Type I receptor tyrosine
receptor kinase family (also known as HER or ErbB family). Overexpression of these
receptors found in a number of cancers (e.g. breast, colon, ovarian, Lung) has aggressive
phenotype with poor prognosis. Homodimerization and heterodimerization
of the ErbB /HER receptors has been demonstrated to be a prerequisite to pathway
activation and thus molecular assays that measure these dimerization events will be
useful to understand the contribution of activated pathway in the progression of cancer.
Recently, it has been suggested that full range of EGFR/HER1 related signaling
pathway is essential and is likely to discover novel panel of molecular biomarkers Here,
we report the application of novel proximity based assays to detect and quantify various
HER dimers in formalin fixed-paraffin embedded (FFPE) preclinical xenograft tissue
models. In this assay, the sample was first deparaffinized and rehydrated by regular xylene/
ethanol/water protocols. After antigen retrieval, the sample was incubated with a
mixture of erbB specific antibodies conjugated either with reporter eTagTM or a chemical
scissor. The reporter eTag were then released based on its proximity to the scissors.
The released eTags were separated by capillary gel electrophoresis and quantified
by eTag-informerTM software. Multiplexed format assays were developed to quantify
the levels of HER1/HER1, HER1/HER2, HER2/HER3, and HER1/HER3 homo- and hetero-
dimers in the FFPE sample. Cytokeratin was used as an internal reference control
for the total cellular content. The assays were used to profile HER dimers in various
types of lung, ovarian, breast, colon, and prostate xenografts. The data demonstrated
the simultaneous detection and quantification of HER receptor expression, dimerization
and phosphorylation in a single tissue section. The validity of the detection and
quantification of HER dimers in FFPE tissue samples was independently confirmed by
eTag assays in total cell lysates from the same tissues.
We conclude that the eTag assays
are simple, sensitive and provide a quantitative assessment of various HER dimers
from the same sample. We will discuss the activation status of ErbB /HER receptor
in xenograft models for the correlation of predictive response to EGFR/HER1 targeted
therapies (e.g. Iressa, Tarceva, and Erbitux).
=========================================================
A127
Effect of Erbitux, Erlotinib, Gefitinib and Rapamicine on the Inhibition
of EGFR Dimer Formation and Downstream Signaling Pathways in Different
Cancer Cell Lines.
Hossein Salimi-Moosavi, Xueguang Jin, Youssouf Badal, Ali
Mukherjee, Hasan Tahir, Sharat Singh. Monogram Biosciences, Inc., S. San Francisco,
CA.
Epidermal Growth Factor Receptor (EGFR) overexpression is associated with several
human cancers. It thus serves as a potential target for therapeutic intervention in a
number of cancer types including lung, ovarian and breast cancers. As the use of
targeted therapies increase, it is important to have the diagnostic tools that can identify
patient populations most likely to benefit from these drugs. This report describes
the use of eTag assays to measure the effects of several of these drugs on growth
factor stimulated cancer cell lines. Nine different cancer cell lines, DU145, BT474,
MDA-MB-468, MDA-MB-231, T47D, Colo205, A549, HCT116 and NCI-H358 were
selected. Serum starved cells were treated for 3 hours with either 100 nM Gefitinib, or
100 nM Erlotinib, or 100 nM Rapamycine, or 100 g/ml Erbitux, or no drug treatment.
These drug treated cells were further stimulated with 100 nM EGF, EGF + HRG, EGF +
HRG + IGF1. The cells were lysed and then analyzed for EGFR/HER receptor dimerization
and downstream signaling pathway activation. The results showed Erbitux selectively
inhibited the EGFR phosphorylation but not HER2 or HER3 phosphorylation, while
Gefitinib and Eroltinib inhibited EGFR as well as HER2 and HER3 phosphorylation under
the experimental conditions. The inhibition of Shc/HER1and MAPK was observed
where the EGFR TK was inhibited. Furthermore, Erbitux inhibited EGFR homodimerization
as well as HER1/2 heterodimerizaton while Gefitinib and Erlotinib increased the
formation of inactive HER1/1 and HER1/2 dimerization while inhibiting EGFR phosphorylation.
HER2/3 dimer formation was not affected by any of these drugs.
Inhibition of
HER3/PI3K and Akt pathways were observed in BT474 cells treated with Gefitinib and
Eroltinib. The data presented in this poster demonstrates unique capability of pathway
profiling to predict response to targeted therapies. The data presented in this poster
demonstrates that eTags can be used to profile receptor signaling pathways. Thus this
system has the unique capability to screen small molecule and antibody drug candidates
for their efficacy and to predict their effects on the activated pathways being
===================================================================
B68
Cetuximab (ERBITUX) Enhances Clinical Efficacy of Oxaliplatin in Human
Colon Carcinoma Xenografts and Reverses Oxaliplatin Resistance.
Marie
Prewett,1 Rajiv Bassi,1 Francine Carrick,1 Bridget Finnerty,1 Lee M. Ellis,2 Larry Witte,1
James R. Tonra,1 Daniel J. Hicklin,1 Fan Fan.2 ImClone Systems Incorporated,1 New
York, New York, University of Texas, MD Anderson Cancer Center,2 Houston, Texas.
Epidermal growth factor receptor (EGFR), a protein tyrosine kinase activated in many
types of human cancers, has been strongly associated with tumor progression. Cetuximab
(ERBITUX) is an anti-EGFR chimeric mouse/human monoclonal antibody that
has been approved in the United States for the treatment of advanced colon cancer.
In this report, we studied the in vivo therapeutic activity of cetuximab combined
with oxaliplatin therapy in two models of oxaliplatin-resistant colon carcinoma.
Mice bearing oxaliplatin-resistant HT29-OxR or KM12-OxR colon carcinoma xenografts
were treated with (1) cetuximab (40mg/kg, i.p., 3x/week), (2) oxaliplatin (12 mg/kg,
i.p., q7d), or (3) cetuximab and oxaliplatin. Treatment with cetuximab alone inhibited
the growth of oxaliplatin-resistant HT29-OxR (T/C% = 73%) and KM12-OxR (T/C%
= 78%) xenografts (P < 0.05 for HT29-OxR).
Oxaliplatin, at a dose previously shown
to inhibit parental HT-29 xenograft growth, had minimal activity in these two models
(T/C% = 87% and 84%, respectively). The combination of cetuximab/oxaliplatin however,
was much more active than either cetuximab or oxaliplatin alone in both models
(T/C% = 33% and 50% for HT29-OxR and KM12-OxR, respectively).
Histological examination
of residual tumors after combination treatment will evaluate mitotic figures
and the percent viable tumor area. The present study supports combining cetuximab
with oxaliplatin therapy for increased anti-tumor effects in both oxaliplatin sensitive
and resistant colon cancer.
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B67
Molecular Targeting of Methotrexate to EGFR Positive Brain Tumors by
Means of Antibody-Dendrimer Bioconjugates. Gong Wu, Rolf F. Barth, Weilian
Yang, Shinji Kawabata, Liwen Zhang, Kari Green-Church. The Ohio State University,
Columbus, Ohio.
The purpose of the present study was to determine if a monoclonal antibody(mAb)-
MTX bioconjugate had the requisite properties for molecular targeting of an experimental
rat glioma. Due to the overexpression of EGFR and EGFRvIII in malignant
gliomas, a variety of agents targeting either the extracellular ligand binding domain or
the intracellular tyrosine kinase region of EGFR currently are among the most promising
therapeutics being clinically evaluated.
Cetuximab, previously known as C225,
which binds to both EGFR and EGFRvIII, has been one of the most intensively studied
mAb directed against these receptors. In the present study we have covalently linked
cetuximab via its Fc region to a 5th generation (G5) polyamidoamino (PAMAM) dendrimer
containing methotrexate (MTX) using two heterobifunctional reagents, SPDP
and KMUH (Bioconjugate Chem. 15:185, 2004).
As measured by mass spectrometry
and UV/vis spectroscopy, the resulting bioconjugate, designated C225-G5-MTX,
contained 12.6 molecules of MTX per molecule of dendrimer. Specific binding and
cytotoxicity of the bioconjugate was evaluated against the EGFR expressing rat glioma
cell line F98EGFR. Using a competitive binding assay, it was shown that the bioconjugate
retained its affinity for F98EGFR cells, but with a ~0.8 log unit decrease in its effective
concentration (EC50). Only cetuximab completely inhibited binding of the bioconjugate,
which was unaffected by MTX or dendrimer. Cetuximab alone was not cytotoxic
to F98EGFR cells at the concentrations tested, while in contrast, the inhibitory concentration
(IC50) of the bioconjugate was 220 nM, which was a 2.7 log unit decrease in
cytotoxicity compared to that of free MTX. The biodistribution of C225-G5-MTX in rats
bearing intracerebral implants of either F98EGFR or EGFR(-) F98 wildtype (wt) gliomas
was determined 24 h following convection enhanced delivery (CED) of 125I-labeled
bioconjugate. At this time 62.9 14.7 % of the injected dose of radioactivity/gram
(ID/g) tumor was localized in rats bearing F98EGFR gliomas versus 11.3 3.6 % in animals
bearing F98WT gliomas, thereby demonstrating specific molecular targeting of
the tumor. The corresponding values for normal brain from the tumor bearing right
and non-tumor bearing left cerebral hemispheres were 5.8 3.4%and 0.8 0.6%ID/g
brain, respectively. Based on these encouraging results, therapy studies were initiated
in F98EGFR glioma bearing rats.
Animals that received C225-G5-MTX, cetuximab or free
MTX by CED had median survival times of 15, 17 and 19.5 d, respectively, which were
not statistically different from each other or untreated control animals. These results,
which are both positive and negative, demonstrate that specific molecular targeting is
but one of a number of requirements that must be fulfilled if an antibody-drug bioconjugate
will be therapeutically useful. (Supported by National Institutes of Health grant
===========================================================
B106
Cetuximab Improves Locoregional Control and Survival of Locoregionally
Advanced Head and Neck Cancer:
Independent Review of Mature Data with a Median Follow-up of 45 Months.
J A. Bonner,1 P M. Harari,2 J Giralt,3 N
Azarnia,4 R B. Cohen,5 C Jones,6 R Sur,7 D Raben,8 J Baselga,3 S Spencer,1 N Amellal,
9 E Rowinsky,4 K K. Ang.10 Univ of AL at Bham (UAB),1 Birmingham, AL, Univ of
WI,2 Madison, WI, Hosp Vall d'Hebron,3 Barcelona, Spain, Spain, ImClone Systems,4
Branchburg, NJ, Fox Chase Cancer Center,5 Philadelphia, PA, Sutter Cancer Center,6
Sacramento, CA, Johannesburg Hospital,7 South Africa, Africa, South Africa, Univ of
Colorado,8 Aurora, CO, Merck KGaA,9 Paris, France, France, MD Anderson Cancer
Center,10 Houston, TX.
Introduction:
This phase III trial was undertaken to determine whether the epidermal
growth factor receptor blocking IgG1 antibody cetuximab improves locoregional
disease control (LRC) and survival when added to radiotherapy (RT) in locoregionally
advanced squamous cell carcinoma of the head and neck (SCCHN).
This report summarizes mature study results, including a determination of the primary endpoint, LRC,
by an Independent Clinical Review Committee (ICRC).
Methods:
Patients with locoregionally advanced SCCHN with measurable disease were randomized to treatment with
either definitive RT alone or definitive RT plus weekly cetuximab, at an initial dose of
400 mg/m2 followed by 250 mg/m2 for the duration of RT.
The patients were stratified according to Karnofsky performance status, tumor stage,
nodal involvement, and RT fractionation regimen.
To ensure consistency and objectivity, the investigator generated
data pertaining to LRC were submitted for blinded review by an ICRC, utilizing
uniform guidelines developed prospectively.
Results:
424 total patients underwent randomization to
RT plus cetuximab (211)
or RT alone (213).
The median age of the patients was 57,
of whom 80% were male,
68 percent had Karnofsky performance
status of 90-100%;
and 60%, 25%, and 15% had oropharyngeal, laryngeal, and hypopharyngeal
primary tumors, respectively.
The treatment arms were well balanced
with regard to relevant demographic and stratification factors.
The addition of cetuximab
to RT significantly improved both LRC and survival.
The median durations of LRC
were 24.4 and 14.9 months (log-rank p=0.005), favoring RT plus cetuximab.
The addition
of cetuximab to RT reduced the risk of locoregional failure by 32% (hazard ratio
= 0.68). At 2 years, 50% and 41% of patients in the RT plus cetuximab and RT arms
had LRC, respectively. The median survival times were 49 and 29 months [median follow-
up, 45 months], favoring RT plus cetuximab.
There was a 26% reduction in the
risk of mortality (hazard ratio = 0.74, log-rank p = 0.03). The 3-year survival rates were
56% and 45% in favor of RT plus cetuximab.
Except for acneiform rashes and infusion
reactions the incidence of grade 3 or 4 toxicity did not differ between the arms.
Conclusions:
An independent review of mature data from a randomized study has
confirmed that the addition of cetuximab to definitive RT improves LRC and survival in
patients with locoregionally advanced SCCHN. This clinical benefit was achieved with
minimal augmentation of the toxicities of definitive radiotherapy. These results confirm
an earlier report after a median follow-up of 28 months (Proc ASCO 22(14S), #5507,
489s, 2004). The regimen of cetuximab and RT represents a unique, new therapeutic
option for treating locoregional SCCHN and a platform for additional efforts aimed at
further improvements in outcome. |
