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Annals of Oncology
1647PD MOLECULAR PROFILING AS AN OUTCOME PREDICTOR IN
THE GALAXY TRIALTM (NCT01348126): A RANDOMIZED
IIB/III STUDY OF GANETESPIB (STA-9090) IN
COMBINATION WITH DOCETAXEL VERSUS DOCETAXEL
ALONE IN SUBJECTS WITH STAGE IIIB/IV NSCLC
R. Rosell 1 , S.S. Ramalingam 2 , D. Fennell 3 , C. Manegold 4 , I. El Hariry 5 ,
V. Vukovic 6 , F. Teofilovici 5 , V. Reichert 7 , G. Goss 8
1 Medical Oncology Service, Catalan Institute of Oncology ICO Badalona Hospital
Germans Trias i Pujol, Medical Oncology, Badalona, SPAIN, 2 Division of Medical
Oncology, Emory University Winship Cancer Institute, Atlanta, GA, UNITED
STATES OF AMERICA, 3 Medicine, University of Leicester, Leicester, UNITED
KINGDOM, 4 Interdisziplinare Thorakale Onkologie, Klinikum Mannheim GmbH,
Mannheim, GERMANY, 5 Oncology, Synta Pharmaceuticals, Lexington, MA,
UNITED STATES OF AMERICA, 6 Clinical Development, Synta Pharmaceuticals
Corp., Lexington, VA, UNITED STATES OF AMERICA, 7 Oncology, Synta
Pharmaceuticals, Lexington, MA, UNITED STATES OF AMERICA, 8 Medical
Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA
Background: Inhibition of Hsp90, a key molecular chaperone required for activation
of many oncoproteins, can lead to cancer cell death. Ganetespib is an Hsp90
inhibitor that has shown single agent activity in molecularly defined disease,
including ELM4-ALK rearrangement, KRAS mutations, HER2 amplification and
BRAF mutations. The AS/RAF/MEK/ERK pathway is a potential therapeutic target
in non-small cell lung cancer (NSCLC).
Methods: This randomized trial compares ganetespib (G) + docetaxel (D) to D in 2 nd
line advanced NSCLC patients. Archival tissue collection was mandatory and
included formalin-fixed paraffin-embedded (FFPE) 10 unstained slides at 5 or 10 um
and 1 matching hematoxylin-eosin (HE)-stained slide. The aim of this study is to
investigate the predictive value of most commonly occurring known mutations in
NSCLC in association with the efficacy of G + D, including KRAS, EGFR, BRCA,
MET, BRAF and others. Genetic mutational analysis was analyzed using Affymetrix
OncoScan FFPE Express platform, which provides information on copy number
variation, allele ration and somatic mutations, Additionally, KRAS mutations were
also analyzed separately using real-time PCR based sequencing. Results are correlated
with baseline demographics and efficacy outcome data.
Results: Approximately 160 of the 300 planned patients were enrolled by early May.
Median age was 60 yrs (range 39-86), M/F: 105/53; adeno/other: 91/67; never/
former/current smokers: 30/77/51. KRAS mutation was detected in 21 of first 140
patients (15%). Full genetic profiling is ongoing, and will be correlated with the
efficacy outcomes from a planned interim analysis in early September, including
disease control rate, PFS, and OS.
Disclosure: I. El Hariry: stock ownership. V. Vukovic: Stock options. F. Teofilovici:
stock options. V. Reichert: stock options. All other authors have declared no conflicts
of interest.
1648P NEOADJUVANT ADDITION OF BEVACIZUMAB TO
CHEMORADIATION IN RECTAL CANCER: IMPACT ON
ANGIOGENIC BIOMARKERS
B. Laquente 1 , J. Capdevila 2 , M. Martínez-Villacampa 3 , C. López 4 , M.J. Safont 5 ,
A. Gómez 6 , J.L. Manzano 7 , C. Grávalos 8 , R. Salazar 3 , E. Aranda Aguilar 6
1 Medical Oncology, ICO. Hospital Duran i Reynals, Barcelona, SPAIN, 2 Medical
Oncology, Hospital Vall d’Hebrón, Barcelona, SPAIN, 3 Medical Oncology, ICO
Hospital Duran i Reynals, Barcelona, SPAIN, 4 Medical Oncology, Hospital
Marqués de Valdecilla, Santander, SPAIN, 5 Medical Oncology, Hospital General
de Valencia, Valencia, SPAIN, 6 Medical Oncology, Hospital Reina Sofía,
Córdoba, SPAIN, 7 Medical Oncology, ICO Hospital Germans Trias i Pujol,
Barcelona, SPAIN, 8 Medical Oncology, Hospital Doce de Octubre, Madrid,
SPAIN
Purpose: We report the clinical results of adding bevacizumab (BEV) to preoperative
chemoradiation (CRT), in patients (pts) with locally advanced rectal cancer (LARC).
This pre-planned sub-study was aimed to evaluate the evolution of several
biomarkers and their correlation with downstaging.
Methods: Patients with LARC were randomized to radiotherapy 45Gy/25f/5 weeks +
capecitabine (CAP: 825mg/m/bid) + BEV every 2 weeks (5 mg/kg for 3 doses) (arm
A) or the same schedule without BEV (arm B): surgery was scheduled 6-8 weeks
after completing CRT. Plasma levels of vascular endothelial growth factor (VEGF),
VEGF receptor 2 (VEGFR-2) and angiopoietin-2 (Ang-2) were measured at baseline
(d1), day 15 (d15) and day 57 (d57). Tissue samples (baseline and at surgery) were
assessed for microvessel density (MVD). Comparisons between concentrations at
different time points were assessed by using appropriate statistical paired tests.
Logistic regression model was adopted to estimate and test the biomarkers for their
association with downstaging.
Results: Samples for biomarker analyses were obtained for 50 out of 90 randomized
pts (arm A/B: 22/28): paired plasma samples were available for 18/23 pts at d1 and
d15, and for 14/17 pts at d57; paired tumor samples were obtained from 12/18 pts.
Eleven pts in each arm were downstaged (lower pT compared with the pretreatment
cT). No differences were observed in baseline levels of any biomarker between both
arms. Ang-2 levels were significantly higher in arm B than in arm A at d15 and d57
(p = 0.0056 and p = 0.0133, respectively). Ang-2 levels significantly decreased at d15
only in arm A (p < 0.05 ). Plasma Ang-2 levels decreased in arm A and increased in
arm B (p < 0.05 at all time points). There were no significant changes in other
biomarker levels. Overall, decrease in Ang-2 levels from baseline to d57, was
significantly associated with tumor downstaging (OR: 0.95, p < 0.0001).
Conclusions: Additional larger tailored studies are needed to corroborate the observed
association between decreasing Ang-2 levels, tumoral downstaging and the role of
Bevacizumab in this effect.
Disclosure: E. Aranda Aguilar: Consultant or Advisory Role: Roche and Merck
Serono. All other authors have declared no conflicts of interest.
1649P MUTATIONS IN NRAS CODON 61 AND KRAS CODON 146
ARE POOR PROGNOSTIC FACTORS IN PATIENTS WHO
RECEIVED ANTI-EGFR MONOCLONAL ANTIBODY FOR
METASTATIC COLORECTAL CANCER
N. Takahashi 1 , Y. Yamada 1 , H. Taniguchi 2 , Y. Honma 3 , S. Iwasa 3 , K. Kato 4 ,
T. Hamaguchi 5 , Y. Shimada 3
1 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo,
Japan., Tokyo, JAPAN, 2 Division of Pathology, National Cancer Center Hospital,
Tokyo, JAPAN, 3 Gastrointestinal Oncolgoy, National Cancer Center Hospital,
Tokyo, JAPAN, 4 Gastrointestinal Oncology, National Cancer Center Hospital,
Tokyo, JAPAN, 5 Gastrointestinal Oncology Division, National Cancer Center
Hospital, Tokyo, JAPAN
Background: Previous studies showed that gene mutations (NRAS, BRAF, PIK3CA)
are associated with a poor prognosis or resistance of anti-EGFR antibody in
metastatic colorectal cancer (mCRC) patients with wild type (WT) of KRAS codon
12/13 (KRAS-WT). However the significance of these biomarkers has not been
clarified. In addition, EGFR immunohistochemistry (IHC) and EGFR gene
amplification by DISH to evaluate the efficacy of anti-EGFR antibody treatment has
not been reported for mCRC.
Method: We evaluated tumor response and survival in patients who received anti-EGFR
antibody by mutation analysis of KRAS, NRAS, BRAF, and PIK3CA in KRAS-WT
patients with mCRC. Tumor DNA samples were obtained from patients treated in our
hospital with anti-EGFR antibody between August 2008 and August 2011.
Result: A total of 117 patients were eligible for this analysis, including 100
KRAS-WT patients. Seventy-one patients (60.7%) were all WT for KRAS, NRAS,
BRAF, and PIK3CA, and 46 patients (39.3%) had at least 1 mutation or had
insufficient DNA samples to analyze. Mutations of KRAS codon 61 (2 patients),
KRAS codon 146 (5), BRAF V600E (2), PIK3CA exon9 (8), NRAS codon 12/13 (2),
and NRAS codon 61 (5) were detected. No patients had a mutation of PIK3CA exon
20. Patients with at least 1 mutation had no response. Mutations of KRAS codon
146, NRAS 61, and BRAF V600E were associated with a shorter progression free
survival (PFS) compared with all WT patients (p = 0.049, p = 0.004, p = 0.036,
respectively). Twelve patients (12% of KRAS-WT patients) with a mutation of KRAS
codon 146, BRAF V600E, NRAS codon 61 had poor prognosis compared with the
other KRAS-WT patients (PFS, 6.4 vs 2.0 months, p < 0.001; overall survival (OS),
13.7 vs 7.9 months, p = 0.012). In all WT patients, EGFR IHC 3+ and gene
amplification by DISH were associated with a better response rate than negative and
weak IHC and no gene amplification (p = 0.046). Conclusion: Mutations of KRAS
codon 146, NRAS codon 61, and BRAF V600E were a strong prognostic factor of
anti-EGFR antibody in patients with mCRC. Combination of IHC and DISH of
EGFR could identify patients with a tumor response to anti-EGFR antibody in
patients that are all wild type for KRAS, NRAS, BRAF, and PIK3CA.
Disclosure: All authors have declared no conflicts of interest.
1650P ANALYSIS OF CD40 EXPRESSION ON CIRCULATING
COLORECTAL CANCER CELLS
M. Torchio 1 , G. Comolli 2 , M. Danova 1 , G. Mazzini 3
1 Medical Oncology and Internal Medicine, Azienda Ospedaliera della Provincia di
Pavia, Ospedale Civile di Vigevano, Vigevano, ITALY, 2 Microbiology and
Molecular Biology, IRCCS San Matteo Pavia, Pavia, ITALY, 3 IGM-CNR di Pavia,
Istituto di Genetica Molecolare IGM-CNR, Pavia, ITALY
Background: In colorectal cancer circulating tumor cells (CTCs) can be clinically
relevant as: prognostic factor and predictive biomarker for treatment efficacy. The
detecting and the carachterization of CTCs remains technically challenging. The cell
surface costimulatory molecule CD40, widely expressed by lymphoid cells and by
various tumour types, has been indicated as prognostic/predictive biomarker and as a
potential target for therapy. In the present study we wanted to demonstrate the value
of a multiparameter flow cytometry (FCM) approach for the detection and the
characterization of circulating colorectal cancer cells in vivo.
Methods: SW48 and HCT116 human colorectal cancer cells (highly positive for
CD40) were serially diluted in normal whole blood to evaluate the sensitivity of the
method in both the cancer cell identification and characterization for CD40
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds417 | ix529