Annual Meeting Proceedings Part 1 - American Society of Clinical ...

360s Head and Neck Cancer
5516^ Poster Discussion Session (Board #6), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Cilengitide with cetuximab, cisplatin, and 5-FU in recurrent and/or metastatic
squamous cell cancer of the head and neck: The ADVANTAGE phase
II trial. Presenting Author: Jan Baptist Vermorken, Department of Medical
Oncology, Antwerp University Hospital, Edegem, Belgium
Background: Prognosis for patients with recurrent and/or metastatic squamous
cell cancer of the head and neck (R/M-SCCHN) is very poor. �v�5
integrin is overexpressed in SCCHN and selective integrin blockade is being
investigated as a treatment strategy. Methods: ADVANTAGE was a phase I/II
study evaluating cilengitide with cetuximab and platinum-based chemotherapy.
Eligible patients were �18 years with �1 measurable lesion,
Karnofski performance status �70%, and confirmed R/M-SCCHN. The
phase II part reported herein was an open-label, randomized, controlled
trial investigating progression-free survival (PFS) in patients treated with 2
cilengitide 2000 mg regimens: once weekly (CIL1W) and twice weekly
(CIL2W) administration combined with cisplatin, 5-FU, and cetuximab
(PFE) as compared with PFE alone (control). Secondary objectives included
overall survival (OS) and objective response (OR). Treatment-emergent
adverse events (TEAEs) were monitored. Results: 184 eligible patients were
enrolled. Overall, patient characteristics were similar across arms. Median
duration of treatments was shorter in the CIL2W arm compared with the
CIL1W arm (cilengitide: 16.1 vs 23.4 wk, cetuximab: 16.0 vs 22.6 wk,
platinum: 16.0 vs 18.0 wk, and 5-FU: 14.6 vs 18.0 wk). Median PFS was
6.4 months in the CIL1W group, 5.6 months in the CIL2W group and 5.7
months in the control group, with CIL1W and CIL2W having HRs of 1.03
(95% CI: 0.67–1.59) and 1.55 (95% CI: 0.99–2.43) vs control. The latter
HR was possibly due to less compliance in the CIL2W arm. Median OS was
12.4, 10.6, and 11.6 months in the CIL1W, CIL2W, and control groups,
respectively. ORs were observed in 46.8%, 26.7%, and 35.5% of patients
in the CIL1W, CIL2W, and control arms, respectively. Most common
(�15%) grade 3/4 TEAEs were neutropenia, hypokalemia, leukopenia,
stomatitis, and fatigue. No safety differences were noted between treatment
arms. Overall, there were 7 drug-related TEAEs (2 in CIL1W, 2 in
CIL2W, and 3 in control) leading to death. Conclusions: In this population,
neither of the cilengitide-containing regimens was able to demonstrate a
PFS benefit over PFE alone.
5518 Poster Discussion Session (Board #8), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Lenvatinib treatment of advanced RAI-refractory differentiated thyroid
cancer (DTC): Cytokine and angiogenic factor (CAF) profiling in combination
with tumor genetic analysis to identify markers associated with
response. Presenting Author: Douglas Wilmot Ball, The Johns Hopkins
University School of Medicine, Baltimore, MD
Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting
VEGFR1-3, FGFR1-4, RET, KIT and PDGFR�. In a phase II study of
lenvatinib, 58 patients (pts) with DTC were enrolled and a response rate of
50% was observed (Sherman, ASCO 2011). Methods: Pts received lenvatinib
at a starting dose of 24 mg oral once daily in 28-day cycles. Serum
was collected at baseline (BL), on day 8 and on day 36 and concentrations
of 47 CAFs were measured using multiplex bead arrays and enzyme-linked
immunosorbent assay (ELISA). 33 genes (443 mutations) were examined
in archival tumor tissues (n�25). Association of baseline CAF, changes in
CAF levels upon treatment and gene mutation status with treatment
outcomes was investigated. Results: Combination of low baseline VEGF and
ANG-2 (p�0.02 and HR�0.386) correlated with longer PFS. Both
baseline and changes in CAF levels demonstrated an association with gene
mutation status. High baseline levels of VEGF were observed in pts with
wild type RAS and BRAF (p�0.035) whereas high baseline sTIE-2 levels
associated with RAS mutation (p�0.023). Supporting pre-clinical mouse
xenograft tumor model developed using ANG2-overexpressing human
thyroid cancer cell line FTC-286 demonstrated reduced sensitivity to
lenvatinib treatment. Increased levels of IL-10 and FGF-2 8-day posttreatment
(8d post-tx) significantly associated with RAS (N- or K-) and
BRAF mutation. Combination of gene mutation status with baseline CAF
levels provided better prediction of longer PFS compared to gene mutation
alone. Hierarchical clustering modeling using changes in CAF levels 8d
post-tx with tumor shrinkage identified a set of CAFs that could predict two
categories of lenvatinib response: longer PFS and greater tumor shrinkage
or longer PFS in the absence of significant tumor shrinkage. Conclusions:
CAF profiling identified potential predictive biomarkers of lenvatinib
treatment outcomes in DTC. Combination of RAS and BRAF mutation with
baseline VEGF and ANG-2 or treatment-associated changes in FGF-2 and
IL-10 level correlated with lenvatinib treatment response.
5517 Poster Discussion Session (Board #7), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Genomic profiling of a clinically annotated cohort of locoregionally advanced
head and neck cancers (HNC) treated with definitive chemoradiotherapy.
Presenting Author: Tanguy Y. Seiwert, The University of Chicago
Medical Center, Chicago, IL
Background: Recent advances in genomic technology and sequencing have
allowed the near comprehensive characterization of genetic abnormalities
in HNC, but their correlation with clinical outcome remains to be determined.
We analysed a clinically annotated cohort of locoregionally advanced
HNC for copy number changes and mutations and correlated with
outcome in an exploratory fashion. Methods: 120 head and neck cancers
(frozen tissue) and matching normal tissues/blood from patients with
locoregionally advanced HNC treated with definitive chemoradiation �/induction
at the University of Chicago were obtained from our tissue bank.
DNA, RNA, protein were extracted. Barcoded, multiplexed sequencing
libraries for 500 head and neck cancer associated genes (Agilent capture)
were built and sequenced on Illumina HiSeq next generation sequencers.
150 commonly copy number altered and HNC relevant genes were analysed
for copy number alterations (CNA) using the Nanostring nCounter platform.
Respective genetic aberrations in curated pathways were allocated to tumor
subgroups. Exploratory analysis correlated data with induction response
and progression free survival. Confirmatory HPV testing was performed
using an E6, nested, multiplex PCR. Results: �80% of targeted sequences
were successfully captured and sequenced. Commonly mutated genes
included: TP53, CDKN2A, PIK3CA, NOTCH1. Of note PIK3CA mutations
were enriched in HPV(�) tumors. Commonly copy number altered genes
included amplifications of VEGF1, CCND1, MYC, EGFR, MDM4, CTTN, as
well as PIK3CA, and deletions of CDKN2A, SUCLG2, FHIT, TGFBR2,
PTPRD, IKBKG, TRAF6, and RASSF1. CCND1, and MYC were commonly
co-amplified and correlated with poor progression free survival, representing
a distinct HNC phenotype. Analysis for additional genes and influence
on induction response will be presented. Conclusions: Targeted, medium
throughput genomic profiling is feasible, and provides the majority of HNC
specific genetic aberrations at a comparably low cost. Impact on outcome
(CCND1/MYC amplification) and potential treatment targets (PIK3CA
mutations in HPV(�) tumors) were identified.
5519 Poster Discussion Session (Board #9), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Safety, molecular, and imaging responses to cetuximab administered in a
window pre-operative study in squamous cell carcinoma of the head and
neck (SCCHN). Presenting Author: Sandra Schmitz, Department of Head
and Neck Surgery, St-Luc Hospital, Catholic University of Louvain, Brussels,
Belgium
Background: Only a minority of SCCHN pts benefits from anti-EGFR mAbs.
Trials with pre- and post-therapy tumor biopsies are crucial to better
characterize the molecular pathways involved in treatment response or
resistance. Targeted agents (TA) are often investigated in unselected
end-stage cancer pts, making difficult optimal translational research. One
way to resolve this issue is to perform “window” studies where a TA is given
during the incompressible period between the diagnosis and surgery.
Methods: We conducted a phase I/II study: cetuximab (C) was given
pre-operatively to treatment-naïve SCCHN pts selected for primary curative
surgery. C (400mg/m2 first wk followed by 250mg/m2/wk) was given
during 2 wks (day -15 until day -1, 3 infusions) before surgery (day 0).
Tumour biopsies, FDG/PET, and CT were performed at diagnosis and
surgery. In the phase I, we investigated the safety of preoperative C by
progressively reducing the delay between the last dose of C and surgery
(minimum delay : 24 hrs ; 3�3 phase 1 design). The aims of the phase II
were (i) safety, (ii) C activity by FDG-PET (Po�0.10, P1�0.35, a�0.05 and
b� 0.10). As controls, 5 additional pts were included without C treatment
but with the same requirements regarding biopsies and imaging. Results:
The phase 1 study (n�18) demonstrated that C infusion given 24 hrs
before surgery was safe. Safety was confirmed in the phase II (n�20). 90 %
had a FDG-PET partial response (PR) (EORTC guideline) in the C group and
0% in the controls. 52% had a �SUVmax decrease of �50%. 2 pts
evaluable by CT/MRI had a PR (RECIST). Then, we compared the pre-and
post treatment biopsies by immunochemistry. For the whole group, C did
not reduce Ki67 (p�0.1) and did not seem to induce apoptosis (caspase).
However, for pts with �SUVmax decrease � 25% or � 50%, Ki67 was
decreased (p�0.04 and 0.006). C induced downregulation of pEGFR
(p�0.0004) and pERK (p�0.007) but not pAKT/AKT (Histoscore).
Conclusions: Pre-operative study with C is safe. Our findings suggest that
the main downstream molecular pathway blocked by C in SCCHN is the
RAS/RAF/ERK. Further analyses are ongoing to better characterize molecular
response and escape mechanisms.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.