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

216s Gastrointestinal (Colorectal) Cancer
3552 General Poster Session (Board #24G), Mon, 8:00 AM-12:00 PM
Phase Ib study of dulanermin combined with first-line FOLFOX plus
bevacizumab (BV) in patients (Pts) with metastatic colorectal cancer
(mCRC). Presenting Author: Mark Kozloff, Ingalls Hospital and University
of Chicago, Harvey, IL
Background: Dulanermin is a recombinant soluble human Apo2 ligand/TNFrelated
apoptosis-inducing ligand (Apo2L/TRAIL) that activates apoptotic
pathways by binding to the pro-apoptotic death receptors DR4 and 5. This
study assessed the safety of dulanermin combined with FOLFOX�BV as
first-line therapy in mCRC pts. Methods: This was a multicenter, open-label
dose-escalation and cohort expansion study with treatment until disease
progression or treatment intolerance. Dulanermin was administered intravenously
in 14-day cycles on Days 1, 2 and 3 at 4.5 mg/kg or 9 mg/kg, with
FOLFOX, and BV 5 mg/kg on Day 1. Dose-limiting toxicity (DLT) was
assessed through 2 cycles (Days 1-28). Adverse events (AE) were recorded
through all cycles. Response was assessed with RECIST (v1.0). Results: A
total of 23 pts received 2-33 cycles (median 15) of dulanermin with
FOLFOX�BV. No DLTs were reported. The most frequent AEs reported as
dulanermin-related were fatigue (26%), neutropenia and nausea (22%
each), and alanine aminotransferase increased and diarrhea (17% each).
The most frequent Grade �3 AEs reported as dulanermin-related were
neutropenia (13%) and infusion-related reaction (9%). Some of these
events were reported as related to dulanermin and other study drugs. Three
pts (13%) discontinued study treatment due to serious AEs: infusionrelated
reaction (2 pts, 9%; both reported as dulanermin-related) and
pulmonary embolism (1 pt, 4%). Other reasons for discontinuation included
disease progression (13 pts, 57%), physician’s decision and pt’s
decision (2 pts each, 9%), and non-compliance (1 pt, 4%). Two pts are still
receiving treatment. Among the 23 patients, best responses included 13
(57%) partial responses (9 confirmed and 4 unconfirmed), 7 (30%) stable
disease and 3 (13%) progressive disease. Conclusions: Addition of dulanermin
to first-line FOLFOX�BV was well tolerated overall in these mCRC pts.
AEs were similar to those previously reported for FOLFOX�BV alone. Tumor
responses suggest no adverse interactions between dulanermin and the
standard first-line treatment evaluated in this study.
3554 General Poster Session (Board #25A), Mon, 8:00 AM-12:00 PM
Prognostic impact of miR-146 polymorphism in patients with resected
colorectal cancer. Presenting Author: Jong Gwang Kim, Kyungpook National
University Hospital, Daegu, South Korea
Background: MicroRNAs (miRNAs) are small noncoding RNAs with regulatory
functions as tumor suppressors and oncogenes. The rs2910164 is a C
to G polymorphism located within the sequence of miR-164a precursor,
which leads to a change from a C:U pair to a G:U mismatch in its stem
region. Recent evidence suggested that the rs2910164 SNP in miR-146a
was associated with development of familial breast and ovarian cancers,
and prostatic cancer. The aim of this study was to investigate the
association between this genetic variant and prognosis of colorectal cancer
(CRC) operated curatively. Methods: A total of 343 CRC patients underwent
curative surgery were consecutively enrolled between 2004 and 2006.
DNA was extracted from fresh frozen normal tissue and miR-146 polymorphism
was genotyped by polymerase chain reaction-restriction fragment
length polymorphism (PCR-RFLP). Results: With a median follow up of
42.3 months, the combined GG�CG genotype demonstrated a better
survival outcome compared with the CC genotype in a Kaplan-Meier
survival analysis. Multivariate analysis showed that the G allele of miR-146
was associated with better progression-free and disease-specific survival as
a dominant model adjusted to age, sex, histologic grade and stage
[HR�0.54 and 0.49; p � 0.018 and 0.025, respectively]. Moreover, the
tumors containing the G allele were histologically associated with more
prominent lymphovascular invasion. Conclusions: Our results suggest that
miR-146 polymorphism is possible prognostic marker in operated CRC
patients in Korean.
3553 General Poster Session (Board #24H), Mon, 8:00 AM-12:00 PM
Influence of BRAF mutations and RAC1b/RAC1 mRNA expression ratio on
outcome in patients with metastatic colorectal cancer (mCRC) treated with
first-line chemotherapy. Presenting Author: Virginia Alonso-Espinaco, Hospital
Clínic, Barcelona, Spain
Background: Metastatic colorectal cancer (mCRC) patients (pts), with BRAF
tumor mutation (V600E) present poor overall survival (OS). RAC1b, a RAC1
spliced variant, is overexpressed in CRC, and impairs apoptosis by
activation of nuclear-factor-KB. Because RAC1b and BRAF (V600E) are
significantly associated in CRC (Matos et al, 2008), we evaluated if
RAC1b/RAC1 mRNA expression ratio (RNA ER) was an independent
prognostic factor in mCRC. Methods: We analyzed tumor samples from 186
mCRC pts, treated in first-line therapy with FOLFOX or CAPOX in three
Spanish hospitals. We examined BRAF (V600E) mutational status by
allelic discrimination, RAC1b/RAC1 expression ratio by mRNA RT-PCR
(quantitative real time polymerase chain reaction) and mismatch repair
(MMR) deficiency by microsatellite instability (MSI) analysis. We assessed
whether these biomarkers were independently predictive of response rate
(RR), progression free survival (PFS) or OS. Results: 88% of samples were
informative for BRAF, 75% for MMR status and 85% for RAC1b/RAC1
(RNA ER). BRAF (V600E) was found in 7%, MSI-H in 5% and high
�0.9-fold RAC1b/RAC1 (RNA ER) in 20% of pts. Five of 11 pts (46%) with
BRAF mutation had high RAC1b/RAC1 (RNA ER) compared with 25/144
(18%) without BRAF mutation (p�0.036). All pts with BRAF mutation
were MMR and none of the MSI-H pts, showed high RAC1b/RAC1 (RNA
ER). Patients with low RAC1b/RAC1 (RNA ER) and BRAF WT had higher
response rate (68% vs 43%; p�0.035). Response rate were not different
according BRAF mutation (64% WT vs 63% mutant) (p�NS). The
multivariate regression analysis identified ECOG PS (HR: 4.2 (CI 1.4-12.7)
as a significant variable for PFS and LDH levels (HR: 2.26 (CI 1.3-3.8), PS
(HR: 3.85 (CI 1.5-9.8) and high RAC1b/RAC1 (RNA ER) (HR: 2.6 (CI
1.1-5.9) for OS in WT BRAF pts. Conclusions: High RAC1b/RAC1 (RNA ER)
constitutes a marker of poor OS and a potential marker of acquired
chemo-resistance in WT BRAF mCRC pts treated with first-line oxaliplatinbased
therapy.
3555 General Poster Session (Board #25B), Mon, 8:00 AM-12:00 PM
Phase II study of panitumumab (P) in combination with FOLFOXIRI as
first-line treatment of metastatic colorectal cancer (mCRC): Activity in
molecularly selected patients (pts). Presenting Author: Sara Lonardi,
Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy
Background: GONO-FOLFOXIRI demonstrated higher activity and efficacy
compared to FOLFIRI. P with oxaliplatin- or irinotecan-based doublets is
feasible and associated with improved activity in KRAS codon 12-13
wild-type pts. BRAF and other RAS rare mutations have been suggested as
additional potential biomarkers for anti-EGFR agents. Methods: Pts with
untreated unresectable mCRC and wild-type BRAF-RAS genes were enrolled
in this GONO multicenter phase II trial of biweekly P 6 mg/kg d1 with
a modified FOLFOXIRI regimen (IRI 150 mg/m2 d1, OXA 85 mg/m2 d1,
l-LV 200 mg/m2 d1 and 5FU 3000 mg/m2 48-h continuous infusion d1,
reduced to 2400 mg/m2 due to grade 3-4 toxicity in 2 of first 3 pts
enrolled). Primary end-point was response rate (RR, RECIST Criteria).
Based on a two stage Simon’s Minimax design (p0�60%, p1�80%;
a�0.05, � �0.2) at least 26 responses on 36 evaluable pts should be
observed to satisfy the primary end-point. Results: 37 out of 87 screened
pts were enrolled (M/F, 57/43%; median age 63 years, range 33-72; ECOG
PS 0/1-2, 76/24%; primary colon/rectum, 70/30%; primary on site, 42%;
sites of disease single/multiple, 54/46%; liver only mts, 35%). Among the
first 3 pts treated with 5FU 3000 mg/m2 , 2 experienced SAEs (1 grade 4
diarrhea and neutropenia; 1 grade 3 diarrhea). Grade 3-4 toxicities
observed among the 34 pts treated at the amended dose were: neutropenia
53% (2 febrile neutropenia); diarrhea 32%; stomatitis 15%; neurotoxicity
(grade 2-3) 30%; cutaneous rash 24%. Delays or dose reductions were
needed only in 9% and 10% of the total 310 cycles, respectively. One SAE
(febrile neutropenia and sepsis) resulting in pt death occurred after
amendment. 32 partial responses, 4 disease stabilizations and 1 progression
were observed, with a RR of 86% (95% CI: 75-97%). 9 pts underwent
local procedures on metastases, achieving an R0 resection in 8 and a
pathologic complete response in 3 of them. At a median follow-up of 7.4
months mPFS has not been reached. Conclusions: In molecularly selected
unresectable pts adding P to FOLFOXIRI resulted in high activity and
interesting resection rate. The regimen appears feasible. Further follow-up
is needed to assess long-term outcome.
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