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

3532 Poster Discussion Session (Board #24), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Randomized phase II open-label study of mFOLFOX6 in combination with
linifanib or bevacizumab for metastatic colorectal cancer. Presenting
Author: Bert H. O’Neil, University of North Carolina at Chapel Hill, Chapel
Hill, NC
Background: Linifanib is a potent and selective inhibitor of VEGF/PDGF
receptors. This trial assessed the efficacy and safety of mFOLFOX6 in
combination with linifanib or bevacizumab as second-line treatment for
metastatic colorectal cancer (mCRC). Methods: Patients (pts) with measurable
mCRC refractory to 1 prior regimen and ECOG PS 0–1, stratified by
prior bevacizumab treatment and radiotherapy, were randomized to receive
mFOLFOX6 with bevacizumab 10 mg/kg on day (d) 1 of 14-d cycle (Arm A),
mFOLFOX6 with daily linifanib 7.5 mg (Arm B), or mFOLFOX6 with daily
linifanib 12.5 mg (Arm C). The primary endpoint was progression-free
survival (PFS). Severity of adverse events (AEs) was graded using NCI-
CTCAE v3.0. Results: 148 pts were randomized at 45 sites in 14 countries.
32 pts (21.6%) had received prior bevacizumab. PFS and response data
are shown below (Table). Median survival (OS) was not reached at median
follow up 7.6 months. Palmar-plantar erythrodysesthesia (PPE) was the
only Grade 3/4 AE significantly higher on linifanib (high dose, 16.3%) vs.
bevacizumab (0%). Rate of any Grade 3� AE was significantly higher on
linifanib vs. bevacizumab.Hypertension rates were 41.7% (Arm A), 40.0%
(Arm B), and 36.7% (Arm C). AEs dose-related to linifanib were constipation,
proctalgia, stomatitis, fatigue, weight decrease, decreased appetite,
and PPE. Conclusions: The addition of linifanib to mFOLFOX6, compared to
mFOLFOX6 � bevacizumab, did not provide a PFS advantage for mCRC.
OS results will be updated for conference presentation.
ArmAN�49 Arm B N�50 ArmCN�49
Median PFS, m [95% CI] 9.0 [6.7, --] 6.6 [5.5, 9.2] 7.7 [6.3, 9.3]
HR 1.45, P�0.186* HR 1.26, P�0.466*
Confirmed response rate, % 34.7 24.0 22.4
Best response rate, % 38.8 32.0 34.7
Best % change in tumor size, median –23.1 –19.5 –22.2
* Stratified log-rank test two-sided P-value compared with mFOLFOX6 � bevacizumab.
3534 General Poster Session (Board #22E), Mon, 8:00 AM-12:00 PM
Analysis of PTEN in patients with advanced colorectal cancer (CRC)
receiving capecitabine alone or in combination with bevacizumab with or
without mitomycin C in the phase III AGITG MAX trial. Presenting Author:
Timothy Jay Price, The Queen Elizabeth Hospital, Adelaide, Australia
Background: There is an urgent need for potential biomarkers for anti-VEGF
therapies. The tumour suppressor gene PTEN is thought to have a potential
role as a biomarker for anti-EGFR therapy in CRC, but there is also evidence
that decreased levels of PTEN leads to increased expression of VEGF
suggesting a potential relationship to outcome with anti-VEGF therapy*.
The prognostic value of PTEN also remains controversial. Methods: Patients
enrolled in the Phase III MAX trial of capecitabine (C) �/- bevacizumab (B)
(�/- mitomycin C (M)) with available tissue were analysed for PTEN
expression (loss v no loss) as assessed using a Taqman copy number assay
to measure copy number variation at the PTEN locus. PTEN status was
correlated with progression-free survival (PFS) and overall survival (OS)
outcomes. The predictive value of PTEN status for bevacizumab efficacy
was also examined. Results: Of the original 471 patients enrolled in the
trial, tissue from 302 (64.1%) patients were analysed. Baseline characteristics
of those with and without tissue were comparable. PTEN loss was
observed in 38.7% of patients. There was no relationship between PTEN
loss and KRAS or BRAF mutation. Patients with PTEN loss were more likely
to have rectal primary (p�0.01) and less likely to have lung metastasis
(p�0.03). By using the comparison of CvCB�CBM, PTEN status was not
significantly predictive of the effectiveness of B for PFS or OS (Table).
PTEN status is also not prognostic for PFS or OS in multivariate analyses
adjusting for other baseline factors (Table). Conclusions: PTEN status did
not significantly predict different benefit with anti-VEGF therapy. PTEN
status was also not prognostic for survival in advanced colorectal cancer.
P value
CvsCB�CBM Loss No loss (for interaction)
PFS HR 0.51
HR 0.72
P � .26
0.33 - 0.79 0.52-0.98
OS HR 0.75
HR 1.00
0.47-1.19 0.70-1.43 P � .35
Prognosis Loss vs no loss P value
PFS HR 0.90
P�.42
0.70 - 1.16
OS HR 1.04
P�.76
0.79 - 1.38
Gastrointestinal (Colorectal) Cancer
3533 Poster Discussion Session (Board #25), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Use of next-generation sequencing (NGS) to detect a novel ALK fusion and
a high frequency of other actionable alterations in colorectal cancer (CRC).
Presenting Author: Jeffrey S. Ross, Albany Medical College, Albany, NY
Background: We hypothesized that NGS could identify genomic alterations
that guide selection of targeted therapies and discover novel drug targets
for primary and metastatic CRC. Methods: DNA was extracted and sequenced
from 4 X 10 � FFPE sections from 40 (32 primary and 8
metastatic) CRCs obtained from 2004-10 (52% male; 48% female; mean
age 60 years; 10% Stages I/II; 40% Stage III; 40% Stage IV; 10% Stage
unknown) using a targeted NGS assay in a CLIA laboratory (Foundation
Medicine). 2574 exons of 145 cancer-related genes plus 37 introns from
14 genes often rearranged in cancer were fully sequenced for point
mutations, insertions/deletions, copy number alterations (CNAs) and select
gene fusions. Results: NGS revealed 125 genomic alterations in 39/40
tumors (mean 3.1, range1-7) in 21 genes, including 80 base substitutions
(64%), 39 insertions/deletions (31%), 4 CNAs (3%) and 2 gene fusions
(1.6%). TP53 and APC were altered in 80% (32/40) and 67.5% (27/40) of
CRCs respectively, with both mutated more frequently than reported in
COSMIC. Alterations associated with potential sensitivity to targeted
therapies were identified in 21 (52.5%) of CRCs including: 10 KRAS
(TK/MEK inhibitors), 6 BRAF (BRAF inhibitors), 5 FBXW7 (mTOR inhibitors);
2 PIK3CA (PI3K/mTOR inhibitors); 2 BRCA2 (PARP inhibitors); 2
GNAS (MEK/ERK inhibitors) and 1 CDK8 (CDK inhibitors). In 1 CRC, a 5.2
Mb tandem duplication generated a novel C2orf44-ALK gene fusion
starting at the canonical exon 20 recombination site previously reported for
the majority of ALK gene fusions. cDNA sequencing identified an 90-fold
increase in 3’ ALK expression, suggesting the C2orf44-ALK fusion results
in ALK kinase domain overexpression and contains the same intracellular
domain as other ALK fusions including the ALK inhibitor sensitive
EML4-ALK. Conclusions: NGS of broad, cancer-related gene content from
FFPE CRC samples uncovered an unexpectedly high frequency of genomic
alterations, many of which may be clinically actionable by informing
treatment decisions, including a novel ALK gene fusion. This previously
unrecognized subset of CRC patients may be candidates for clinical trials of
crizotinib or other ALK inhibitors.
3535 General Poster Session (Board #22F), Mon, 8:00 AM-12:00 PM
Final results of study 20050181: A randomized phase III study of FOLFIRI
with our without panitumumab (pmab) for the second-line treatment (tx) of
metastatic colorectal cancer (mCRC). Presenting Author: Alberto F. Sobrero,
Ospedale San Martino, Medical Oncology, Genova, Italy
Background: The primary analysis of study 20050181 showed that in
patients (pts) with wild-type (WT) KRAS mCRC, pmab plus FOLFIRI given
as second-line therapy significantly improved progression-free survival
(PFS) vs FOLFIRI alone. Here, we report on a prespecified descriptive
analysis planned for 30 months (mos) after the last pt was enrolled.
Methods: Pts with mCRC, ECOG 0-2, who had one prior fluoropyrimidinebased
chemotherapy regimen were randomized 1:1 to pmab 6.0 mg/kg
Q2W�FOLFIRI (Arm 1) vs FOLFIRI (Arm 2). Co-primary endpoints were OS
and PFS (central assessment). Secondary endpoints included objective
response rate (ORR) and safety. Tumor KRAS status was determined by a
blinded central lab. Results: 1186 pts were randomised and received tx:
591 in Arm 1, 595 In Arm 2. 1083 pts (91%) had KRAS results. Adverse
event rates were consistent with the primary analysis. Results are shown
below. Conclusions: In pts with WT KRAS mCRC receiving pmab�FOLFIRI
vs FOLFIRI, PFS and ORR were significantly improved, and there was a
trend toward improved OS. Post-progression anti-EGFR tx may have
attenuated any significant difference in OS between tx arms. In pts with MT
KRAS mCRC, no difference in efficacy was observed between tx arms.
KRAS testing is critical to select appropriate pts for tx with pmab.
WT KRAS
(n�597)
PFS
Median, mos
(95%CI)
Arm 1
Pmab�FOLFIRI
(n�303)
Arm 2
FOLFIRI
(n�294)
HR or OR
(95%CI) p value
6.7 (5.8–7.4) 4.9 (3.8–5.5) HR�0.82
(0.69–0.97)
HR�0.73a (0.60–0.88)
14.5 (13.0–16.1) 12.5 (11.2–14.2) HR�0.92
(0.78–1.10)
OS
Median, mos
(95% CI)
ORRb 36 (31–42) [107/297] 10 (7–14) [28/286] OR�5.50
% (95%CI), [x/n]
(3.32–8.87)
MT KRAS
(n�486)
(n�238) (n�248)
PFS
Median, mos (95%CI)
5.3 (4.2–5.7) 5.4 (4.0–5.6) HR�0.95
(0.78–1.14)
OS
Median, mos (95% CI)
ORR
11.8 (10.4–13.3) 11.1 (10.3–12.4) HR�0.93
(0.77–1.13)
b
13 (9–18) [31/232] 15 (11–20) [35/237] OR�0.93
% (95%CI), [x/n]
Pts receiving post-study
anti-EGFR tx, n (%)
(0.53–1.63)
WT KRAS 38 (12.5) 101 (34.4)
MT KRAS 21 (8.8) 79 (31.9)
211s
0.023
0.001 a
0.366
�0.0001
0.561
0.482
0.885
aOn tx (including deaths occurring �60 days after last tumor assessment); bPts with baseline measurable
disease (modified RECIST).
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