Positive Phase III
Results of Regorafenib
in mCRC Patients Who
have Progressed after
Standard Therapies
Regorafenib (BAY
73-4506) is an oral
multikinase inhibitor of
a broad range of
angiogenic, oncogenic,
and stromal kinases. The
Phase III CORRECT trial
was conducted to
evaluate efficacy and
safety of regorafenib in
patients with mCRC who
had progressed after
treatment with all
approved standard
therapies. Patients were
randomized 2:1 to
receive regorafenib (160
mg OD PO, 3 weeks on/1
week off) plus BSC (best
supportive care), or
placebo (PL) plus BSC.
From May 2010 to March
2011, 760 patients were
randomized (regorafenib:
505; PL: 255).
The estimated
hazard ratio (HR) for
overall survival (OS)
was 0.773 (95% CI:
0.635–0.941; 1-sided P =
0.0051). Median OS was
6.4 months for
regorafenib and 5.0
months for PL. The
estimated HR for PFS was
0.493 (95% CI:
0.418–0.581; 1-sided P <
0.000001). Median PFS
was 1.9 months for
regorafenib and 1.7
months for PL. ORR was
1.6% for regorafenib and
0.4% for PL. DCR was 44%
for regorafenib and 15%
for PL (P < 0.000001).
Since the pre-specified
OS efficacy boundary was
crossed, the Data
Monitoring Committee
recommended unblinding
the study and patients
on PL were allowed to
cross over to
regorafenib. The most
frequent grade 3+ AEs in
the regorafenib arm were
hand–foot skin reaction
(17%), fatigue (15%),
diarrhea (8%),
hyperbilirubinemia (8%),
and hypertension (7%).
Source:
2012 ASCO GI Cancers
Symposium, Abstract No:
LBA385
Phase III Results of
Everolimus in Previously
Treated Patients with
Advanced Gastric Cancer
Prognosis for patients
with advanced gastric
cancer (AGC) after
failure of first-line
chemotherapy is poor.
Currently, there is no
level 1 evidence
established for
second-line treatment.
In a randomized Phase
III study, patients aged
≥18 years with confirmed
AGC and disease
progression after one or
two lines of systemic
chemotherapy were
randomized 2:1 to oral
everolimus (EVE) 10 mg/d
plus BSC or placebo (PL)
plus BSC. Randomization
was stratified by region
(Asia vs. rest of world)
and previous lines of
chemotherapy (one vs.
two).
A total of 656 patients
from 23 countries were
enrolled from July 2009
to December 2010; 439
were randomized to EVE
and 217 to PL. Median OS
was 5.39 months with EVE
vs. 4.34 months with PL
(HR: 0.90; 95% CI:
0.75–1.08; P = 0.1244).
Median PFS per local
investigator assessment
was 1.68 months with EVE
vs. 1.41 months with PL
(HR: 0.66; 95% CI:
0.56–0.78; P < 0.0001).
Six-month PFS estimates
were 12.0% with EVE and
4.3% with PL. OS and PFS
results were consistent
across the various
subgroups. ORR (95% CI)
was 4.5% (2.6%–7.1%)
with EVE vs. 2.1%
(0.6%–5.3%) with PL. The
most common grade 3/4
adverse events were
anemia (16.0% with EVE
vs. 12.6% with PL),
decreased appetite
(11.0% vs. 5.6%), and
fatigue (7.8% vs. 5.1%).
Source:
2012 ASCO GI Cancers
Symposium, Abstract No:
LBA3
Negative Phase III
Results of Cetuximab
plus Brivanib in
Patients with
Chemo-refractory KRAS
WT
mCRC
Addition of brivanib, a
tyrosine kinase
inhibitor targeting
VEGFR/FGFR, to cetuximab
has shown encouraging
activity in an
early-phase clinical
trial. Patients with
mCRC previously treated
with combination
chemotherapy were
randomized 1:1 to
receive cetuximab 400
mg/m2 IV loading dose
followed by weekly
maintenance of 250 mg/m2
plus either brivanib 800
mg PO daily (Arm A) or
placebo (Arm B).
Patients may have had
one prior anti-VEGF, but
no prior anti-EGFR
therapy.
A total of 750 patients
were randomized (376 in
Arm A and 374 in Arm B).
Median OS in the
intent-to-treat
population was 8.8
months in Arm A and 8.1
months in Arm B (HR:
0.88; 95% CI: 0.74–1.03;
P = 0.12). Median PFS
was 5.0 months in Arm A
and 3.4 months in Arm B
(HR: 0.72; 95% CI:
0.62–0.84; P < 0.0001).
Both partial responses
(13.6% vs. 7.2%, P =
0.004) and stable
disease (50% vs. 44%)
were higher in Arm A.
Incidence of any ≥grade
3 AEs was 78% in Arm A
and 53% in Arm B. Most
frequent ≥grade 3 AEs
were fatigue (25%),
hypertension (11%), and
rash (10%) in Arm A vs.
fatigue (11%), rash
(5%), and dyspnea (5%)
in Arm B. Time to
deterioration of
physical function was
shorter and global
quality-of-life scores
were lower in Arm A than
in Arm B. Despite
positive effects on PFS
and OR, the combination
of cetuximab plus
brivanib did not
significantly improve OS
in patients with
chemotherapy-refractory,
KRAS WT mCRC.
Source:
2012 ASCO GI Cancers
Symposium, Abstract No:
386
Results of Two Phase
III Trials of
Panitumumab for First-
and Second-line mCRC
In the primary analysis
of Study 181,
panitumumab + FOLFIRI
significantly improved
PFS vs. FOLFIRI as
second-line therapy in
patients with KRAS WT
mCRC. Patients were
randomized 1:1 to
panitumumab (6.0 mg/kg
Q2W) + FOLFIRI (Arm 1)
vs. FOLFIRI alone (Arm
2). Patients had one
prior fluoropyrimidine-based
chemotherapy regimen for
mCRC. A total of 1,186
patients received
treatment: 591 in Arm 1
and 595 in Arm 2. Of the
1,186 patients, 1,083
(91%) had KRAS results.
In Arm 1, PFS (6.7
months in Arm 1 vs. 4.9
months in Arm 2; HR:
0.82; P = 0.023) and ORR
(36% in Arm 1 vs. 10% in
Arm 2) were improved,
and there was a trend
toward improved OS (14.5
months in Arm 1 vs. 12.5
months in Arm 2; HR:
0.92; P = 0.366) in
patients with KRAS WT
mCRC. In patients with MT KRAS, there was no
difference in efficacy.
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Final PRIME results
showed that panitumumab
+ chemotherapy
significantly improved
PFS and ORR vs.
chemotherapy alone for
first-line KRAS WT mCRC.
Patients had no prior
chemotherapy for mCRC.
Out of 1,183 patients
with WT or MT KRAS mCRC,
1,057 met the criteria
for inclusion in the
skin toxicity (ST)
analysis. mPFS was 11.3
months in panitumumab Gr
2-4 ST arm vs. 6.1
months in panitumumab Gr
0-1 ST arm vs. 8.7
months in
chemotherapy-alone arm
in KRAS WT mCRC
patients. mOS were 27.7
months in panitumumab Gr
2-4 ST arm vs. 11.5
months in panitumumab Gr
0-1 ST arm vs. 19.7
months in
chemotherapy-alone KRAS
WT mCRC patients. The
overall safety profile
was broadly comparable
across ST groups and
treatment arms. It was
concluded that patients
with KRAS WT mCRC
receiving panitumumab
with ST Gr 2-4 had
longer PFS and OS than
patients receiving
chemotherapy alone.
Source:
2012 ASCO GI Cancers
Symposium, Abstract No:
387;
2012 ASCO GI Cancers
Symposium, Abstract No:
531
Significant Phase III
Results of Bevacizumab
plus FOLFOX4 in
Previously Treated
Advanced CRC Patients
VEGF-A gene is
alternatively spliced
into two families by
alternative splice site
usage in exon 8. The
pro-angiogenic (e.g.,
VEGF165) isoforms are
generated by proximal
splice site selection
and the anti-angiogenic
(e.g., VEGF165b) by
distal splice site
selection. The relative
levels of the isoforms
vary in CRC. VEGF165b overexpression in mice
inhibits bevacizumab
treatment.
To determine whether
survival was better in
patients with low
VEGF165b when treated
with FOLFOX4 + bevacizumab (Arm A) than
FOLFOX4 + placebo (Arm
B), 108 coded patient
samples from the E3200
trial of FOLFOX4 ±
bevacizumab were
successfully stained for
VEGF-A165b and scored in
well-differentiated
tissue relative to
normal tissue blind to
outcome. Adjusted Cox
binary analysis of
VEGF165b/normal
comparing staining ratio
in bevacizumab- vs.
placebo-treated patients
demonstrated
significantly better
survival for the less
than median ratios (HR:
0.28; P = 0.0031; mPFS:
8.4 months vs. 5.1
months in placebo),
whereas in the higher
than median
VEGF165b/normal group,
there was no effect of bevacizumab (HR: 0.96,
mPFS: 11.9 months vs.
11.0 months in placebo).
These results indicate
that low VEGF165b levels
in well-differentiated
tumors may predict
response to bevacizumab.
Source:
2012 ASCO GI Cancers
Symposium, Abstract No:
545
Preliminary Safety
Data of Phase II/III
Trial with MGN1703 in
Patients with Advanced
CRC
The synthetic DNA–based
immunomodulator MGN1703
acts as an agonist of
toll-like receptor 9. A
Phase II/III study
(IMPACT) was initiated
in patients with
advanced CRC having
disease control after
first-line therapy. The
efficacy and safety of
the study treatment will
be evaluated based on
extensive immunological
tests, radiological
assessment, safety
laboratory results, and
assessments of the
quality of life.
Preliminary safety data
were presented at the
2012 ASCO GI cancer
symposium. The majority
of adverse events were
assessed as not
drug-related by the
investigator. The
remaining AEs were mild
night sweat (not
assessable), mild fever
(at three occasions,
possible related), and
mild arthralgia (certain
related) in one patient
each. Three SAEs have
been reported so far, of
which one was assessed
as probably drug-related
– atypical pneumonia.
Local reactions such as
mild redness and
swelling at injection
site were reported only
in one patient. No
laboratory or clinical
signs of autoimmunity or
dose-limiting toxicities
have been reported so
far. With these
preliminary safety
results of the ongoing
clinical study in
patients with advanced
CRC, it could be shown
that treatment with
MGN1703 at the dosage of
60 mg is well tolerated
and safe.
Source:
2012 ASCO GI Cancers
Symposium, Abstract No:
633
Prolongation of
Doxifluridine and
Addition of Cisplatin to
Mitomycin C did not
Improve Treatment
Outcome in Advanced
Gastric Cancer Patients
To improve adjuvant MF (mitomycin
C and fluoropyrimidine)
chemotherapy,
researchers prolonged
the administration of
oral fluoropyrimidine
(F), added cisplatin (P)
to MF (MFP), and
performed a Phase III
randomized trial to
determine whether this
strategy could improve
the 3-year relapse-free
survival (3yRFS) in
curatively resected
advanced gastric cancer
(AGC) patients.
For MFP group, the
administration of
doxifluridine was
extended for 12 months,
and 6 shots of monthly
60 mg/m2 of cisplatin
were added to MF.
Between February 2002
and August 2006, a 871
patients were randomized
(435 in MF and 436 in
MFP). With a median
follow-up of 6.6 years
in April 2011, a total
of 353 events (relapse
or death) have been
observed. There was no
difference in RFS
between the two groups
(HR: 1.10; 95% CI:
0.89–1.35; P = 0.3918;
5yRFS 61.1% in MF and
57.9% in MFP).
Difference in OS was
also insignificant (HR:
1.11; 95% CI: 0.89–1.39;
P = 0.3349; 5yOS 66.5%
in MF and 65.0% in MFP).
Source:
2012 ASCO GI Cancers
Symposium, Abstract No:
76
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