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

204s Gastrointestinal (Colorectal) Cancer
3504 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
Final analysis of the phase III randomized trial of cetuximab (CET) plus
either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy
refractory, K-RAS wild-type (WT), metastatic colorectal carcinoma
(mCRC): The NCIC Clinical Trials Group and AGITG CO.20 trial. Presenting
Author: Lillian L. Siu, Princess Margaret Hospital and University of Toronto,
Toronto, ON, Canada
Background: The anti-EGFR monoclonal antibody CET has improved survival
in pts with chemotherapy refractory, K-RAS WT mCRC. BRIV is a
potent inhibitor of multiple receptor tyrosine kinases including both VEGFR
and FGFR. The combination of CET and BRIV targets tumor growth and
angiogenesis and demonstrated encouraging activity in an early phase
clinical trial. Methods: Pts with mCRC previously treated with combination
chemotherapy were randomized 1:1 to receive CET 400 mg/m2 IV loading
dose followed by weekly maintenance of 250 mg/m2 plus either BRIV 800
mg PO daily (Arm A) or placebo (Arm B). Pts may have had 1 prior
anti-VEGF, but no prior anti-EGFR therapy. Primary endpoint was overall
survival (OS). Results: From 02/2008 to 02/2011, 750 pts were randomized
(376 in Arm A and 374 in Arm B). Demographics: median age�64
(range 27-88); male�64%; ECOG 0:1:2 (%)�32:58:10; �3 prior chemotherapy
regimens�92%; prior anti-VEGF therapy�41%; K-RAS WT�97%.
Primary analysis was conducted per protocol after 536 deaths were
observed, with median OS of 8.8 months in Arm A and 8.1 months in Arm
B, hazard ratio (HR)�0.88; 95% CI�0.74 to 1.03; p�0.12. Median
progression-free survival (PFS) was 5.0 months in Arm A and 3.4 months in
Arm B, HR�0.72; 95% CI�0.62 to 0.84; p�0.0001. Incidence of any
�grade 3 adverse event (AE) was 78% in Arm A and 53% in Arm B. Time to
deterioration of physical function was shorter and global quality of life
scores were lower in Arm A vs Arm B. Planned subgroup analyses revealed
no statistically difference in treatment effects on OS based on pre-specified
factors of age, gender, ECOG and race. Likewise, no difference was
detected based on exploratory subgroup analyses of LDH and prior
anti-VEGF therapy. Conclusions: Despite positive effects on PFS, the
combination of CET�BRIV did not significantly improve OS in pts with
chemotherapy refractory, K-RAS WT mCRC. Final updated results based on
20-25% additional events for a total of nearly 700 deaths, as well as
further exploratory subgroup analyses, will be presented.
3506 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles)
followed by FOLFIRI (6 cycles) in patients with initially resectable
metastatic colorectal cancer: A GERCOR randomized phase III study
(MIROX). Presenting Author: Mohamed Hebbar, Medical Oncology Unit -
Hôpital Huriez, Lille, France
Background: Perioperative FOLFOX4 is the standard chemotherapy (CT) in
patients with resectable metastases from colorectal cancer (CRC) (Nordlinger
et al, Lancet 2008). To increase curability and reduce the risk of
severe neuropathy, we evaluated the sequential administration of a
dose-dense oxaliplatin-based regimen followed by an irinotecan-based
regimen. Methods: Patients with CRC and initially resectable or resected
metastases were randomized between arm A (control): FOLFOX4 (12
cycles; oxaliplatin 85 mg/m²) or arm B (investigational): FOLFOX7 (6
cycles; oxaliplatin 130 mg/m²) followed by FOLFIRI (6 cycles; irinotecan
180 mg/m²). CT was either perioperative or postoperative. Stratification
criteria were: perioperative vs. postoperative CT, surgery alone vs. radiofrequency
ablation �/- surgery, Blumgart’s prognostic score (0-1 vs. 2-3 vs.
4-5). Only one metastatic site was allowed, but the number of metastases
per organ was not limited. The primary endpoint was disease-free survival
(DFS). Results: From May 2004 to June 2010, 284 patients were
randomized (142 in each arm). Baseline patient characteristics were
similar in both arms. Liver was the main metastatic site. There was only one
metastasis in 70 (49.3%) patients in arm A and 69 (48.6%) patients in
arm B. CT was administered perioperatively in 168 (59.1%) patients, and
postoperatively in 116 (40.9%) patients. In case of perioperative CT,
R0-R1 resection was achieved in 58/85 (68.2%) patients in arm A and
67/83 (80.7%) patients in arm B. Grade 3 neuropathy occurred in 34
(23.9%) and 28 (20.0%) patients in arm A and B, respectively. Grade 3/4
thrombocytopenia and gastrointestinal toxicities (nausea, vomiting, diarrhea)
were more frequent in arm B. Median follow-up was 50.4 months
[95% CI: 45.6-54.4]. Median DFS were 22.4 months [95% CI: 17.9-36.2]
in arm A and 23.0 months [95% CI: 19.7-35.6] in arm B (HR�0.97 [95%
CI: 0.72-1.31]; p�.856). Conclusions: FOLFOX7 followed by FOLFIRI is
not superior to the standard FOLFOX4 chemotherapy in patients with
resectable metastatic colorectal cancer.
3505 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
Effects of prior bevacizumab (B) use on outcomes from the VELOUR study:
A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with
metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen.
Presenting Author: Carmen Joseph Allegra, University of Florida/Shands,
Gainesville, FL
Background: Aflibercept (Afl; also known as VEGF Trap) is a recombinant
human fusion protein that acts as a decoy receptor and prevents the
interaction of vascular endothelial growth factor (VEGF)-A, VEGF-B, and
placental growth factor (PlGF) with their receptors. In the phase III
VELOUR study, Afl � FOLFIRI improved overall survival (OS) compared
with FOLFIRI � placebo (pbo) in mCRC (ECCO 2011, abstract 6LBA). We
report outcomes from a pre-specified subgroup analysis by prior B use.
Methods: Pts with mCRC and progression during or after oxaliplatin were
randomized 1:1 to receive either FOLFIRI � pbo or FOLFIRI � Afl 4 mg/kg
IV Q2W with stratification by ECOG performance score (PS, 0v1v2)and
prior B. OS and progression-free survival (PFS) in the prior B-treated pts are
reported as median estimate and hazard ratios (HRs); 95.34% CI for OS
and 95% CI for PFS. Results: Of the 1226 pts in the overall study, 187 in
the pbo and 186 in the Afl group were stratified to prior B. The 2 arms were
well balanced: median age 60 yrs; male 58%; PS 0-1 97%; and 55% �1
metastatic organ. Although not powered for survival, Afl produced a
consistent trend towards prolonged OS and PFS, regardless of prior B use,
with no evidence of interaction (OS, P�0.7231; PFS, P�0.6954). The
incidence of treatment-emergent adverse events in the Afl arm was similar
in pts with prior B (100%) to those without (98.9%), with a similar
incidence of grade 3/4 events (82.5% and 83.9%, respectively).
Conclusions: Results of this pre-specified subgroup analysis indicate that
adding Afl to FOLFIRI resulted in a consistent trend of increased OS and
PFS, regardless of prior B use. Prior treatment with B did not appear to
impact the safety profile of Afl.
Pbo Afl HR
Overall survival
All pts
12.1
13.5
0.817
(N�1,226) (11.07-13.11) (12.52-14.95) (0.713-0.937)
No prior B (N�853) 12.4
13.9
0.788
mo
(11.17-13.54) (12.72-15.64) (0.669-0.927)
Prior B (N�373)
11.7
12.5
0.862
mo
(9.82-13.77) (10.78-15.51) (0.673-1.104)
Progression-free survival
No prior B
5.4
6.9
0.797
mo
(4.53-5.68) (6.37-7.20) (0.679-0.936)
Prior B
3.9
6.7
0.661
mo
(3.02-4.30) (5.75-8.21) (0.512-0.852)
3507 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
Impact on survival of primary tumor resection in patients with colorectal
cancer and unresectable metastasis: Pooled analysis of individual patients’
data from four randomized trials. Presenting Author: Matthieu Faron,
Institut Gustave Roussy, Villejuif, France
Background: In patients with colorectal cancer (CRC) and unresectable
metastasis, the prognostic impact of primary tumor resection still remains a
matter of debates. The goal of this study was to estimate, after adjustment
for prognostic factors, the effect of primary tumor resection on survival.
Methods: Individual patients’ data of the 1155 patients with metastatic
CRC included in 4 first-line chemotherapy trials (FFCD 9601, FFCD
2000-05, ACCORD 13 and ML 16987) where retrieved. Patients were
eligible for this study if they had synchronous metastasis judged unresectable.
Primary endpoint was overall survival (OS), secondary endpoint was
progression free survival (PFS). A Cox proportional hazard model stratified
on the trial was used to estimate the impact on survival. Results: 810
patients beginning first-line chemotherapy with either fluoropyrimidine
alone, oxaliplatin, irinotecan and/or bevacizumab were eligible. Patients
with a history of resection (n � 478 (59%)), as compared to those without
(n � 332 (41%)), were more likely to have colonic primary (p � 0.0001),
lower carcino embryonic antigen (CEA) (p � 0.0001) or alkaline phosphatase
(ALP) level (p�0.04) and normal white blood cell count (WBC) (p �
0.0001). In the univariate analysis, stratified on the trial, primary tumor
resection was associated with a better OS (Hazard Ratio HR: 0.73
[0.63-0.84]; p � 0.0001) and PFS (HR : 0.73 [0.63-0.84]; p � 0.0001).
Multivariate analysis, adjusted for primary tumor location, CEA, ALP and
WBC levels, OMS performance status and number of metastatic sites
confirmed that primary tumor resection was an independent predictor of
better OS (HR : 0.63 [0.53-0.75] ; p � 0.0001), and PFS (HR : 0.82
[0.70-0.95] ; p � 0.0007). Significant interactions were found between
resection and CEA level (p�0.02) and resection and primary tumor
location (p�0.01) for OS (not for PFS) with a lower impact of resection with
higher CEA levels or a colonic primary. Conclusions: This study confirmed
the independent prognostic value on survival of primary tumor resection in
patients with unresectable metastases of CRC.
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