NcXHF

BIOLOGIC THERAPIES IN COLORECTAL CANCER
TABLE 4. Anti-EGFR Versus Bevacizumab Plus Chemotherapy Studies in the First-Line Treatment of Metastatic
Colorectal Cancer
Author/Study
Schwartzberg et al 31
PEAK Study
Heinemann et al 49
Stintzing et al 50
FIRE-3 Study
Venook et al 2
Lenz et al 27
CALGB 80405
Study Design
Randomized phase II
clinical trial in
KRAS-WT (exon 2)
285 patients
Randomized phase III
clinical trial in
KRAS-WT
WT (exon-2) 592
patients
RAS-WT: 400 patients
Randomized phase III
clinical trial
1,137 patients KRAS-
WT (exon 2)
RAS-WT: 526 patients
Control
Arm
Experimental
Arm(s)
FOLFOX/BV FOLFOX/Pmab Primary:
PFS
Secondary:
OS, RR
FOLFIRI/BV FOLFIRI/Cmab Primary:
RR
(FOLFOX or (FOLFOX or
FOLFRI)/BV FOLFIRI)/
Cmab
Efficacy
Objectives Primary Efficacy Endpoint Other Efficacy Endpoints
Secondary:
PFS, OS
Primary:
OS
Secondary:
PFS
KRAS-WT
PFS: 10.9 (Pmab) vs.
10.1 months (BV)
(HR 0.87, p
0.353)
RAS-WT
PFS: 13 m (Pmab) vs.
9.5 months (BV)
(HR 0.65, p
0.029)
KRAS-WT (independent review): RR: 66.5%
(Cmab) vs. 55.6% (BV) (OR 1.58, p
0.016)
RAS-WT (independent review): RR: 72%
(Cmab) vs. 56% (BV)
(OR 2, p 0.003)
KRAS-WT: OS: 29.9 (Cmab) vs. 29 months
(BV) (HR 0.92, p 0.3)
RAS-WT: OS: 30.8 (Cmab) vs. 30.3 months
(BV) (HR 0.9, p 0.4)
KRAS-WT
RR: 57.8% (Pmab) vs.
53.5% (BV)
OS: 34.2 (Pmab) vs. 24.3
months (BV) (HR
0.62, p 0.009)
RAS-WT
RR: 63.6% (Pmab) vs.
60.5% (BV)
OS: 41.3 (Pmab) vs. 28.9
months (BV) (HR
0.63, p 0.058)
KRAS-WT: OS: 28.7 (Cmab) vs. 25 months (BV)
(HR 0.77, p 0.017)
PFS 10 (Cmab) vs. 10.3 months (BV) (HR 1.06,
p 0.55)
RAS-WT: OS: 33.1 (Cmab) vs. 25 months (BV) (HR
0.7, p 0.0059)
PFS 10.3 (Cmab) vs. 10.2 months (BV) (HR 0.97,
p 0.77)
KRAS-WT: RR: 65.6%
(Cmab) vs. 57.2%
(BV) (p 0.002)
KRAS-WT: PFS: 10.4
(Cmab) vs. 10.8
months (BV) (HR
1.04, p 0.55)
RAS-WT: RR: 68.8%
(cetuximab) vs. 56%
(BV)
(p 0.001)
RAS-WT: PFS: 10.9
(Cmab) vs. 11.4 m
(BV) (HR 1.1, p 0.31)
Abbreviations: EGFR, epidermal growth factor receptor; Pmab, panitumumab; Cmab, cetuximab; BV, bevacizumab; PFS, progression-free survival; OS, overall survival; RR, response rate; HR, hazard
ratio; OR, odds ratio; WT, wild type.
evaluated cetuximab and panitumumab in the setting of singleagent
irinotecan. 38,51 The EPIC trial did not select patients
based on RAS status but reported improvements in response
rate and PFS. 51 The PICCOLO study excluded patients
with KRAS codon 12, 13, and 61 mutations and
showed an improvement in response rate and PFS, but no
benefıt in OS. 38 The 20050181 study randomized patients
to FOLFIRI plus panitumumab compared with FOLFIRI
in patients with KRAS (exon-2) WT disease. 52 A signifıcant
improvement in response rate and PFS was noted on
the panitumumab arm. A recent update on this study
showed further accentuation of benefıt in favor of panitumumab
in the RAS-WT population (Table 5). 53
It is unclear at this time what the best strategy is for a biologic
therapy in the second-line setting of RAS-WT tumors after progression
on fırst-line bevacizumab-based combinations. The
continuation of bevacizumab or a switch to anti-EGFR–based
therapy (in the setting of irinotecan-based backbone) is acceptable.
However, in the setting where down-staging is important,
anti-EGFR therapy is more appropriate.
Targeted Therapies in the Third-Line Treatment of
RAS-WT mCRC
There is no current data to support the continuation of bevacizumab
in the third-line treatment in mCRC. In patients
who have progressed on all cytotoxic chemotherapies, the
combination of anti-EGFR plus irinotecan is considered the
most appropriate choice in patients with good PS who are
irinotecan tolerant. 54 The use of cetuximab or panitumumab
monotherapy in this setting is also considered appropriate
based on the C017 and the ASPECCT trials (Table 6). 55,56 Regorafenib
should only be considered after failure (or intoler-
TABLE 5. EGFR Targeting in the Second-Line Treatment in KRAS-WT Metastatic Colorectal Cancer
Peeters et al 52
20050181 Study
Seymour et al 38
PICOLLO Study
Study Design
Control Arm
Second-line randomized
phase III clinical
trial
KRAS exon 2 WT: 597
patients
Second-line randomized
phase III clinical
trial
KRAS WT (codon 12, 13,
61) 460 allocated
to irinotecan with or
without panitumumab
Experimental
Arm(s)
Efficacy
Objectives
FOLFIRI FOLFIRI Pmab Primary:
PFS
Secondary:
OS
Irinotecan 300 mg/m 2
to 350 mg/m 2
every 3 weeks
Irinotecan/panitumumab
(9 mg/kg every
3 weeks)
Primary:
OS
Secondary:
PFS, RR
Primary Efficacy
Endpoint
PFS: 5.9 m (FOLFIRI
Pmab) versus
3.9 m (FOLFIRI)
(HR 0.73,
p 0.004)
OS: 10.4 (irinotecan/
Pmab) vs. 10.9
months (irinotecan)
(HR 1.01, p 0.91)
Other Efficacy Endpoints
OS: 14.5 m (FOLFIRI
Pmab) versus
12.5 m (FOLFIRI)
(HR 0.85, p 0.12)
PFS: Pmab/irinotecan
arm was superior
to irinotecan
(HR 0.78, p 0.015)
Abbreviations: EGFR, epidermal growth factor receptor; OS, overall survival; RR, response rate; PFS, progression-free survival; HR, hazard ratio; OR, odds ratio; WT, wild type.
RR: 35% (FOLFIRI
Pmab) versus 10%
(FOLFIRI) (p 0.001)
RR: 33% (Pmab/irinotecan)
vs. 12% (irinotecan) (OR
4.12, p 0.0001)
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