1. Tumor Location Prognostic and Predictive in KRAS wt mCRC: Retrospective Analysis of CALGB/SWOG 80405
CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
mCRC, metastatic colorectal cancer; wt, wild type.
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. CALGB/SWOG 80405 Substudy: Tumor Location in KRAS wt mCRC
CALGB/SWOG found no significant difference in OS or PFS between cetuximab and bevacizumab when added to first-line FOLFIRI or FOLFOX in pts with RAS wt mCRC[1]
Primary tumor location may affect outcome in mCRC
Retrospective analysis of data from CALGB/SWOG evaluated to determine effect of primary tumor location on outcomes in KRAS wt mCRC[5]
Study N
Molecular Selection
Treatment
Outcome Mos
Tumor Side
Right
Left
O’Dwyer 2001[2]
1120
None
5-FU variations OS
10.9
15.8
Brulé 2015[3]
399
KRAS wt
BSC
BSC + CET
PFS
1.9
1.8
5.4
Loupakis 2015[4]
2027
FOLFIRI/BEV
FOLFOX4/XELOX/BEV
IFL/BEV
24.8
18.0
14.6
42.0
23.0
20.4
5-FU, 5-fluorouacil; BEV, bevacizumab; BSC, best supportive care; CET, cetuximab; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; FOLFOX4, 5-fluorouracil, foiling acid, oxaliplatin; FU, fluorouracil; IFL, irinotecan/bolus fluorouracil/leucovorin; mCRC, metastatic colorectal cancer; wt, wild type; XELOX, capecitabine plus oxaliplatin.
1. Lenz H, et al. ESMO Abstract 501O. 2. O’Dwyer PJ, et al. J Clin Oncol. 2001;19: Brulé SY, et al. Eur J Cancer. 2015;51: Loupakis F, et al. J Natl Cancer Inst. 2015;107:dju Venook AP, et al. ASCO Abstract 3504.
Slide credit: clinicaloptions.com

3. CALGB/SWOG 80405 Substudy: Study Design
Retrospective analysis of 1137 pts with KRAS wt mCRC from main CALGB/SWOG analysis
Data extracted from study chart or other available documentation
Side of primary tumor determined by colonoscopy, surgical or imaging report
Right, n = 293; left, n = 732; transverse/ND, n = 112
Primary objective: evaluate effect of sidedness on OS, PFS in pts with KRAS wt mCRC
Exploratory analysis performed in 213 pts with KRAS mutant mCRC
mCRC, metastatic colorectal cancer; ND, not determined; wt, wild type.
Slide credit: clinicaloptions.com
Venook AP, et al. ASCO Abstract 3504.

4. CALGB/SWOG 80405 Substudy: Baseline Population
Characteristic
Overall*
(N = 1137)
Tumor Side
P Value
Right
(n = 293)
Left
(n = 732)
Mean age, yrs
58.4
61.2
57.3
< .0001
Male, %
62.1
54.9
65.0
.002
Synchronous stage IV, %
79.3
86.9
76.0
.0009
Previous adjuvant therapy, %
14.2
10.6
15.7
.03
FOLFOX/FOLFIRI, %
73.4/26.6
74.4/25.6
72.4/27.6
.51
Primary in place, %
26.6
19.2
29.6
.0007
Metastases pattern, %
Liver only
Liver metastases
Extrahepatic
30.9
42.8
28.5
27.5
40.5
32.0
32.1
43.2
24.7
.02†
FOLFIRI, irinotecan/5-fluorouacil/leucovorin; FOLFOX, oxaliplatin/5-fluorouacil/leucovorin; mCRC, metastatic colorectal cancer; wt, wild type.
*Side totals excluding 66 pts with tumor in transverse colon and 46 pts with unknown location.
†Any liver metastases vs extrahepatic.
Slide credit: clinicaloptions.com
Venook AP, et al. ASCO Abstract 3504.

5. CALGB/SWOG 80405 Substudy: Tumor Sidedness Prognostic for PFS
Median PFS, Mos
(n = 1025)
Primary Tumor Side
HR (95% CI)
P Value*
Right
(n = 293)
Left
(n = 732)
All pts
8.9
11.7
1.03
( )
.0006
Cetuximab
7.8
12.4
1.56
( )
< .0001
Bevacizumab
9.6
11.2
1.06
( )
.55
*Adjusted for biologic, protocol chemotherapy, previous adjuvant therapy, previous radiotherapy, age, sex, synchronous disease, in place primary, liver metastases.
Slide credit: clinicaloptions.com
Venook AP, et al. ASCO Abstract 3504.

6. CALGB/SWOG 80405 Substudy: Tumor Sidedness Prognostic for Overall OS
OS prolonged for left-sided vs right-sided tumors
Median (95% CI)
HR (95% CI)
Side
N (Events)
P Value
100
33.3 ( )
19.4 ( )
Left
Right
732 (550)
293 (242)
1.55 ( ) 80
< .0001 60
OS (%)
Left 40
CI, confidence interval; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival; wt, wild type.
Right 20 12 24 36 48 60 72 84 96
108
Mos
Slide credit: clinicaloptions.com
Venook AP, et al. ASCO Abstract Reproduced with permission.

7. CALGB/SWOG 80405 Substudy: Tumor Sidedness Prognostic for OS by Therapy
OS for pts with left-sided tumors is 19.3 mos longer than for right-sided tumors treated with cetuximab[1]
Findings consistent with FIRE-3 trial in pts with all RAS wt[2,3]
Median OS, Mos
(N = 1025)
Primary Tumor Side
HR (95% CI)
P Value*
Right
(n = 293)
Left
(n = 732)
All pts
19.4
33.3
1.55
( )
< .0001
Cetuximab
16.7
36.0
1.87
( )
Bevacizumab
24.2
31.4
1.32
( )
.01
mCRC, metastatic colorectal cancer; wt, wild type.
*Adjusted for biologic, protocol chemotherapy, previous adjuvant therapy, previous radiotherapy, age, sex, synchronous disease, in place primary, liver metastases.
1. Venook AP, et al. ASCO Abstract Stintzing S, et al. ESMO Abstract E Heinemann V, et al. ASCO Abstract 3600.
Slide credit: clinicaloptions.com

8. CALGB/SWOG 80405 Substudy: Conclusions
Location of primary tumor prognostic in KRAS wt mCRC
PFS, OS longer in pts with left- vs right-sided tumors
Tumor sidedness predictive of response to biologics
Markedly longer OS in pts with left-sided tumors treated with first-line chemotherapy + cetuximab vs bevacizumab
Pts with right-sided tumors showed greater benefit with first-line chemotherapy + bevacizumab vs cetuximab
Investigator conclusions:
Sidedness is a surrogate marker for tumor biology
Identification of other biomarkers may replace sidedness, help individualize care
Pts should be stratified by sidedness in clinical trials
mCRC, metastatic colorectal cancer; wt, wild type.
Slide credit: clinicaloptions.com
Venook AP, et al. ASCO Abstract 3504.

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