1. Prognostic Factors for First-line Chemotherapy + Bevacizumab or Cetuximab in Metastatic Colorectal Cancer
CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
*Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals
mCRC, metastatic colorectal cancer.
This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

2. CALGB/SWOG 80405 Prognostic Factors: Background
Tumor biology, including sidedness, has been correlated with prognosis in mCRC[1]
Somatic mutation analysis via NGS may identify genetic alterations associated with prognosis in solid tumors[2]
Phase IIII CALGB/SWOG trial demonstrated no significant difference in OS, PFS with cetuximab vs bevacizumab addition to first-line FOLFOX or FOLFIRI in pts with KRAS wild-type mCRC[3]
mOS, cetuximab vs bevacizumab: 29.9 vs 29.0 mos; mPFS: 10.4 vs 10.8 mos
mOS, left-sided vs right-sided tumors: 33.3 vs 19.4 mos; P < .0001[4]
Current subanalyses of CALGB/SWOG evaluated sidedness (independent of molecular features)[5] and genetic markers[6] as prognostic indicators in pts with mCRC
CT, chemotherapy; FOLFIRI, fluorouracil/leucovorin/irinotecan; FOLFOX, fluorouracil/leucovorin/oxaliplatin; m, median; mCRC, metastatic colorectal cancer; NGS, next-generation sequencing; SOC, standard-of-care.
1. Holch JW, et al. Eur J Cancer. 2017;70: Yu B, et al. Transl Pediatr. 2015;4: Venook A, et al. JAMA In press. 4. Venook AP, et al. ASCO Abstract Venook AP, et al. ASCO Abstract Innocenti F, et al. ASCO Abstract 3504.
Slide credit: clinicaloptions.com

3. CALGB/SWOG 80405: Study Design and Survival
Randomized, open-label phase III trial
No difference between cetuximab and bevacizumab when combined with FOLFIRI or FOLFOX with respect to OS or PFS[1]
OS, Mos
PFS, Mos
29.9
10.4
29.0
10.8
Pts with KRAS wild-type (Codons 12, 13) metastatic/advanced CRC and no previous therapy for advanced disease (N = 1137)
Cetuximab + Chemotherapy*
(n = 578)
Bevacizumab + Chemotherapy*
(n = 559)
*Physician choice of FOLFIRI or FOLFOX.
CRC, colorectal cancer; FOLFIRI, fluorouracil/leucovorin/irinotecan; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
1. Venook A, et al. JAMA (in press). 2. Venook A, et al. ASCO Abstract Innocenti F, et al. ASCO Abstract 3504.
Slide credit: clinicaloptions.com

4. CALGB/SWOG 80405 Prognostic Factors: Current Analyses
Multivariate analysis of prognostic utility of tumor sidedness (independent of other molecular features)[1]
Evaluated in subset of pts with left-/ right-sided tumors (no transverse) and available molecular data (n = 728)
Used Cox proportional hazard models*
Evaluated potential biomarkers of sidedness/tumor burden
Analysis of mutational profile and prognostic, clinical value of DNA alterations[2]
DNA from 504 tumor specimens
Mutation profile determined by PCR genotyping in 12 genes, MSI-high status by microsatellite mutation analysis, mutational load in genes by NGS
Primary endpoint: OS
Used Cox proportional hazard models* to test association with molecular alterations†
CT, chemotherapy; MSI, microsatellite instability; NGS, next-generation sequencing; RT, radiation therapy.
*Models stratified by adjuvant CT, prior RT. Models adjusted for age, race, sex, synchronous vs metachronous, BRAF. Sidedness analysis also adjusted for consensus molecular subtypes, MSI, NRAS, KRAS, HRAS; mutational analysis for liver metastases only, sidedness. †No adjustment for multiple comparisons.
Slide credit: clinicaloptions.com
1. Venook AP, et al. ASCO Abstract Innocenti F, et al. ASCO Abstract 3504.

5. OS by Side and Treatment
CALGB/SWOG Prognostic Factors: OS by Side of Tumor and Biologic Treatment
Pts with right-sided tumor, n = 293 (27%); left-sided, n = 732 (68%)
Pts with transverse colon tumors excluded from analysis (n = 66)
OS by Sidedness
OS by Side and Treatment
Side
Left
Right
mOS
(95% CI)
33.3
( )
19.4
( )
N (Events)
732 (550)
293 (242) HR
1.55
( )
P Value
< .0001
Left/Bevacizumab
mOS 31.4 (95% CI: )
Left/Cetuximab
mOS 36.0 (95% CI: )
Right/Bevacizumab
mOS 24.2 (95% CI: )
Right/Cetuximab
mOS 16.7 (95% CI: )
100
100 80 80 60 60
OS (%)
OS (%) 40
Bev, bevacizumab; Cet, cetuximab.
Left 40
Right 20 20 12 24 36 48 60 72 84 96
108 12 24 36 48 60 72 84 96
108
Mos
Mos
Slide credit: clinicaloptions.com
Venook A, et al. ASCO Abstract Reproduced with permission.

6. Right-Sided Tumors (n = 167) Left-Sided Tumors (n = 330)
CALGB/SWOG Prognostic Factors: Sidedness Independent of Molecular Features
Multivariate analysis found that sidedness a significant prognostic factor independent of other molecular features
HR: (95% CI: ; P = *)
Clinical characteristics compared between pts with right- vs left-sided tumors to determine whether sidedness potentially a surrogate for tumor burden
Pattern of metastases significantly differed by side (Chi-squared P = .0136)
No significant differences with other tumor burden indicators
Tumor Burden Indicator, %
Right-Sided Tumors (n = 167)
Left-Sided Tumors (n = 330)
Median LDH, IU/L
195.5
196.5
Metastatic sites, n 1 2
≥ 3
53.9
33.9
11.5
55.9
30.1
13.1
Prior adjuvant tx
12.0
18.8
1⁰ in place at tx initiation
4.8
1.8
Intent, palliative/curative
86.4/13.6
83.1/16.9
Pattern of metastases
Liver only
Liver + extrahepatic
Extrahepatic only
30.3
62.4
37.0
38.3
73.3
25.8
LDH, lactate dehydrogenase; tx, treatment.
*Per stratified, adjusted Cox proportional hazard model.
Slide credit: clinicaloptions.com
Venook AP, et al. ASCO Abstract 3503.

7. Pts With NGS and Mutational Load Data
CALGB/SWOG Prognostic Factors: Pt Characteristics for Genetic Analysis
Characteristics, n (%)
Pts With 12-Gene Data
(n = 504)
Pts With NGS and Mutational Load Data
(n = 293)
Male
313 (62)
191 (65)
Treated with cetuximab
Treated with bevacizumab
248 (49)
256 (51)
163 (56)
130 (44)
Synchronous tumor growth
Metachronous tumor growth
393 (78)
110 (22)
236 (81)
56 (19)
Metastases in liver, only
Metastases in other than liver
322 (64)
179 (36)
178 (61)
112 (39)
Tumor on right or transverse colon
Tumor on left colon
183 (39)
285 (61)
103 (38)
167 (62)
NGS, next-generation sequencing.
Slide credit: clinicaloptions.com
Innocenti F, et al. ASCO Abstract 3504.

8. CALGB/SWOG 80405 Prognostic Factors: OS by BRAF Genotype
Patient Genotype Group
Median OS, Mos (95% CI)
HRadj (95% CI)
P for Interaction, BRAF/biologics
BRAF genotype
Wild type (n = 432)
Mutant (n = 72)
34.2 ( )
12.9 ( )
1.82 ( ) P = .0001*
BRAF wild type
Treated with cetuximab (n = 225)
Treated with bevacizumab (n = 207)
33.4 ( )
34.4 ( )
0.97 ( ) P = .75
.13
BRAF mutant
Treated with cetuximab (n = 31)
Treated with bevacizumab (n = 41)
11.7 ( )
15.0 ( )
0.61 ( ) P = .51
adj, adjusted.
*If further adjusted for sidedness of tumor, HR: 1.67 (95% CI: ; P = .0035).
Slide credit: clinicaloptions.com
Innocenti F, et al. ASCO Abstract 3504.

9. CALGB/SWOG 80405 Prognostic Factors: OS by MSI Status
Patient Subgroup
Median OS, Mos (95% CI)
HRadj (95% CI)
P for Interaction, MSI/biologics
Microsatellite instability
High level of instability (n = 29; 52% BRAF mutant)
Stable (n = 389; 11% BRAF mutant)
30.3 (22.6-NE)
31.8 ( )
0.84 ( ) P = .50
Microsatellite stable
Treated with cetuximab (n = 224)
Treated with bevacizumab (n = 220)
33.4 ( )
32.8 ( )
1.03 ( ) P = .48
.0002
Microsatellite instability-high
Treated with cetuximab (n = 13, 46% BRAF mutant)
Treated with bevacizumab (n = 18, 61% BRAF mutant)
11.5 (10.3-NE)
30.3 (23.6-NE)
0.17 ( ) P = .002
adj, adjusted; MSI, microsatellite instability; NE, not evaluable.
Slide credit: clinicaloptions.com
Innocenti F, et al. ASCO Abstract 3504.

10. CALGB/SWOG 80405 Prognostic Factors: OS by Mutational Load
Patient Subgroup
Median OS, Mos (95% CI)
HRadj (95% CI)
P for Interaction, Mutational Load/Biologics
Mutational Load in MSS mCRC
≤ 8 (n = 228)
> 8 (n = 65)
30.1 ( )
35.7 ( )
0.67 ( ) P = .02
Mutational Load ≤ 8 in MSS mCRC
Treated with cetuximab (n = 103)
Treated with bevacizumab (n = 125)
29.1 ( )
30.3 ( )
1.00 ( ) P = .97
.56
Mutational Load > 8 in MSS mCRC
Treated with cetuximab (n = 27)
Treated with bevacizumab (n = 38)
35.8 ( )
35.1 ( )
0.81 ( ) P = .79
adj, adjusted; mCRC, metastatic colorectal cancer; MSS, microsatellite stable.
Slide credit: clinicaloptions.com
Innocenti F, et al. ASCO Abstract 3504.

11. CALGB/SWOG 80405 Prognostic Factors: Investigator Conclusions
In pts with mCRC and no previous therapy for advanced disease:
Left-sided tumors significantly associated with improved OS, regardless of biologic tx[1]
Sidedness a prognostic factor independent of other molecular features (HR: 1.392; P = .031)
Investigators concluded that tumor sidedness differences not due to tumor burden; further study warranted to identify mechanisms behind sidedness as independent prognostic factor
BRAF status strong prognostic marker, even when adjusted for tumor sidedness, but has no predictive interaction with biologic therapy[2]
MSI status not prognostic but may be predictive for biologic therapy[2]
Mutational load in pts with MSS CRC has prognostic potential but does not seem to be predictive for biologic therapy[2]
According to investigators, these data indicate that pt and tumor characteristics may help predict response to biologic therapy but larger numbers of pts and more markers need to be explored[1,2]
CRC, colorectal cancer; mCRC, metastatic colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; tx, treatment.
Slide credit: clinicaloptions.com
1. Venook AP, et al. ASCO Abstract Innocenti F, et al. ASCO Abstract 3504.

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