Higher Vitamin D Levels Associated With Improved Survival in Metastatic Colorectal Cancer.2015

1. May 29 - June 2, 2015
Higher Vitamin D Levels
Associated With Improved Survival
in Metastatic Colorectal Cancer
CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting*
*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.
This program is supported by educational grants from AstraZeneca, Bayer,
Bristol-Myers Squibb, Celgene Corporation, Genentech, Incyte, and Novartis.

2. clinicaloptions.com/oncology
Higher Vitamin D Levels Associated With Improved Survival in Metastatic CRC
Vitamin D in mCRC: Background
 Vitamin D inhibits cell proliferation and angiogenesis
 Epidemiological data suggest higher prediagnosis vitamin
D associated with improved survival in colorectal cancer
– Relationship unknown in mCRC
 Current study prospectively assessed association between
vitamin D and survival outcomes in pts with previously
untreated mCRC in CALGB/SWOG 80405
Ng K, et al. ASCO 2015. Abstract 3503.

3. clinicaloptions.com/oncology
Higher Vitamin D Levels Associated With Improved Survival in Metastatic CRC
CALGB/SWOG 80405: Cetuximab and/or
Bevacizumab + Combination CT
 Plasma 25(OH)D data available for 1043 pts of 1137 randomized
– Pretreatment radioimmunoassay and diet/lifestyle questionnaires
– Multivariate analyses using Cox proportional hazards models
Pts with untreated
mCRC
(N = 1137)
Patient/physician
choice: mFOLFOX6
or
FOLFIRI
Cetuximab 400 mg/m2
IV
on Day 1, then
250 mg/m2
once weekly
Bevacizumab 5 mg/kg IV
every 2 wksPrimary endpoint: OS.
Secondary endpoints: PFS, response rate
Ng K, et al. ASCO 2015. Abstract 3503.

4. clinicaloptions.com/oncology
Higher Vitamin D Levels Associated With Improved Survival in Metastatic CRC
Vitamin D in mCRC: Pt Population
 Vitamin D cohort similar characteristics as full trial cohort
Characteristic
Q1
(n = 208)
Q2
(n = 209)
Q3
(n = 208)
Q4
(n = 210)
Q5
(n = 208)
P Value
Median 25(OH)D,
ng/mL (range) 8.0
(2.2-10.8)
13.6
(10.9-
15.4)
17.2
(15.4-
19.2)
21.4
(19.3-
24.0)
27.5
(24.1-
72.7)
--
Median age, yrs 59 60 60 61 61 .07
Male, % 48 64 58 64 55 .004
Black, % 25 12 6 7 2 < .0001
ECOG PS 1, % 50 36 42 37 30 .002
RAS mutant, % 30 30 39 29 21 .02
Ng K, et al. ASCO 2015. Abstract 3503.

5. clinicaloptions.com/oncology
Higher Vitamin D Levels Associated With Improved Survival in Metastatic CRC
Ng K, et al. ASCO 2015. Abstract 3503.
Vitamin D in mCRC: Plasma 25(OH)D
Outcomes
 Median plasma 25(OH)D: 17.2 ng/mL (below normal)
 Significantly lower plasma 25(OH)D observed for:
– Male
– Black
– Living in northeast
– Lower dietary and
supplemental vitamin D intake
 No significant association of 25(OH)D level with treatment arm,
chemotherapy backbone, or treatment history
– ECOG PS 1 vs 0
– Tumoral RAS mutation
– Higher BMI
– Lower physical activity
– Winter/spring blood draw timing

6. clinicaloptions.com/oncology
Higher Vitamin D Levels Associated With Improved Survival in Metastatic CRC
Vitamin D in mCRC: Survival Outcomes
 35% OS improvement and 21% PFS improvement in highest quintile
compared with lowest
Ng K, et al. ASCO 2015. Abstract 3503.
Outcome
Q1
(n = 208)
Q2
(n = 209)
Q3
(n = 208)
Q4
(n = 210)
Q5
(n = 208)
P Value
Median OS, mos 24.5 30.0 28.4 27.2 32.6 .01
95% CI 21.7-28.6 25.8-32.2 24.2-31.0 25.0-31.5 27.7-36.9
Median PFS, mos 10.1 10.9 11.4 12.7 12.2 .02
95% CI 9.2-11.3 9.6-11.6 9.7-12.9 11.1-13.6 10.8-14.2
OS multivariate HR
1.0 0.83 0.81 0.79 0.65 .001
PFS multivariate
HR 1.0 0.99 0.84 0.83 0.79 .01

7. clinicaloptions.com/oncology
Higher Vitamin D Levels Associated With Improved Survival in Metastatic CRC
 Exploratory SNP analysis identified potential association of A/A
genotype vs A/G or G/G at SNP rs3818740 in RXR gene (P = .01)
Vitamin D in mCRC: Greater Benefit in A/A
Genotype
Ng K, et al. ASCO 2015. Abstract 3503. Reprinted with permission.
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8
Yrs
ProbabilityofOS
Vitamin D < median
Vitamin D ≥ median
rs3818740: A/A
n = 320
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8
Yrs
Adjusted interation P = .0103
ProbabilityofOS
Vitamin D < median
Vitamin D ≥ median
rs3818740: A/G or G/G
n = 340 + 69

8. clinicaloptions.com/oncology
Higher Vitamin D Levels Associated With Improved Survival in Metastatic CRC
Vitamin D in mCRC: OS Subgroup
Analysis, Comparing Extreme Quintiles
Ng K, et al. ASCO 2015. Abstract 3503. Reprinted with permission.
Wild type
Mutant
Female
Male
< 60
> 60
White
Black
1
0
FOLFOX
FOLFIRI
Bevacizumab
Cetuximab
Both
< 25
≥ 25
< 3
≥ 3
Age (yrs)
Race
Sex
ECOG performance status
Planned chemotherapy
Assigned treatment arm
RAS mutation status
Body mass index (kg/m2
)
Physical activity
(MET-hrs/wk)
1.61.41.210.80.60.40.20Adjusted HR:
Favors Higher 25(OH)D
.27
.10
.09
.85
.32
.90
.20
.78
.50
P interation

9. clinicaloptions.com/oncology
Higher Vitamin D Levels Associated With Improved Survival in Metastatic CRC
Vitamin D in mCRC: Conclusions
 Many pts with mCRC are vitamin D deficient prior to
treatment
 Higher plasma 25(OH)D levels associated with
significantly improved OS and PFS in response to
chemotherapy + biologic treatment in mCRC[1]
– Between highest and lowest quintile
– 35% OS improvement
– 21% PFS improvement
 Phase II double-blind randomized trial of vitamin D
supplementation plus chemotherapy in mCRC currently
ongoing[2]
1. Ng K, et al. ASCO 2015. Abstract 3503. 2. ClinicalTrials.gov. NCT01516216.

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