1. Higher Vitamin D Levels Associated With Improved Survival in Metastatic Colorectal Cancer CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting*
May 29 - June 2, 2015
*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. 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
mCRC, metastatic colorectal cancer.
Ng K, et al. ASCO Abstract 3503.

3. CALGB/SWOG 80405: Cetuximab and/or Bevacizumab + Combination CT
Cetuximab 400 mg/m2 IV on Day 1, then 250 mg/m2 once weekly
Patient/physician choice: mFOLFOX6 or FOLFIRI
Pts with untreated mCRC
(N = 1137)
Bevacizumab 5 mg/kg IV every 2 wks
Primary endpoint: OS. Secondary endpoints: PFS, response rate
FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; IV, intravenous; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival.
The CALGB/SWOG study (planned N = 2289) is evaluating first-line combined biologic therapy for patients with metastatic colorectal cancer. Patients and physicians decided on FOLFOX or FOLFIRI, after which patients are randomized to cetuximab, bevacizumab, or both. The primary endpoint here is overall survival, which was mandated by the US Food and Drug Administration (FDA); progression-free survival is the secondary endpoint.
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
Ng K, et al. ASCO Abstract 3503.

4. Vitamin D in mCRC: Pt Population
Vitamin D cohort similar characteristics as full trial cohort
Characteristic Q1
(n = 208) Q2
(n = 209) Q3 Q4
(n = 210) Q5
P Value
Median 25(OH)D, ng/mL (range)
8.0
( )
13.6
( )
17.2
( )
21.4
( )
27.5
( ) --
Median age, yrs 59 60 61
.07
Male, % 48 64 58 55
.004
Black, % 25 12 6 7 2
< .0001
ECOG PS 1, % 50 36 42 37 30
.002
RAS mutant, % 39 29 21
.02
ECOG, Eastern Cooperative Oncology Group; mCRC, metastatic colorectal cancer; PS, performance status.
Ng K, et al. ASCO Abstract 3503.

5. 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
BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; mCRC, metastatic colorectal cancer; PS, performance status.
Ng K, et al. ASCO Abstract 3503.

6. Vitamin D in mCRC: Survival Outcomes
35% OS improvement and 21% PFS improvement in highest quintile compared with lowest
Outcome Q1
(n = 208) Q2
(n = 209) Q3 Q4
(n = 210) Q5
P Value
Median OS, mos
24.5
30.0
28.4
27.2
32.6
.01
95% CI
Median PFS, mos
10.1
10.9
11.4
12.7
12.2
.02
OS multivariate HR
1.0
0.83
0.81
0.79
0.65
.001
PFS multivariate HR
0.99
0.84
mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival.
Ng K, et al. ASCO Abstract 3503.

7. Vitamin D in mCRC: Greater Benefit in A/A Genotype
Exploratory SNP analysis identified potential association of A/A genotype vs A/G or G/G at SNP rs in RXR gene (P = .01)
rs : A/A
n = 320
rs : A/G or G/G
n =
1.0
Vitamin D < median
Vitamin D ≥ median
1.0
Vitamin D < median
Vitamin D ≥ median
0.8
0.8
0.6
0.6
Probability of OS
Probability of OS
0.4
mCRC, metastatic colorectal cancer.
0.4
0.2
0.2 2 4 6 8 2 4 6 8
Yrs
Yrs
Adjusted interation P = .0103
Ng K, et al. ASCO Abstract Reprinted with permission.

8. Vitamin D in mCRC: OS Subgroup Analysis, Comparing Extreme Quintiles
P interation
< 60
Age (yrs)
.27
> 60
White
Race
Black
.10
Male
Sex
.09
Female
ECOG performance status
.85 1
FOLFIRI
Planned chemotherapy
.32
FOLFOX
Bevacizumab
Assigned treatment arm
Cetuximab
.90
Both
ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; mCRC, metastatic colorectal cancer; OS, overall survival.
Wild type
RAS mutation status
.20
Mutant
< 25
Body mass index (kg/m2)
.78
≥ 25
Physical activity (MET-hrs/wk)
< 3
.50
≥ 3
Adjusted HR:
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
Favors Higher 25(OH)D
Ng K, et al. ASCO Abstract Reprinted with permission.

9. 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]
mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival.
1. Ng K, et al. ASCO Abstract ClinicalTrials.gov. NCT

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