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.

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 2015. Abstract 3503.

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 80405 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 2015. Abstract 3503.

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 (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 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 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 BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; mCRC, metastatic colorectal cancer; PS, performance status. Ng K, et al. ASCO 2015. Abstract 3503.

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 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 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 0.99 0.84 mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival. Ng K, et al. ASCO 2015. Abstract 3503.

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 rs3818740 in RXR gene (P = .01) rs3818740: A/A n = 320 rs3818740: A/G or G/G n = 340 + 69 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 2015. Abstract 3503. Reprinted with permission.

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 2015. Abstract 3503. Reprinted with permission.

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 2015. Abstract 3503. 2. ClinicalTrials.gov. NCT01516216.

Go Online for More CCO Coverage of ASCO 2015! Short slidesets of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Gastrointestinal cancers Genitourinary cancer Hematologic malignancies Immunotherapy Lung cancer clinicaloptions.com/oncology