“The investigators of the current study tested the hypothesis that vitamin D supplementation is associated with a reduced risk of checkpoint-induced colitis by rigorously assessing 37 variables in both discovery and validation cohorts,” said invited discussant Jarushka Naidoo, MBBCh, Assistant Professor of Oncology at Johns Hopkins Kimmel Comprehensive Cancer Center. “In their discovery cohort, they identified that pre-treatment vitamin D intake (> 400 IU) was associated with the condition, and this was validated in their independent cohort.”

Jarushka Naidoo, MBBCh

Dr. Naidoo did point out that the incidence of colitis in the discovery cohort was nearly double that in the validation cohort. In addition, there were also more low-grade events in the discovery group, suggesting the cohorts may have had some relevant differences.

Study Strengths and Limitations

As for study strengths, she noted that it is based on a strong rationale from the inflammatory bowel disease literature; is a robust analysis that uses both a discovery and a validation set, validates pre-treatment vitamin D as a potential risk factor for colitis in patients with melanoma mainly treated with a combination of checkpoint inhibitors, and identifies a potentially modifiable risk factor.

The main limitations, Dr. Naidoo maintained, are that the use of vitamin D supplementation cannot be verified; there is an imbalance in colitis incidence and grade between the cohorts; the multivariate model adjusts for multiple comparisons (without using a Bonferroni adjustment) and may have excluded some potential risk factors (HLA type has recently been implicated); overlapping mechanisms may have been at play; and the analysis was restricted to patients with melanoma.

Questions Remain

Dr. Naidoo posed several outstanding questions that remain to be answered:

• Is vitamin D colitis protected by similar mechanisms as the gut microbiota? Mechanistic studies in germ-free mice are likely to shed light here.
• Are colitis risk factors the same across tumor types? The inclusion of patients with renal cell carcinoma and lung cancer, treated with nivolumab and ipilimumab, would be an important next step.
• Do the findings justify a prospective study of vitamin D supplementation to prevent or treat colitis? There is a precedent for prospective studies to mitigate subsequent development of immune-related colitis, as well as prospective studies utilizing vitamin D in inflammatory bowel disease (eg, ClinicalTrials.gov identifier NCT04225819). 

DISCLOSURE: Dr. Naidoo disclosed financial relationships with AstraZeneca/MedImmune, Bristol-Myers-Squibb, and Roche/Genentech.