TOPLINE

High-dose vitamin D3 supplementation added to standard chemotherapy plus bevacizumab does not improve progression-free survival (PFS) compared with standard-dose vitamin D3 in patients with previously untreated metastatic colorectal cancer (mCRC). Among 455 randomized patients, median PFS was 11.8 months in the high-dose group vs 10.3 months in the standard-dose group, with no significant differences in objective response rates or overall survival.

METHODOLOGY

• The SUNSHINE phase 2 randomized clinical trial demonstrated that high-dose vitamin D3 added to standard treatment improved PFS compared with standard-dose vitamin D3 in patients with previously untreated mCRC. The SOLARIS trial was conducted to confirm the findings from the SUNSHINE trial.
• Researchers conducted the double-blind phase 3 randomized SOLARIS trial in 455 patients with previously untreated mCRC through the National Clinical Trials Network in the United States from October 2019 to December 2022, with database freeze on July 15, 2024.
• Patients received investigator’s choice chemotherapy consisting of modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab 5 mg/kg intravenously every 2 weeks, randomly assigned 1:1 to receive either high-dose vitamin D3 (8000 IU daily for 14 days as loading dose followed by 4000 IU daily) or standard-dose vitamin D3 (400 IU/d). The primary end point was PFS, while secondary end points included objective response rate, overall survival, and toxicity.
• Prespecified subgroup analyses of PFS were performed according to known prognostic factors including primary tumor location, Eastern Cooperative Oncology Group (ECOG) performance status, age, sex, race, body mass index, number of metastatic sites, and molecular markers.
• Mandatory plasma samples were collected at baseline, first and second restaging (after cycles 4 and 8), and treatment discontinuation to assess 25-hydroxyvitamin D (25[OH]D) levels using liquid chromatography-mass spectrometry.

TAKEAWAY

• Among 455 randomized patients with median follow-up of 20 months, median PFS for high-dose vitamin D3 (n = 228) was 11.8 months vs 10.3 months for standard-dose vitamin D3 (n = 227).
• No significant differences were observed in objective response rates between high-dose and standard-dose vitamin D3 groups (51% vs 44%) or in overall survival (median, 25.6 vs 27.0 months).
• A significant interaction was observed between primary tumor location and vitamin D3 treatment (P for interaction = .02), with patients with left-sided primary tumors showing improved PFS with high-dose vs standard-dose vitamin D3 (median, 13.8 vs 10.2 months; P = .05; unadjusted hazard ratio [HR], 0.74).
• High-dose vitamin D3 was well tolerated with no clinically meaningful differences in grade 3 or greater adverse events between groups, including neutropenia (67 patients [31.6%] vs 62 [29.7%]) and hypertension (42 [19.8%] vs 49 [23.4%]), and vitamin D-associated toxicities were rare.

IN PRACTICE

“On the basis of these findings, the addition of high-dose vitamin D to standard chemotherapy cannot be recommended for unselected patients with previously untreated mCRC…. However, these findings remain exploratory and require further investigation,” the authors of the study wrote.

SOURCE

The study was led by Kimmie Ng, MD, MPH, Dana-Farber Cancer Institute in Boston. It was published online on August 3 in JAMA.

LIMITATIONS

Patients in the current study had higher baseline plasma 25[OH]D concentrations (median, 21.8 ng/mL) than those in the prior SUNSHINE trial (median, 17.6 ng/mL), which may have reduced the potential benefit from high-dose supplementation. The median baseline 25[OH]D level was statistically higher in the high-dose group than the standard-dose group by chance, potentially reducing the ability to detect differences between groups. Patients receiving standard-dose vitamin D3 had a median increase from baseline of 5.9 ng/mL, representing less of a true active control than that of the SUNSHINE trial where standard-dose patients showed no increase. The study was restricted to patients receiving modified FOLFOX6 or FOLFIRI with bevacizumab, excluding other commonly used regimens such as FOLFOXIRI or anti-epidermal growth factor inhibitors, potentially limiting generalizability. Consumption of additional supplemental vitamin D outside of the protocol-specified treatment cannot be ruled out, although plasma 25[OH]D levels remained statistically significantly lower in the standard-dose group throughout the study.

DISCLOSURES

This study was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821, U10CA180882, UG1CA189848, UG1CA189850, UG1CA189953, UG1CA232760, UG1CA233180, UG1CA233290, UG1CA233320, UG1CA233328, U10CA180820, U10CA180868, and R01CA205406. Pharmavite LLC provided the vitamin D3 and placebo capsules for the trial. Ng disclosed receiving nonfinancial support from Pharmavite and Janssen to the institution, personal fees from Bayer, GSK, Pfizer, CytomX, Jazz Pharmaceuticals, Revolution Medicines, Agenus, Johnson & Johnson, AbbVie, Sanofi, Genmab, Flagship Pioneering/Etiome, AstraZeneca, Amgen, and Seagen outside the submitted work, and holding future stock options from Manta Cares. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.