Baseline vitamin D status and clinical outcomes in advanced non-small cell lung cancer patients treated with nivolumab

Immune checkpoint inhibitors such as nivolumab have brought meaningful benefits to patients with advanced non-small cell lung cancer (NSCLC), yet many patients still experience limited responses. Vitamin D is a key modulator of immune function, and deficiency is common in individuals with cancer. Given its potential role in shaping immunotherapy response, we retrospectively assessed whether baseline vitamin D levels were associated with clinical outcomes in advanced NSCLC patients treated with nivolumab. We retrospectively analyzed patients with stage IV NSCLC treated with nivolumab across multiple centers, predominantly as second-line therapy. Prior to nivolumab initiation, all patients were confirmed to be negative for common driver mutations, including EGFR, ALK, ROS1, and other actionable genomic alterations. Baseline serum 25-hydroxyvitamin D levels were measured prior to nivolumab initiation, and patients were categorized as having severe deficiency (< 10 ng/mL), deficiency (10–20 ng/mL), or sufficient levels (≥ 20 ng/mL). The presence of liver metastases was recorded at baseline. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared with log-rank tests. Multivariable Cox proportional hazards models adjusted for age, sex, ECOG performance status, liver metastasis, and other metastatic sites were used to evaluate the independent prognostic value of vitamin D status. Objective response rates (ORR) were assessed in patients with available radiologic data. A total of 890 patients were screened, and after excluding those with missing baseline vitamin D data, 305 patients were included in the analysis. The median age was 64 years (range 34–85), and 68% of patients were male. Vitamin D levels were < 10 ng/mL in 30%, 10–20 ng/mL in 44%, and ≥ 20 ng/mL in 26% of patients. Patients with severe vitamin D deficiency were numerically older (median age 65 vs. 63 years) and had higher rates of ECOG PS ≥ 2 (15.1% vs. 7.5%) and squamous histology (37.6% vs. 27.5%), though these differences were not statistically significant (p > 0.05 for all). Liver metastases were present in 54 patients (17.7%), and the distribution was similar across vitamin D groups (p = 0.92). Median PFS was shortest in patients with severe vitamin D deficiency (3.4 months), intermediate in the 10–20 ng/mL group (5.2 months), and longest in patients with sufficient levels (8.1 months). Median OS ranged from 8.6 months in the < 10 ng/mL group to 15.8 months in the ≥ 20 ng/mL group. Patients with liver metastases had significantly shorter OS compared to those without (median OS 9.8 vs. 13.6 months, HR 1.48, p = 0.006). Vitamin D deficiency was associated with significantly worse PFS and OS on univariate analysis. In multivariable analysis, vitamin D levels < 20 ng/mL remained independently associated with poorer OS. ORR was numerically higher in patients with sufficient vitamin D levels (30% vs. 14%). Lower baseline vitamin D levels were associated with inferior clinical outcomes in advanced NSCLC patients treated with nivolumab. Patients with vitamin D levels ≥ 20 ng/mL demonstrated longer PFS and OS and a trend toward higher response rates. These findings support a prognostic role for vitamin D status in immunotherapy-treated NSCLC; however, prospective studies are required to determine whether vitamin D optimization can causally enhance immunotherapy efficacy.