Optimizing Nivolumab Efficacy: The Role of Dosing Time in Advanced Non-Small Cell Lung Cancer - Article abstract #950963

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.

Background: Biomarkers guiding immunotherapy in non-small cell lung cancer (NSCLC) are limited. The glucose-to-lymphocyte ratio (GLR), integrating metabolic and immune status, has shown prognostic value in several cancers but has not been systematically evaluated in patients receiving PD-1 blockade. Methods: We retrospectively analyzed 837 patients with advanced or metastatic NSCLC treated with nivolumab across 21 oncology centers in Turkey (2015–2025). Baseline GLR was calculated from fasting glucose and absolute lymphocyte counts. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier and compared with log-rank tests. Multivariate Cox regression models identified independent predictors. Receiver operating characteristic (ROC) analysis determined the optimal GLR cut-off for OS, which was subsequently applied to PFS analyses for consistency. Results: The optimal GLR cut-off for mortality was ≥70.76 (AUC = 0.635, 95% CI: 0.597–0.674; p < 0.001). Patients with GLR <70.76 achieved significantly longer OS (median 24.1 vs 9.6 months; p < 0.001) and PFS (9.7 vs 5.8 months; p < 0.001) compared with those with GLR ≥70.76. In multivariate analysis, high GLR and poor ECOG performance status independently predicted worse OS. Prior thoracic radiotherapy was associated with improved outcomes. Conclusion: Baseline GLR is a practical, cost-effective biomarker that independently predicts OS in advanced NSCLC patients treated with nivolumab. Elevated GLR likely reflects metabolic dysfunction and impaired immune reserve, both unfavorable for PD-1 blockade efficacy. Prospective studies are warranted to validate GLR and define its role in clinical decision-making.

Aims: This study aimed to investigate whether the efficacy of neoadjuvant chemotherapy differs between HER2-low and HER2-zero subgroups in hormone receptor–positive, HER2-negative breast cancer. Materials and Methods: A total of 61 patients who received neoadjuvant chemotherapy between 2015 and 2025 were retrospectively analyzed. HER2 status was determined from pre-treatment core biopsy specimens and classified as HER2-low (IHC 1 + or 2 + and FISH-negative) or HER2-zero (IHC 0). The pathological complete response (pCR) rates were compared between the two groups. Results: Among 61 patients, 28 had HER2-low and 33 had HER2-zero tumors. The pCR rate was 7.1% in the HER2-low group and 27.3% in the HER2-zero group (p = 0.042). A post-hoc power analysis based on these results showed a moderate power (0.59) to detect the observed difference. Conclusions: HER2-low expression may negatively influence chemosensitivity in hormone receptor–positive breast cancer treated with neoadjuvant chemotherapy. Further studies are warranted to evaluate the potential role of trastuzumab deruxtecan (T-DXd) and other antibody–drug conjugates in this newly defined subgroup.

Nivolumab is currently widely used in the treatment of lung cancer. Studies have been conducted using flat doses of 240 mg and 3 mg/kg. In fact, studies involving a small number of patients have begun to explore low-dose immunotherapies. The literature on the optimal dose of immunotherapy, the use of weight based, or fixed doses is very recent and has become a one of the subject of ongoing research. This multicenter study included 716 patients with NSCLC. Patients receiving standard doses of 3 mg/kg and 240 mg of nivolumab were divided into subgroups based on their weight. Patients weighing 80 kg have already received a flat dose. However, patients weighing < 80 kg who received a flat dose were considered to be receiving high-dose therapy. Conversely, patients weighing more than 80 kg who received a flat dose were maintained on a low dose. Therefore, overall survival, progression-free survival, and toxicity were examined according to weight-based usage. The median progression free survival (PFS) for those receiving a 3 mg/kg dose was 6 months, whereas it was 9.8 months for those receiving a flat dose (p < 0.001). The median (metastatic overall survival) OS for those receiving a 3 mg/kg dose was 12 months, whereas it was 14 months for those receiving a 240 mg dose (p = 0.03). This study was based on real-world data. Therefore, our results may be instructive regarding the nivolumab dose, which is a commonly used treatment for NSCLC patients. Our results suggest that a flat dose may be preferred in all groups and as a subgroup, especially in patients weighing < 80 kg.

Eurasian Journal of Medical Advances