Metabolic signatures of response: 2-hydroxybutyric acid as a biomarker in melanoma patients receiving ipilimumab–nivolumab.

Abstract

9521 Background: 2-Hydroxybutyric acid (α-HB) is an established biomarker in metabolic disease of insulin resistance and oxidative stress but its role in immuno-oncology remains unclear. This study conducted an exploratory analysis to evaluate whether α-HB could be used as a biomarker in advanced melanoma patients treated with ipilimumab-nivolumab, and its association with treatment response and toxicity. Methods: In this single-center retrospective study, 36 patients with unresectable/metastatic melanoma received ipilimumab-nivolumab. α-HB levels were measured by targeted mass spectrometry and measured relative metabolomic signal intensities. Descriptive statistics assessed α-HB across subgroups defined by age, sex and BRAF status. Associations between α-HB and grade ≥3 immune-related toxicity, treatment response, and survival at last contact were tested using univariable logistic regression with α-HB entered as a continuous predictor (log2-transformed). Prespecified sensitivity analyses dichotomized α-HB at the median (1.13) and 75th percentile (1.55). For mortality, we additionally derived an exploratory ROC-based Youden threshold to define a “high α-HB” group and report diagnostic performance (specificity, PPV, NPV) and odds ratios. Results: Median age was 53.5; 63.9% were male; 80.6% had cutaneous melanoma; 33.3% were BRAF-mutant; 80.6% received first-line therapy. Baseline α-HB was lower in patients who developed grade ≥3 toxicity (mean 1.01 vs 1.54; p=0.013) and in responders (1.09 vs 1.60; p=0.021), while it was higher among those who died (1.49 vs 1.06; p=0.045). In logistic models using log2-transformed α-HB, each doubling in α-HB was associated with reduced odds of grade ≥3 toxicity (OR 0.165, 95%CI 0.036–0.744; p=0.019) and response (OR 0.268; 95% CI 0.075–0.961; p=0.043; AUC = 0.79; HL p=0.803, where higher p indicates better fit), consistent with lower α-HB marking both toxicity and response. Higher α-HB trended toward increased death risk (OR 3.3 per doubling; p=0.066). Using a Youden-derived cutoff (α-HB ≥1.58), high α-HB defined a high-risk subgroup (OR 10.0; 95% CI 1.09–91.4; p=0.041) with high specificity for death (94%); PPV 89% and NPV 56%. Conclusions: Elevated α-HB was associated with reduced response, lower incidence of immune-related toxicity, and higher rates of death, suggesting a metabolically suppressed immune phenotype. Further validation is needed to determine whether metabolic interventions could improve immunotherapy outcomes in selected patients.