Prognostic Value of the CONUT Score with Immune Checkpoint Inhibitors as First-Line Therapy for Metastatic Malignant Melanoma

Immunology Oncology Life Sciences Medicine
Immune checkpoint inhibitors Nutritional status Melanoma Prognostic marker Inflammation

Prognostic Value of the CONUT Score in Immune Checkpoint Inhibitor Therapy for Metastatic Malignant Melanoma

Academic Background

The incidence of malignant melanoma (MM) is increasing annually, with approximately 20% of patients progressing to advanced or metastatic melanoma. Immune checkpoint inhibitors (ICIs) have significantly transformed the treatment strategy for advanced melanoma by enhancing the immune system’s response to tumors. However, despite their excellent efficacy, many patients still do not benefit from ICIs. Additionally, immunotherapy is associated with significant toxicity and high treatment costs, making it crucial to select patients likely to respond to ICIs, especially in Asian populations, where melanoma subtypes and ICI responses differ from those in Caucasians.

Nutrition and inflammation play important roles in cancer development and treatment. Nutritional and inflammatory scoring systems such as the Modified Glasgow Prognostic Score (mGPS), Neutrophil-Lymphocyte Ratio (NLR), Systemic Immune-Inflammation Index (SII), Controlling Nutritional Status (CONUT), Prognostic Nutritional Index (PNI), and Body Mass Index (BMI) have been used to assess cancer-related prognosis. However, the prognostic value of the CONUT score in melanoma has not been studied.

Study Source

This study was conducted by Ken Horisaki, Shusuke Yoshikawa, Shoichiro Mori, Wataru Omata, Arata Tsutsumida, and Yoshio Kiyohara from Shizuoka Cancer Center and Nagoya University Graduate School of Medicine in Japan. The research was published in 2025 in the Journal of Dermatology, with the article number 10.1111⁄1346-8138.17613.

Research Process

Study Population and Data Collection

This retrospective cohort study was conducted at Shizuoka Cancer Center in Japan, analyzing 123 patients with stage IV melanoma treated with ICIs as first-line systemic therapy between February 2012 and July 2024. Inclusion criteria included pathologically confirmed melanoma, primary sites including skin, mucosa, uvea, and unknown primary sites, classified as stage IV according to the American Joint Committee on Cancer (AJCC) 8th edition, and treatment with nivolumab, pembrolizumab, or nivolumab plus ipilimumab, with recorded total lymphocyte count (TL), serum albumin (Alb), and total cholesterol (T-Chol) levels before ICI administration.

Definition of the CONUT Score

The CONUT score consists of three components: TL, Alb, and T-Chol. TL values of ≥1600, 1200-1599, 800-1199, and <800/μl were scored 0, 1, 2, and 3 points, respectively. Alb levels of ≥3.5, 3.0-3.49, 2.5-2.99, and <2.5 g/dl were scored 0, 2, 4, and 6 points, respectively. T-Chol levels of ≥180, 140-179, 100-139, and <100 mg/dl were scored 0, 1, 2, and 3 points, respectively. Patients were divided into CONUT≥3 and CONUT≤2 groups based on the total CONUT score.

Efficacy Assessment

The primary outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR was defined as the proportion of patients achieving complete response (CR) or partial response (PR).

Statistical Analysis

Baseline characteristics were compared using the Mann-Whitney U test and chi-square or Fisher’s exact tests. ROC curve analysis was used to determine the optimal cutoff value for the CONUT score. PFS and OS were calculated using the Kaplan-Meier method, and survival differences were assessed using the log-rank test. Cox proportional hazards regression models were used to evaluate independent prognostic factors.

Main Results

Optimal Cutoff Value for CONUT Score

The optimal cutoff value for the CONUT score was determined to be 3 through ROC curve analysis, with an area under the curve (AUC) of 0.762.

Baseline Characteristics

Among the 123 patients, 67 (55.5%) had a CONUT score ≤2, and 56 (45.5%) had a CONUT score ≥3. The median age of the CONUT≤2 group was significantly lower than that of the CONUT≥3 group (65.0 vs. 70.5 years, p=0.016). The proportion of males was similar between the two groups (56.7% vs. 53.6%, p=0.856). The CONUT≥3 group had a significantly higher proportion of patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2 compared to the CONUT≤2 group (16.1% vs. 3.0%, p=0.022). Primary sites were predominantly skin (50.4%), mucosa (35.0%), uvea (7.3%), and unknown (7.3%). Approximately half of the patients (49.6%) had elevated lactate dehydrogenase (LDH) levels.

Objective Response Rate

The overall ORR was 22.0% (4.9% CR, 17.1% PR). The ORR was significantly higher in the CONUT≤2 group compared to the CONUT≥3 group (30.0% vs. 12.5%, p=0.020). In patients treated with anti-PD-1 antibody monotherapy, the ORR was also significantly higher in the CONUT≤2 group (30.7% vs. 12.8%, p=0.05).

Progression-Free Survival and Overall Survival

The PFS in the CONUT≤2 group was significantly better than in the CONUT≥3 group (median PFS time: 6.2 vs. 2.5 months, p=0.017). The OS in the CONUT≤2 group was also significantly better than in the CONUT≥3 group (median OS time: 23.8 vs. 7.0 months, p<0.001). The 1-year PFS was 33.7% vs. 22.8% (HR, 1.735; 95% CI 1.103-2.728; p=0.017), and the 3-year PFS was 22.6% vs. 10.6% (HR, 1.696; 95% CI 1.108-2.598; p=0.015). The 1-year OS was 75.6% vs. 32.4% (HR, 4.031; 95% CI 2.22-7.318; p<0.001), and the 3-year OS was 38.4% vs. 15.2% (HR, 2.504; 95% CI1.597-3.927; p<0.001).

Multivariate Analysis

Multivariate analysis showed that the CONUT score (CONUT≥3, HR, 1.65, p=0.030), first-line systemic therapy (anti-PD-1, HR, 0.47, p=0.017), and immune-related adverse events (IRAE) ≥ grade 3 (HR, 0.44, p=0.011) were independent prognostic factors for PFS. For OS, the CONUT score (CONUT≥3, HR, 2.68, p<0.001), ECOG PS (PS≥2, HR, 2.76, p=0.008), and primary site (cutaneous, HR, 1.65, p=0.042) were independent prognostic factors.

Subgroup Analysis

Subgroup analysis by primary site and treatment method showed that patients with cutaneous primary melanoma and those treated with anti-PD-1 had significantly worse OS in the CONUT≥3 group. There was no significant difference in OS between the two groups for patients with mucosal primary melanoma.

Conclusion

This study demonstrates that the CONUT score can serve as a prognostic indicator for patients with stage IV melanoma treated with ICIs as first-line systemic therapy. Patients with CONUT≥3 had worse ORR, PFS, and OS, and the CONUT score independently predicted PFS and OS. Additionally, the CONUT score was not significantly associated with the development of severe immune-related adverse events (IRAE). The simplicity of the CONUT score may help identify melanoma patients suitable for ICI treatment.

Research Highlights

  1. First Study of CONUT Score in Melanoma ICI Therapy: Fills a gap in the application of the CONUT score in melanoma.
  2. Independent Prognostic Factor: CONUT≥3 is an independent prognostic factor for PFS and OS, with significant clinical implications.
  3. Simple and Practical Scoring System: The CONUT score, based on serum albumin, total cholesterol, and total lymphocyte count, is straightforward and applicable in clinical practice.
  4. Detailed Subgroup Analysis: Subgroup analysis by primary site and treatment method provides more nuanced prognostic information.

Research Value

This study provides a simple and effective prognostic tool for melanoma patients undergoing ICI therapy, helping clinicians optimize treatment strategies, improve treatment efficiency, and reduce costs. Additionally, the findings offer new insights into the role of nutritional and inflammatory status in cancer treatment. Despite the limitations of a retrospective study and a relatively small sample size, this research lays the foundation for future prospective studies and validation cohorts.