Introduction

The therapeutic landscape for metastatic melanoma is rapidly changing with novel immunotherapy agents, which have demonstrated significantly improved response rates and outcomes compared with conventional chemotherapy. Immune Checkpoint Inhibitor (ICI) options for stage IV melanoma include anti-PD-1 monotherapy with pembrolizumab or nivolumab or nivolumab/ ipilimumab combination therapy [1-6]. Ipilimumab is a CTLA-4 inhibitor, and CTLA-4/PD-1 inhibitor combination therapies from the Checkmate 067 and Checkmate 069 results demonstrated a higher response rate with nivolumab/ipilimumab combination therapy compared with ipilimumab alone [3-5,7,8].

Cancer-related inflammation responses, such as increased and defective myelopoiesis and both local and systemic inflammation, play an important role in tumorigenesis, disease progression, and patient prognosis [9-11]. Several studies have demonstrated the Neutrophil to Lymphocyte Ratio (NLR) to be associated with clinical outcomes regardless of cancer type [12-14].

Platelets are also well-known as an important indicator of systemic inflammation [15] by secreting various cytokines to support tumor growth, protecting tumors from apoptosis, and promoting tumor metastasis [16]. The prognostic and predictive roles of platelets and the Platelet to Lymphocyte Ratio (PLR) in melanomas have been less investigated, and published data remain controversial [17,18].

In this study, we evaluated the associations of several blood counts and their ratios at baseline with prognostic factors, Overall Survival (OS), and Progression-Free Survival (PFS) in patients with metastatic melanoma treated with first-line ICI.

Materials and methods

Data collection

Among the patients with metastatic melanoma who received immune checkpoint inhibitors (nivolumab or pembrolizumab) as a first-line treatment at Samsung Medical Center between December 2016 and June 2021, 82 with available hematological values before initiating ICIs were included in the analysis. For all patients, White Blood Cell (WBC) count, Absolute Neutrophil Count (ANC), Absolute Lymphocyte Count (ALC), platelet count within 2 weeks prior to initiation of therapy, and other clinical and molecular data were collected before beginning ICI treatment. NLR was calculated as ANC/ALC, derived NLR (dNLR) was calculated as ANC/ (WBC-ALC), and PLR was calculated as platelet/ALC. This study was approved by the Institutional Review Board of Samsung Medical Center. The requirement of informed consent was waived due to the retrospective nature of this study.

Response evaluation

Tumor assessment was performed at baseline, 6-9 weeks, and every 8-9 weeks thereafter, and clinical responses were classified according to the response evaluation criteria in solid tumors (RECIST 1.1). Response Rate (RR) was calculated as the percentage of patients experiencing a confirmed Complete Response (CR) or Partial Response (PR), and Disease Control Rate (DCR) was calculated as RR + Stable Disease (SD) per the RECIST 1.1 guidelines.

Statistical analysis

Progression-Free Survival (PFS) was determined from the first cycle of treatment to disease progression documented by imaging, death (event), or last follow-up (censored). Overall Survival (OS) was calculated from the first cycle of treatment to death (event) or last follow-up (censored). Data cut-off for survival analysis was set at May 30, 2023. Pearson’s chi-square test or Fisher’s exact test was used to compare discrete data. Continuous variables were transformed into categorical variables by X-Tile software (Yale University, New Haven, CT, USA) and determined the best cut-off values for each parameter [19]. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed by Cox-regression analysis. The analyses were conducted using the Statistical Package for the Social Sciences (SPSS), version 19.0 (SPSS Inc., Chicago, IL, USA).

Results

Patient characteristics

We collected data for 82 patients treated either with nivolumab or pembrolizumab. All patients were treated with ICIs as first line treatment -68(82.9) patients with pembrolizumab, eight (9.8%) with nivolumab, four (4.9%) with pembrolizumab +/- lenvatinib, and two (2.4%) patients with nivolumab plus ipilimumab. Baseline patient characteristics are presented in Table 1. The median age was 60 years (range: 27-82 years), and the numbers of females and males were 40(49%) and 42(51%), respectively. The most common site of primary cancer was cutaneous melanoma (N=67, 61%), followed by mucosal type (N=35, 42.7%), uveal melanoma (N=3, 3.7%), and acral melanoma (N=2, 2.4%). BRAF V600E-mutated tumors were observed in 12 patients (14.6%).

Response and survival

Of the 82 patients, 13(15.9%) achieved Complete Response (CR), 31 PR (37.8 %), 19 SD (23.2%), and 16 had progressive disease (PD) (23.2%) (Table 2). The Overall Response Rate (ORR) and disease control rate (DCR) were 53.7% and 76.9%, respectively. Among all patients, the median PFS was 10.3 months (95% confidence interval (CI): 7.30-13.30) and the median OS was 33.5 months (95% CI 24.78-42.22) (Figure 1).

Forty-four patients were categorized as responders and 40 patients as non-responders. There was a significant difference in median PFS between the groups: 15.2 months [95% Confidence Interval (CI), 12.71-17.69] in the responders and 2.8 months (95% CI, 1.97-3.63) in the non-responders [Hazard ratio (HR) 3.87 (95% CI, 2.36-3.63); P<0.001; Figure 1A]. The median OS was 38.0 months (95% CI, 28.87-47.13) in the responder group and 24.7 months (95% CI, 13.77-35.63) in the non-responder group [HR 2.43 (95% CI, 1.29-4.57); P=0.006; Figure 1B].

Blood counts

Among the various blood counts, mean levels of baseline NLR and PLR were significantly lower in the responder group compared to the non-responder group (Figure 2). X-tile software was used to verify the cut-off values in relation to PFS and OS. Regarding the total WBC and neutrophil counts, respective cut-off values were 5,180/uL and 3,100/uL. For platelets and PLR, cut-off values were 283,000/uL and 155, respectively. Univariable analyses of PFS and OS were performed for all patients, and the results are included in Table 3. Multivariable analysis identified high serum platelets (≥283,000/uL) and high PLR (≥155) as significant prognostic factors for worse PFS, and high PLR was identified as an independent prognostic factor for worse OS. Median PFS of 11.8 months (95% CI, 7.73-15.87) was observed in patients with low PLR and of 5.5 months (95% CI, 7.30-13.30) in patients with high PLR (P=0.041; Figure 3A). Median OS was significantly prolonged up to 34.0 months (95% CI, 24.51-43.49) in patients with low PLR and to 22.3 months (95% CI, 16.77-27.83) in patients with high PLR (P=0.010; Figure 3B).

Table 1: Baseline characteristics.

Abbreviations: ICI: Immune checkpoint inhibitor; WBC: White blood cell count; ANC: Absolute neutrophil count; ALC: Absolute lymphocyte count; NLR: Neutrophil to lymphocyte ratio; PLR: Platelet to lymphocyte ratio.

Table 2: Clinical activity of first-line immune checkpoint inhibitors.

Table 3: Univariable analysis for prognostic factors.

Abbreviations: PFS: Progression-free survival; OS: Overall survival; HR: Hazard ratio; CI: Confidence interval; Ref: Reference; TMB: Tumor mutation burden; WBC: White blood cell count; ANC: Absolute neutrophil count; dNLR: derived neutrophil to lymphocyte ratio; NLR: Neutrophil to lymphocyte ratio; PLR: Platelet to lymphocyte ratio.

Discussion

We described the clinical outcomes of first-line ICI in 82 Korean patients with metastatic melanoma and potential blood biomarkers to predict the response to ICI at a single institution. The acral/mucosal, uveal, and cutaneous subtypes accounted for 45.1%, 3.7%, and 51.2% of ICIs, respectively. The overall ORR was 53.7%, while ORRs for the acral/mucosal and cutaneous subtypes were 56.8% and 54.8%, respectively. All three patients with uveal melanoma did not achieve more than a partial response, and the overall DCR of all patients was 76.9%.

Clinical responders to ICI treatment exhibited significantly better survival outcomes than non-responders. Responsiveness to first-line ICI is considered to improve PFS and OS rates [20], as observed in the present study where responders exhibited higher PFS and OS rates compared to non-responders. Regarding the baseline various blood counts, mean NLR and PLR were significantly lower in the responder group compared to the non-responder group. Mean WBC, ANC, and platelet count were also lower in the responder group than in the non-responder group, but the difference was not significant.

In our retrospective cohort study, the median PFS of all patients was 10.3 months and the median OS was 33.5 months, comparable to those of phase 3 clinical trials [21,22]. We determined that higher platelet count and PLR value exhibited a negative impact on PFS, while higher PLR value closely correlated with worse OS. There is no consensus regarding the optimal cutoff value of PLR as a prognostic marker. Previous meta-analysis results identified a PLR cutoff of 120, and the pooled HRs of higher PLR for OS and PFS in melanoma were 1.70 (95% CI, 1.22-2.37) and 1.65 (95% CI, 1.10-2.47), respectively [18]. PLR ≥200 was associated with worse OS (HR: 1.94; 95% CI: 1.29-2.94; P=0.002) and worse PFS (HR: 1.894; 95% CI: 1.27-2.82; P=0.002) in patients with metastatic melanoma and non-small cell lung cancer on PD-1 inhibitors [23]. Patients with PLR ≥200 consisted of only 13.4% of our cohort, and no significant difference was observed between patients with baseline PLR>200 or <200.

There were several studies that demonstrated elevated NLR as a prognostic indicator for survival in melanoma patients treated with PD-1 inhibitors [12,13,24]. In this study, the baseline mean NLR value was significantly higher in non-responder patients. However, NLR with multiple cut-offs did not exhibit a significant association with PFS or OS. If there is a unified cut-off value for NLR and PLR, it would be easy to predict the response to treatment for clinicians. However, since there is no such absolute value, further research in different cohorts is necessary.

This study had some limitations associated with its retrospective design, including the presence of uncontrolled confounding factors, lack of Lactate Dehydrogenase (LDH) values, and absence of information on adverse events. In addition, the sample size was relatively small. However, we enrolled a homogeneous cohort of patients with metastatic melanoma who received first-line ICI treatment at a single institution, and we reported the predictive role of PLR for first-line ICI treatment and also the prognostic value of PLR in metastatic melanoma in Korean patients.

Conclusion

In conclusion, our results demonstrated that high PLR above 155 was associated with poorer PFS and OS in patients with stage IV melanoma treated with first-line immune checkpoint inhibitors.

Acknowledgments

Conflicts of interest statement: All the authors declare no conflicts of interest.

Funding: No funding.

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