Comprehensive molecular and clinical characterization of Asian melanoma patients treated with anti-PD-1 antibody

The role of anti-PD-1 therapy is well established in malignant melanoma – pembrolizumab and nivolumab have been approved as first-line therapy in advanced melanoma. Such advances in immunotherapy have significantly improved the response rates and survival outcomes in patients with advanced melanoma [1, 2]. Melanoma was traditionally classified based on histologic growth pattern – superficial spreading, lentigo maligna, nodular, and acral lentiginous melanoma. However, with increasing data on distinct molecular aberrations and primary locations, a novel classification has been proposed – cutaneous (with or without chronic sun-induced damage), acral, and mucosal melanoma. Previous studies have shown that acral and mucosal melanoma, which have higher frequency of KIT mutation [3, 4], are the most prevalent subtypes in Asian populations [5, 6]. Conversely, cutaneous melanoma is the predominant subtype in Caucasian populations, which have higher incidence of BRAF mutation [4, 7].

Despite the increasing incidence of malignant melanoma in Asia, the absolute incidence remains small [6, 8, 9], and there are limited data available on immunotherapy treatment outcomes in Asian patients with melanoma. The effect of mutation status on response to immunotherapy is poorly understood. Despite the role of anti-PD-1 therapy as a first-line agent, the use of biomarkers for patient selection is an area of ongoing debate. In search of a readily available biomarker, the ratio of neutrophils to lymphocytes (NLR) has been evaluated in many solid cancers, including melanoma [10‐12], and has emerged as an important biomarker to predict response to immunotherapy.

The aim of the present study was to evaluate the treatment efficacy of anti-PD-1 therapy in Asian patients with melanoma. Additionally, we sought biomarkers to predict treatment response to anti-PD-1 antibody in patients with melanoma.

To our knowledge, this is the largest integrated genomic analysis of Asian patients with melanoma treated with anti-PD-1 therapy. In this study, the ORR and DCR were 17% (95% CI, 11–22%) and 60% (95% CI, 52–68%), respectively. These values are slightly lower than those of previous prospective studies, which reported ORR ranging from 21 to 40%. However, our study included patients with poor performance status and brain metastases. This is more representative of patients with advanced melanoma in the clinical setting and possibly explains the low response rates. The median PFS and OS of 4.2 and 32.9 months, respectively, were comparable to those of Caucasian patients [1, 2, 15, 16]. These findings suggest that immune checkpoint blockades are viable treatment options for Asian patients, especially considering the limited utilization of BRAF/MEK inhibitors due to low BRAF^V600 mutant prevalence.

In exploratory analysis, mBRAF^V600 patients who were previously treated with BRAF/MEK inhibitors were analyzed for response rates and survival outcomes. They demonstrated poor PFS and OS compared to mBRAF^V600 patients without previous therapy with BRAF/MEK inhibitors. It is also notable that no mBRAF^V600 patients with previous BRAF/MEK inhibitor therapy experienced a clinical response to immunotherapy. Although we should be cautious about drawing conclusions from a small subset population, the results suggest that early immunotherapy in mBRAF^V600 patients is more effective than early targeted therapies. Two randomized trials (NCT02224781 and NCT02631447) are currently investigating the optimal treatment sequence in a larger mBRAF^V600 cohort, and the results are highly awaited.

The incidence of KIT mutations in our study population was relatively low compared to that of previous reports [3, 17]. This is due to the low accessibility of the c-KIT inhibitor imatinib in the real-world setting. Consequently, clinicians are reluctant to pursue genomic testing for KIT mutational status.

NRAS mutation was detected in 19% of our cohort who underwent NGS, an incidence similar to that of previous reports [18]. Johnson et al. reported that NRAS-mutant patients demonstrate a superior response to immunotherapy (ORR 32 vs. 20%, p = 0.07), particularly to anti-PD-1 and anti-PD-L1 agents (ORR 64 vs. 30%, p-value not provided), which is possibly related to higher PD-L1 expression [19]. Horn et al. reported that melanoma cell lines with chromosomal loss of CDKN2A associated with JAK2 deletion are prone to immunotherapy resistance. However, neither NRAS mutation nor CDKN2A deletion status had statistically significant effects on response rate or survival outcome with anti-PD-1 therapy in our cohort. Whether this conflicting outcome is related to ethnic differences requires further validation in future prospective studies.

Studies regarding response outcomes to immunotherapy according to PD-L1-positivity are confounding [1, 15]. There is an increasing need for an easily accessible and affordable biomarker to predict anti-PD-1 therapy responses, and NLR has emerged as a promising option. The tumor microenvironment is characterized by chronic inflammation, and neutrophils reflect the host inflammatory status in patients with cancer [20]. Although their role is multifactorial, neutrophils have been shown to contribute to tumor initiation, angiogenesis, proliferation, and metastatic spread [21]. However, the utility of NLR as a predictive biomarker in Asian patients with melanoma has not been previously validated.

In our study, NLR was the only independent factor, other than LDH, associated with superior PFS and OS on both univariate and multivariate Cox regression analyses. This is consistent with findings from previous studies [22‐24], highlighting the role of NLR as an important biomarker to predict response and survival outcomes to immunotherapy in patients with melanoma. A cut-off value of 2.10 was utilized in this study; however, similar trends were demonstrated with cut-off values of 2.0, 3.0, and 5.0. Further studies are needed to validate the best cut-off value for utilization of NLR.

This study is the largest integrated genomic analysis of Asian patients with melanoma treated with anti-PD-1 therapy. The heterogeneous patient population in our study reflects the real-world efficacy and safety of anti-PD-1 therapy in patients with advanced melanoma. Despite different distributions in subtypes, BRAF^V600 or KIT mutational status does not affect response to immunotherapy. Low NLR is a strong predictor of higher response and longer survival in response to immunotherapy, and it may be useful as a biomarker.