Real life clinical management and survival in cutaneous malignant melanoma: the Italian Clinical National Melanoma Registry (CNMR) experience

: Background: Cutaneous malignant melanoma (CMM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice for the treatment of metastatic CMM. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CMM in several Italian centers which are part of the Clinical National Melanoma Registry (CNMR), and the oncological outcomes obtained. Methods: CNMR collects data of patients with a histologically confirmed diagnosis of primary CMM treated in one of the 38 Italian institutions (hospitals, research institutes, etc.) participating in the network. Melanoma-specific survival and Overall survival were calculated. Kaplan-Meier curves and medians of OS and 95% CI are presented overall and by immunotherapy and target treatments. The Log-rank test compared curves by treatments. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors. Results: The median follow-up time was 36 months (range 1.2-185.1). 787 CMM were included in the analysis with completed information about therapies.Global immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by nivolumab/pembrolizumab immunotherapy (anti-PD1 HR=0.25 95% CI 0.14-0.42), globally immunotherapy was significantly associated with improved survival, either for anti-CTL A4 monotherapy or combined with anti-PD1 (HR=0.47;95% CI 0.33-0.66 and HR=0.26; 95% CI 0.15-0.46, respectively). Conclusions: The nivolumab/pembrolizumab and the combination of ipilimumab can be considered the best therapy to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment. Graphical Abstract


Simple Summary:
Cutaneous malignant melanoma (CMM) is one of the most aggressive types of skin cancer.
The aim of this study is to investigate the oncological treatments employed in the real-life clinical management of patients with advanced CMM in several Italian centers which are part of the Clinical National Melanoma Registry (CNMR. The immunotherapy can be considered the best therapy to improve survival in a real-world-population of cutaneous malignant melanoma. In the future, the main challenge of CNMR is the identification of the best therapy that patients could benefit to improve survival.

Introduction
Cutaneous malignant melanoma (CMM) is one of the most aggressive types of skin cancer.
The incidence of CMM has increased in Europe over the last years, and cohort studies suggest that the increasing trend of incidence will continue for at least the next 2 decades [1][2][3] Mortality rates have also increased in the last decades, especially in men, despite a clear decrease of Breslow tumor thickness in the USA and Europe [1,4]. In the USA, the raw mortality rates per 100,000 inhabitants per year increased from 2.8 to 3.1, with an estimate of 10,130 deaths from melanoma in 2016 (they were 8650 in 2009) [1]. In Italy, 12,3000 new cases and over 2,000 deaths were estimated in 2019 [5][6].
Surgery is currently the golden standard for patients with early stage CMM, who represent only part of the global cases. The treatment of patients with advanced stage CMM is more complex, as for decades no chemotherapy regimens have been found effective in prolonging survival. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice for the treatment of metastatic CMM. Target therapies are based on the use of drugs targeting specific genetic alterations in candidate genes, blocking specific pathways implicated in the oncogenesis of melanoma [7]. BRAF mutations represent currently the main molecular targets for melanoma treatment, as they involve approximately 50% of the cases, and identify patients who may benefit from treatment with BRAF inhibitors, like vemurafenib or dabrafenib [8][9][10].
Recently, the combination of anti-BRAF drugs with MEK inhibitors showed improved oncological outcomes in comparison to monotherapies (70% one-year and 50% two-years survival), with a better safety profile [11][12][13].
Immuno-therapy takes advantage of the fact that treatments indirectly affect cancer cells by stimulating the patient's immune system, particularly enhancing the immune system's T-cell response [14]. Ipilimumab, a monoclonal antibody that blocks the activity of the CTLA-4, has shown a long-term survival in about 20% of the patients treated [15][16][17].
Programmed death 1 (PD1) is a membrane receptor of tumor cells (its main ligand is PD-L1) that represents a powerful brake to the immune system's response, and the target of specific inhibitors (nivolumab and pembrolizumab) which have been recently introduced into clinical practice, as they were shown more effective than ipilimumab in terms of overall survival (OS) and toxicity [18][19]. Recent studies showed that the combination of anti-CTLA-4 and anti-PD-1 is more effective than monotherapy, but a higher incidence of high-grade adverse events was found [20]. Combinations of targeted therapies and immunotherapies are currently investigated; the advantage of such combinations is that more than one anti-tumoral mechanism are employed against CMM. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility.
The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CMM in several Italian centers which are part of the Clinical National Melanoma Registry (CNMR), and the oncological outcomes obtained.

Results
A total of 8,163 CMM cases were registered in CNMR in the period under investigation.
17% (1,401) were melanoma in situ, 63% (5121 patients) had a stage from IA to IIC, 20% had a stage from IIIA (Table 1). Total 8163 100 Table 2 shows the distribution of the melanoma stage in accordance to their demographic data, geographic origin: 4,242 (52%) were males and the mean age was 58±15years, 3,916 (48%) were females and the mean age was 54±16 years, the majority of the sample coming from northern Italian centers. Stage III counts 751 patients, but only 14% were IIIB-IIIC unresectable that were included in the analysis. Patients characteristics, data on tumor and BRAF mutational status were restricted to advanced melanoma (IIIB-IIIC unresectable, IV), and the total sample counted 787 patients.
Regarding to stage 12% had aninitial diagnosis of in situ, 38% had an early diagnosis (IA-IIC), 37% stage III and 13% had a confirmed advanced melanoma stage (IV). 76% was the percentage of BRAF executed in our sample and the incidence of BRAF mutations was slightly greater than 50%; most cases were analyzed after the year 2013 when target therapies were diffusely employed in clinical practice; in addition, more cases among those analyzed harbored stage IV tumors rather than stage IIIB-IIIC melanomas. (Table3)  Immunotherapy showed animproved survival compared with all other therapies (p=0.001)

Discussion
In this study, we examined data of advanced melanoma in the Italian Clinical National Melanoma Registry (CNMR). CNMR doesnot have the typical aim of cancer registries to estimate incidence data, but as a clinical registry may collect data from the real world experience which is different from that coming from clinical studies which included selected patients. [22][23]. Indeed, much of the existing research on advanced melanoma patients has been conducted in clinical trials settings among patients who meet stringent inclusion and exclusion criteria.
The analysis of the 787 patients from the advanced cohort showed some interesting results.
As first, looking at the advanced patients' characteristics, a good percentage of them come from the initial stages more than from the high risk conditions. Indeed, 50% of advanced melanoma had an initial diagnosis of early stage that then developed into advanced one.
Interestingly, the BRAF mutational status wasnot evaluated in all patients; indeed, the BRAF status has been documented in as much as 76% of these patients.An important consideration is that the CNMR collected data from December 2011 and the most important drug in the field of melanoma, like BRAF inhibitors, anti-CTLA4, anti-PD1 were approved in the following years. Specifically ipilimumab was the first treatment to be approved, on It seems that the greater advantage in terms of OS is in those patients who have performed immunotherapy lines, even compared to those who have performed target therapies. This finding could be explained by the fact that many patients received BRAF inhibitor therapy as single agent (69,5%), and only a minority had benefit from the addition of the MEK inhibitor. Indeed, we learned that disease progression during therapy with the BRAF inhibitor alone was often rapid and unresponsive to subsequent treatments [25];with the addition of MEK inhibitors, the fast progression from target therapy was reduced.
The data on the combination nivolumab + ipilimumab also appears intriguing, especially in terms of long survival; however, the low number of patients does not allow us to give definitive conclusions.
The correlation between survival and the LDH value is also consistent with the literature data. Analyzing the LDH values, there is an increased risk of death for patients with high LDH, compared to those with normal LDH, especially in the group of patients who received immunotherapy (HR = 2.45, p = 0.01) We found that immunotherapy allows better results in terms of overall survival in patients with advanced melanoma, however in our analysis there is no statistically significant benefit of the treatment-sequence variable (Immuno in 1 st and Target in 2 nd vs. Target in 1 st and Immuno in 2 nd line). In consideration of the retrospective analysis, the small number of patients who started with anti-PD-1, and the lack of patients who received the dual MAPK blockade, definitive conclusions cannot be made.
At the moment several combination studies of target and immunotherapies as well as protocols to establish the best sequential therapy areongoing. [26]. Our study has several limitations. In fact, most patients received chemotherapy as a first systemic treatment for advanced disease, because more effective drugs such as BRAF/MEK inhibitors, anti-CTLA4 and anti-PD1 inhibitors were approved subsequently in different years. In addition, many centers did not test all patients for BRAF, especially at the beginning. A diagram of the CNMR's organizational structure can be found in Figure 1.

Statistical analysis
Descriptive statistics for the categorical data were reported. All statistical tests were two-sided. P-values < 0.05 were considered significant. Statistical analyses were performed using statistical software SAS (version 9.02 for Windows), and Statistical Package for Social Science (SPSS) version 25 (SPSS inc., Chicago IL, USA).

Conclusions
Finally, this study shows that immunotherapy improves survival in advanced melanoma in a real-world population. The CNMR represents a set of data useful not only to plan the appropriate prevention measures but to better understand the effectiveness of anti-cancer treatments in a large unselected population from a real world experience. Furthermore, qualified data is essential and it is important that this information is constantly updated in order to maintain high levels of evidence.
The nivolumab/pembrolizumab and the combination of ipilimumab can be considered the best therapy to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment.