Systemic Therapy in Advanced Nodular Melanoma versus Superficial Spreading Melanoma: A Nation-Wide Study of the Dutch Melanoma Treatment Registry
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Daan Jan Willem Rauwerdink
1,*
,
Remco van Doorn
1,
Jos van der Hage
2,
Alfonsus J. M. Van den Eertwegh
3,
John B. A. G. Haanen
4,
Maureen Aarts
5,
Franchette Berkmortel
6,
Christian U. Blank
4,7,
Marye J. Boers-Sonderen
8,
Jan Willem B. De Groot
9, 
Geke A. P. Hospers
10,
Melissa de Meza
11,12,13,
Djura Piersma
14,
Rozemarijn S. Van Rijn
15,
Marion Stevense
16,
Astrid Van der Veldt
17
,
Gerard Vreugdenhil
18,
Michel W. J. M. Wouters
11,12,13,
Karijn Suijkerbuijk
19
,
Monique van der Kooij
20,† and
Ellen Kapiteijn
20,†
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1
Department of Dermatology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2300 RC Leiden, The Netherlands
2
Department of Surgery, Leiden University Medical Center, Leiden University, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands
3
Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands
4
Department of Molecular Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
5
Department of Medical Oncology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
6
Department of Medical Oncology, Zuyderland Medical Centre Sittard, Dr. H. van der Hoffplein 1, 6162 BG Sittard-Geleen, The Netherlands
7
Department of Medical Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
8
Department of Medical Oncology, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
9
Isala Oncology Center, Isala, Dokter van Heesweg 2, 8025 AB Zwolle, The Netherlands
10
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
11
Scientific Bureau, Dutch Institute for Clinical Auditing, Rijnsburgerweg 10, 2333 AA Leiden, The Netherlands
12
Department of Surgical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
13
Department of Biomedical Data Sciences, Leiden University Medical Centre, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
14
Department of Internal Medicine, Medisch Spectrum Twente, Koningsplein 1, 7512 KZ Enschede, The Netherlands
15
Department of Internal Medicine, Medical Centre Leeuwarden, Henri Dunantweg 2, 8934 AD Leeuwarden, The Netherlands
16
Department of Internal Medicine, Amphia Hospital, Molengracht 21, 4818 CK Breda, The Netherlands
17
Department of Medical Oncology and Radiology & Nuclear Medicine, Erasmus Medical Centre, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
18
Department of Internal Medicine, Maxima Medical Centre, De Run 4600, 5504 DB Eindhoven, The Netherlands
19
Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
20
Department of Medical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2022, 14(22), 5694; https://doi.org/10.3390/cancers14225694
Submission received: 18 October 2022
/
Revised: 6 November 2022
/
Accepted: 18 November 2022
/
Published: 19 November 2022
(This article belongs to the Section Cancer Therapy)
Abstract
:Simple Summary
Nodular melanoma is associated with a higher locoregional recurrence rate and worse overall survival outcomes. Whether this histologic subtype affects the efficacy of immunotherapy or targeted therapy is unclear. The aim of our multi-center nationwide study is to identify the efficacy of immunotherapy and BRAF/MEKi therapy in metastatic nodular melanoma compared with the efficacy in metastatic superficial spreading melanoma. Our study results demonstrate no difference between the effectiveness of immunotherapy and BRAF/MEKi in metastatic nodular versus superficial melanoma patients. A shorter distant metastasis-free survival and reduced overall survival (measured as the time between primary melanoma up to death or last follow-up) was observed in the nodular melanoma patient group, suggesting worse overal survival of nodular melanoma is mainly driven by propensity of metastatic outgrowth of nodular melanoma after primary diagnosis.
Abstract
Nodular melanoma (NM) is associated with a higher locoregional and distant recurrence rate compared with superficial spreading melanoma (SSM); it is unknown whether the efficacy of systemic therapy is limited. Here, we compare the efficacy of immunotherapy and BRAF/MEK inhibitors (BRAF/MEKi) in advanced NM to SSM. Patients with advanced stage IIIc and stage IV NM and SSM treated with anti-CTLA-4 and/or anti-PD-1, or BRAF/MEKi in the first line, were included from the prospective Dutch Melanoma Treatment Registry. The primary objectives were distant metastasis-free survival (DMFS) and overall survival (OS). In total, 1086 NM and 2246 SSM patients were included. DMFS was significantly shorter for advanced NM patients at 1.9 years (CI 95% 0.7–4.2) compared with SSM patients at 3.1 years (CI 95% 1.3–6.2) (p < 0.01). Multivariate survival analysis for immunotherapy and BRAF/MEKi demonstrated a hazard ratio for immunotherapy of 1.0 (CI 95% 0.85–1.17) and BRAF/MEKi of 0.95 (CI 95% 0.81–1.11). A shorter DMFS for NM patients developing advanced disease compared with SSM patients was observed, while no difference was observed in the efficacy of systemic immunotherapy or BRAF/MEKi between NM and SSM patients. Our results suggests that the worse overall survival of NM is mainly driven by propensity of metastatic outgrowth of NM after primary diagnosis.
1. Introduction
Cutaneous melanoma is a highly heterogeneous cancer comprised of distinct histologic subtypes based on cell of origin, role of ultraviolet radiation exposure, pattern of oncogenic mutations, and type of histological growth [1,2]. The two major histologic subtypes are superficial spreading melanoma (SSM), covering 70% of the cases, followed by nodular melanoma (NM) with approximately 20% of the cases, whereas the majority of the remaining melanoma cases are of the histologic subtype lentigo maligna melanoma (3–10%) and the histologic subtype acral melanoma is less common [2,3]. It is important to underline the exact histologic subtype of melanoma, as the histologic subtype can potentially play a prognostic role in disease recurrence. NM, in general, has worse prognostic tumor characteristics. including a higher Breslow thickness, ulcerative status, higher dermal mitotic rate, and more frequent satellite lesions [3,4]. The histologic subtype NM is associated with a vertical growth rate and tends to grow more rapidly compared with SSM. As for the mutation profile, NM is more frequently NRAS mutated, while SSM harbors the BRAF mutation more often. Molecular analysis shows that NM contains a lower mutational load compared with SSM, illustrating the distinct biologic molecular background [5,6,7]. Importantly, primary NM, even corrected for Breslow thickness and ulceration, is associated with lower overall survival and a reduced recurrence-free survival rate compared with primary SSM [8,9,10]. A retrospective study conducted by Lin et al. in melanoma research suggested that the aggressiveness of NM is attributed to a decreased presence of tumor-infiltrating lymphocytes and an upregulation of PD-L1 expression in neoplastic cells compared with SSM; however the exact mechanism of the aggressive behavior of NM has not yet been unraveled.
In the last decade, the advent of immune checkpoint inhibitors and targeted therapy has revolutionized the treatment landscape of metastatic cutaneous melanoma [11,12,13]. The efficacy of immunotherapy ought to be lower in patients with melanoma types with a lower mutation rate, such as acral melanoma, and immunotherapy is more effective in melanoma types with a higher mutation rate, which is the case in the histologic subtype desmoplastic melanoma [14,15]. Despite this, it is unclear whether the primary histologic subtype NM affects the efficacy of immunotherapy and targeted therapy, as the exact significance of the lower mutational profile of NM compared with SSM remains inconclusive.
To date, only two studies compared the efficacy of systemic immune checkpoint inhibitors in NM versus SSM patients and demonstrated contradictory results: Lattanzi et al. observed no difference in survival outcomes of NM versus SSM patients treated with immunotherapy (anti-PD-1 n = 29, anti-CTLA-4 n = 119), while Pala et al. displayed an improved survival of NM patients treated with immunotherapy compared with SSM patients (anti-PD-1 n = 35, anti PD-1/anti-CLTA-4 n = 7) [16,17]. As previously conducted studies were small, unclarity remains regarding the efficacy of immunotherapy and targeted therapy in NM. Identifying the prognostic value of the melanoma subtype can be important in choosing the optimal systemic treatment for the individual patient. Hence, we conducted an analysis using data from a nation-wide prospective registry for systemic treatment of melanoma (the Dutch Melanoma Treatment Registry) to assess survival outcomes of advanced SSM and NM treated with first-line immunotherapy or targeted therapy.
2. Methods
2.1. Study Design
The Dutch Melanoma Treatment Registry (DMTR) prospectively registers data of systemic therapy in advanced melanoma patients in the Netherlands since 2012 and of resectable stage III and IV melanoma since 2018. This registry and quality assurance has been described in detail by Jochems et al. [18]. The medical ethics committee of each participating hospital approved research using DMTR data and this research was not deemed subject to the Medical Research Involving Human Subjects Act, in compliance with Dutch regulations.
2.2. Patients
Eligible patients were 18 years and older, had histologically confirmed advanced (irresectable stage III and IV) cutaneous superficial spreading or nodular melanoma, according to the eighth edition of the American Joint Committee on Cancer (AJCC) classification (including metastases to skin (M1a), lung (M1b), other visceral sites (M1c), and brain (M1d)) [19]. Included patients were naïve to treatment and received first-line systemic anti-CTLA-4 and/or anti-PD-1, or either first-line BRAF inhibitor monotherapy or the combination of BRAF inhibitors and MEK inhibitors. Adjuvant-treated patients were excluded from this study. Data on all patients were collected spanning the period January 2012 to January 2019, while the follow-up data cut off was set at 1 February 2020.
2.3. Clinical Variables
Demographic variables (age, gender, and WHO-status) and primary tumor characteristics (Breslow thickness (mm), presence of ulceration, dermal mitosis, satellites, mutation status, location, and histologic subtype were extracted from the DMTR database. Furthermore, clinical data on metastatic melanoma were collected, including site of metastasis, number of disease sites with metastasis, lactate dehydrogenase value (LDH), and details on the type and duration of systemic therapy.
2.4. Assessment
A comparative analysis, comparing demographic variables in the NM versus SSM groups based on treatment type, was conducted.
2.5. Primary Tumor
Distant metastasis-free survival (DMFS) was determined in both groups and was calculated from the diagnosis of primary melanoma until the occurrence of distant metastasis. Overall survival (OS) was calculated from the diagnosis of the primary tumor until death by any cause or the last moment of follow-up.
2.6. Advanced Disease
Progression-free survival (PFS) was calculated from the start of systemic therapy until disease progression or the last moment of follow-up. Furthermore, the response to therapy was assessed and included progressive disease (PD), stable disease (SD), partial response (PR), or complete response (CR). An objective response rate to therapy was calculated per treatment type by comparing the best overall response between NM and SSM patients. Lastly, OS was calculated from the start of systemic therapy until death by any cause or last moment of follow-up and compared between the NM versus SSM groups based on treatment type.
2.7. Statistical Analysis
Descriptive analysis was conducted to assess demographic variables, clinicopathological characteristics, and treatment type. Identified frequencies of variables were compared between the SSM and NM groups, using a Chi-square test or Wilcoxon rank test. Survival analyses were conducted with the Kaplan–Meier method and compared with the log rank test across each type of treatment group. Patients not reaching the endpoint were censored at the date of the last contact.
Cox regression analysis was performed to correct for potential confounders. p-values were two-sided and p-values less than 0.05 were considered to be statistically significant. All statistical analyses were conducted using IBM SPSS Statistics version 24 (Armonk, New York, NY, USA).
3. Results
Between 2012 and 2021, a total of 2685 advanced (stadium IIIC or stadium IV) SSM and 1329 NM patients were identified (Table 1). Advanced SSM patients were significantly younger, with a median age of 58 (IQR 47–69) compared with the NM group 63 (IQR 52–72) (p < 0.01). Patients with NM had ulceration more often (p < 0.01), a higher median Breslow thickness ((3.9 mm (IQR 2.4–6.0) versus 1.9 mm in SSM patients (IQR 1.2–3.3) (p < 0.01)), and more frequently had dermal mitoses (p < 0.01) and satellite lesions (p < 0.01) (Table 2), compared with SSM patients. Considering mutation status, NM harbored NRAS-mutations more often (24% versus 16% than SSM patients (p < 0.01)), while SSM harbored BRAF mutations more frequently (61% compared with 49% in NM patients (p < 0.01)).
3.1. Distant Metastasis Free Survival between Primary Tumor and Advanced Disease
NM patients had a significantly shorter median DMFS compared with SSM patients when adjusting for Breslow thickness, BRAF-status, mitotic rate, and ulceration, respectively, that is, 1.9 years (95% CI 1.7–2.1) and 3.1 years (95% CI 2.9–3.3) (p < 0.01) (Kaplan Meier DMFS analysis, Figure S1 and Cox regression DMFS analysis, Table S1, are displayed in the Supplementary Materials). Overall survival calculated from primary tumor up to decease or last follow-up moment, corrected for age, gender, Breslow thickness, BRAF-status, mitotic rate, and ulceration, demonstrated a median OS of 5.9 years (95% CI 2.7–13) and 8.0 years (95% CI 4.0–16) for NM and SSM, respectively (long-rank test p < 0.05).
3.2. Immunotherapy in Advanced Disease
A total of 747 advanced NM and 1357 SSM patients received first-line anti-CTLA-4, anti-PD-1 or anti-PD-1/anti-CTLA-4. The specific type of the immunotherapy did not differ significantly between NM and SSM patients (p = 0.08) (Table 2).
Immunotherapy-treated NM patients were older with a median age of 67 years (IQR 55–74) versus 64 years (IQR 53–73) (p = 0.01) and the majority of NM patients were male, 521 patients (70%) versus 812 (60%) SSM patients (p < 0.01). No significant differences were observed between the two groups of patients with brain metastases, with metastases present in three or more organ sites, or with elevated LDH levels. Considering response to immunotherapy, NM and SSM patients had similar objective response rates of 47% and 46%, respectively (Table 3).
Progression-free survival demonstrated a median progressive-free survival of 16.2 months (95% CI 17.3–22.9) for NM patients and 18.1 months for SSM patients (95% CI 14–21) (log-rank test p = 0.72) (Kaplan–Meier PFS analysis, Figures S2 and S3, and Cox regression PFS, Tables S2 and S3, in the Supplementary Materials).
Overall survival analysis, calculated from the start of therapy up to death or last follow-up, showed a median overall survival of 36 months (95% CI 23–49) for NM patients and a median overall survival of 34 months (95% CI 28–41) for SSM patients (log-rank test p = 0.53) (Figure 1a).
Cox regression demonstrated that the histologic subtype NM was not associated with decreased survival (HR 0.90 (95% CI 0.76–1.08)) (Table 4). Factors associated with a decreased overall survival since the start of immunotherapy were the presence of brain metastasis (HR 1.05 95% CI 1.01–1.11), elevated LDH levels at the moment of metastasis detection/diagnosis (HR 1.27 (95% CI 1.17–1.38)), and the presence of NRAS mutation (HR 1.16 (95% CI 1.05–1.28), while BRAF mutation demonstrated a favorable effect with an HR of 0.69 (95% CI 0.58–0.83) (Table 4).
3.3. Targeted Therapy in Advanced Disease
In total, 339 advanced NM and 889 SSM patients were treated with BRAF inhibition monotherapy or BRAF/MEK combination therapy. NM patients received BRAF/MEKi combination therapy more frequently compared with SSM patients, 478 (54%) versus 157 (46%), respectively (p = 0.02).
NM patients were significantly older with a median age of 64 (IQR 54–73) versus SSM patients with a median age of 60 years (IQR 50–69) (p < 0.01). Regarding characteristics of metastatic disease in the two groups, no difference was observed in elevated LDH levels at the moment of metastasis, brain metastasis, and total organ sites with metastatic lesions. As for treatment response, the objective response rate for NM patients was 46%, and 45% for SSM patients. Kaplan–Meier analysis demonstrated a PFS of 7.4 months (95% CI 6.2–8.6) for NM patients, while PFS was 7 months (95% CI 6.3–7.8) in SSM patients (log-rank test p = 0.70). Kaplan–Meier analysis for treatment-related overall survival demonstrated a median overall survival of 9.6 months (95% CI 7.9–11.0) and 9.6 months (95% CI 8.5–11.0) for NM and SSM patients, respectively (Figure 1b) (log-rank test p = 0.31).
Cox regression analysis showed a hazard ratio of 0.92 (95% CI, 0.78–1.08) for the NM histologic subtype (Table 5). In addition, the presence of brain metastasis (HR 1.08, 95% CI 1.04–1.13), decreased WHO classification (HR 1.08, 95% CI 1.06–1.11), and elevated LDH levels (HR 1.24, 95% CI 1.12–1.32) were associated with a decreased overall survival.
4. Discussion
To the best of our knowledge, this is the largest prospective cohort study investigating the efficacy of immune checkpoint inhibitors and targeted therapy in advanced NM compared with SSM patients.
NM patients had a significantly shorter median DMFS compared with SSM patients when adjusting for Breslow thickness, BRAF-status, mitotic rate, and ulceration.
No significant difference in terms of overall survival upon start of systemic therapy was observed in the NM versus SSM group: immune checkpoint inhibition-related survival analysis demonstrated similar survival outcomes. A multivariate analysis, corrected for metastatic and demographic variables, revealed that the histologic subtype NM was not independently associated with decreased treatment-related survival in immunotherapy patients. Considering patients treated with BRAF/MEKi, treatment-related survival analysis showed that survival outcomes did not differ between the NM and SSM group, and multivariate Cox regression analysis demonstrated that the histologic subtype NM was not associated with decreased survival in BRAF/MEKi-treated patients. Interestingly, we did not observe that gender was an independent risk factor for survival in this group, as, is in contrast to the recently published study conducted by Vellano et al. in Nature, it demonstrated that female patients treated with BRAF/MEKi neo-adjuvant treatment had significantly better relapse-free survival rates compared with male patients.
Regarding the importance of histologic subtype of NM in the metastatic setting, only one study, in 21 NM patients, performed by Pala et al., analyzed the survival outcome in addition to the metastatic immunologic behavior of NM compared with SSM and demonstrated a prolonged survival of NM versus SSM [16]. The study attributes the improved survival in NM patients compared with SSM patients to an overexpression of MHC-II molecules and IFN gamma signature, which are both involved in antigen processing and presentation mechanism, which play a significant role in tumor immunogenicity. Despite the improved survival outcome in NM patients, the study was limited in size (anti-PD-1 n = 35, anti-PD-1/anti-CTLA-4 = 7). In contrast, a study conducted by Lantazzi et al. demonstrated no improved survival for metastatic NM compared with SSM treated with immune checkpoint inhibition [17]. Nonetheless, this study was also limited by the fact that the most given treatment was anti-CTLA-4, with only 29 out of the 119 patients receiving anti-PD-1.
In spite of the published results on advanced NM treated with immunotherapy, no large study has been performed investigating the efficacy of targeted therapy. Only the study by Lantazi et al. analyzed the efficacy of targeted therapy in NM and SSM patients and demonstrated a decreased survival for BRAF-mutated NM as compared with BRAF-mutated SSM patients, and histologic subtype NM in the multivariate analysis was independently associated with a decreased survival. However, the power of this study was limited as only 52 patients were included.
It is interesting that a large population-based cross-sectional analysis performed by Allais et al. showed that the diagnosis of primary detected histologic subtype NM, corrected for Breslow thickness and ulceration, was associated with a decreased 5-year relative survival compared with SSM, suggesting that the histologic subtype should be taken into consideration in making treatment decisions [9]. In addition, a large international multi-center study, conducted by Di Carlo and colleagues, demonstrated similar results, with an increased hazard ratio for death in patients with NM (N = 5375) compared with SSM patients (N = 19.592), adjusted for sex, age, and disease stage at diagnosis [8].
The reduced overall survival (measured from primary melanoma up to death), as mentioned in these studies, could be explained by the shorter distant-free metastasis survival for NM versus SSM, as we found in our analysis.
Considering similar treatment-related survival outcomes in advanced SSM and NM patients, we hypothesize that decreased overall survival, measured as time from diagnosis of the primary tumor up to death or the last follow-up moment, in NM patients is mainly driven by primary tumor characteristics and primary tumoral genetic environment, leading to a shorter distant metastasis-free survival. Thus, if NM metastasizes earlier, this will ultimately lead to a worse prognosis. Yet, the histologic subtype NM has not been considered a prognostic metastatic variable, despite a shorter distant metastasis-free survival compared with SSM patients. This underlines the importance of reassessing the follow-up concerning NM patients, and the histologic subtype should be taken into consideration when a decision with regards to adjuvant immunotherapy is made, in order to prolong recurrence-free survival and distant metastasis-free survival.
5. Conclusions
Our study shows similar efficacy of immune checkpoint inhibition and BRAF/MEKi in advanced NM compared with SSM patients. However, overall survival, measured as the moment of primary diagnosis up to decease or the last follow-up moment, is shorter because of a shorter distant metastases-free interval in NM as compared with SSM. This might have implications for the follow-up from primary tumor diagnosis and for the consideration of (neo) adjuvant therapy. Future studies should focus on the biologic metastatic behavior.
Supplementary Materials
The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/cancers14225694/s1. Figure S1: Kaplan Meier curve distant metastasis free survival analysis demonstrating the cumulative survival of NM (red) versus SSM (blue); Figure S2: Kaplan Meier curve progression free survival analysis demonstrating the cumulative survival of NM (red) versus SSM (blue) patients treated with immune checkpoint inhibition; Figure S3: Kaplan Meier curve survival analysis demonstrating the cumulative survival of NM (red) versus SSM (blue) patients treated with immune checkpoint inhibition; Table S1: Multi variable treatment related cox regression distant metastasis free survival analysis; Table S2: Multi variable treatment related cox regression progression free survival analysis in patients treated with immune checkpoint inhibition; Table S3: Multi variable treatment related cox regression progression free survival analysis in patients treated with immune checkpoint inhibition.
Author Contributions
Conceptualization, D.J.W.R., R.v.D., J.v.d.H., M.v.d.K. and E.K. Data curation, D.J.W.R., R.v.D., J.v.d.H., E.K. and M.v.d.K.; Formal analysis, D.J.W.R. and M.v.d.K.; Funding acquisition, E.K.; Investigation, D.J.W.R., E.K., M.v.d.K. and R.v.D.; Methodology, D.J.W.R., E.K., M.v.d.K. and R.v.D.; Project administration, D.J.W.R., E.K., M.v.d.K. and R.v.D.; Resources, E.K.; Software, D.J.W.R., E.K., M.v.d.K. and R.v.D.; Supervision, D.J.W.R., E.K., M.v.d.K., R.v.D. and J.v.d.H.; Validation, D.J.W.R., R.v.D., J.v.d.H. and M.v.d.K.; Visualization, D.J.W.R. and M.v.d.K.; Writing—original draft, D.J.W.R., R.v.D., J.v.d.H., M.v.d.K. and E.K.; Writing—review and editing, D.J.W.R., R.v.D., J.v.d.H., M.v.d.K., A.J.M.V.d.E., J.B.A.G.H., M.A., F.B., C.U.B., M.J.B.-S., J.W.B.D.G., G.A.P.H., M.d.M., D.P., M.S., A.V.d.V., G.V., R.S.V.R., M.W.J.M.W., E.K. and K.S. All authors have read and agreed to the published version of the manuscript.
Funding
For the Dutch Melanoma Treatment Registry (DMTR), the Dutch Institute for Clinical Auditing foundation received a start-up grant from governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002). The DMTR is structurally funded by Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis, and Roche Pharma. Roche Pharma stopped funding in 2019, and Pierre Fabre started funding the DMTR in 2019. For this work, no funding was granted.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Leiden University Medical Center (LUMC).
Informed Consent Statement
Patient consent was waived because of the setting of the study. The medical Ethics Committee has approved the study and has formulated no need for informed consent procedure, as no reducible patient data were used.
Data Availability Statement
The data presented in this study are available upon request from the corresponding author. The data are not publicly available because of the protection of privacy.
Conflicts of Interest
A.J.M.v.d.E. has advisory relationships with Amgen, Bristol Myers Squibb, Roche, Novartis, MSD, Pierre Fabre, Sanofi, Pfizer, Ipsen, and Merck; has received research study grants not related to this paper from Sanofi, Roche, Bristol Myers Squibb, Idera, and TEVA; has received travel expenses from MSD Oncology, Roche, Pfizer, and Sanofi; and has received speaker honoraria from BMS and Novartis. J.v.d.H. has advisory relationships with Aimm, Achilles Therapeutics, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, BioNTech, GSK, Immunocore, Ipsen, MSD, Merck Serono, Molecular Partners, Novartis, Neogene Therapeutics, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, and Vaximm, and has received research grants not related to this paper from Amgen, Bristol Myers Squibb, MSD, BioNTech, Neogene Therapeutics, and Novartis. All grants were paid to the institutions. C.U.B. has received commercial research grants from Novartis, BristolMyers Squibb, and NanoString; is a paid advisory board member for Bristol Myers Squibb, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, and Pierre Fabre; and holds ownership interest in Uniti Cars, Neon Therapeutics, and Forty Seven. M.A. has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, and Bayer and research grants from Merck-Pfizer not related to the current work and paid to the institute. J.W.B.d.G. has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, and Novartis. G.A.P.H. has consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, and Pierre Fabre, and has received research grants not related to this paper from Bristol Myers Squibb, and Seerave that were paid to the institution. E.K. has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, and Pierre Fabre, and received research grants not related to this paper from Bristol Myers Squibb. D.P. has declared no conflicts of interest. R.S.v.R. has advisory board/consultancy honoraria from Pfizer and an expert meeting fee from Roche. A.v.d.V. has consultancy relationships with Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, Eisai, and Merck. M.J.B.-S. has consultancy/advisory relationships with Pierre Fabre, MSD, and Novartis. K.S. has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, and AbbVie and received honoraria from Novartis, MSD, and Roche and research funding from Bristol Myers Squibb, Philips, and TigaTx. All remaining authors have declared no conflicts of interest.
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Figure 1.
Kaplan–Meier curve survival analysis demonstrating the cumulative survival of NM (red) versus SSM (blue) patients treated with immune checkpoint inhibition (a) and Kaplan–Meier curve survival analysis demonstrating the cumulative survival of NM (red) versus SSM (blue) patients treated with immune checkpoint inhibition (b).
Figure 1.
Kaplan–Meier curve survival analysis demonstrating the cumulative survival of NM (red) versus SSM (blue) patients treated with immune checkpoint inhibition (a) and Kaplan–Meier curve survival analysis demonstrating the cumulative survival of NM (red) versus SSM (blue) patients treated with immune checkpoint inhibition (b).
Table 1.
The demographic and tumor characteristics of the entire cohort of SSM and NM patients.
| Variables | SSM (N = 2685) | NM (N = 1329) | p-Value |
|---|---|---|---|
| Median age at moment of diagnosis (IQR) | 58 (47–69) | 63 (52–72) | |
| Gender—no. (%) | <0.01 | ||
| Female | 1133 (42) | 457 (34) | |
| Male | 1552 (58) | 872 (66) | |
| WHO—no. (%) | 0.03 | ||
| 0 | 1338 (50) | 702 (53) | |
| 1 | 762 (28) | 345 (26) | |
| >1 | 290 (11) | 125 (10) | |
| Not reported | 288 (11) | 157 (12) | |
| Location primary melanoma—no. (%) | <0.01 | ||
| Head/neck | 344 (13) | 227 (17) | |
| Trunk | 1405 (52) | 589 (44) | |
| Extremities | 903 (34) | 497 (37) | |
| Acral | 33 (1) | 16 (1) | |
| Breslow thickness in mm (IQR) | 1.9 (1.2–3.3) | 3.9 (2.4–6.0) | <0.01 |
| Ulceration—no. (%) | <0.01 | ||
| Absent | 1602 (60) | 580 (44) | |
| Present | 796 (30) | 644 (49) | |
| Unknown | 275 (10) | 88 (7) | |
| Dermit—no. (%) | <0.01 | ||
| None | 287 (11) | 98 (7) | |
| Any | 1391 (52) | 820 (62) | |
| Not reported | 978 (36) | 400 (30) | |
| Satellite lesions * | <0.01 | ||
| None | 3917 (80) | 1748 (77) | |
| Any | 380 (8) | 295 (13) | |
| Not reported | 574 (12) | 231 (10) | |
| Mutation status—no. (%) ** | |||
| BRAF mutation | 1629 (61) | 655 (49) | <0.01 |
| NRAS mutation | 439 (16) | 323 (24) | <0.01 |
| KIT mutation | 24 (0.01) | 13 (0.01) | 0.08 |
* Satellite lesions and/or in-transit metastasis. ** Total tested patients tested taken as the denominator.
Table 2.
Comparative analysis demonstrating demographic, treatment, and metastatic variables in SSM and NM patients treated with first-line systemic immunotherapy. The right side of the table displays a comparative analysis of demographic, treatment, and metastatic variables in SSM and NM patients treated with first-line targeted therapy.
Table 2.
Comparative analysis demonstrating demographic, treatment, and metastatic variables in SSM and NM patients treated with first-line systemic immunotherapy. The right side of the table displays a comparative analysis of demographic, treatment, and metastatic variables in SSM and NM patients treated with first-line targeted therapy.
| First-Line Systemic Immunotherapy | First-Line Targeted Therapy | ||||||
|---|---|---|---|---|---|---|---|
| SSM (N = 1357) | NM (N = 747) | p-Value | SSM (N = 889) | NM (N = 339) | p-Value | ||
| Treatment type | 0.08 | 0.02 | |||||
| Anti-CTLA-4 | 277 (20) | 185 (25) | BRAF | 411 (46) | 182 (54) | ||
| Anti-PD-1 | 865 (64) | 464 (62) | BRAF/MEK | 478 (54) | 157 (46) | ||
| Anti-PD-1/anti-CTLA-4 | 215 (16) | 98 (13) | |||||
| Median age (IQR) | 64 (53–73) | 65 (55–74) | 0.01 | 60 (50–69) | 64 (54–73) | <0.01 | |
| Gender—no. (%) | <0.01 | 0.22 | |||||
| Female | 545 (40) | 226 (30) | 394 (44) | 137 (40) | |||
| Male | 812 (60) | 521 (70) | 495 (56) | 202 (60) | |||
| WHO—no. (%) | 0.22 | 0.34 | |||||
| 0 | 863 (64) | 479 (64) | 324 (36) | 143 (42) | |||
| 1 | 371 (27) | 189 (25) | 309 (35) | 114 (34) | |||
| >1 | 49 (4) | 30 (4) | 167 (19) | 48 (14) | |||
| Not reported | 73 (5) | 49 (7) | 89 (10) | 34 (10) | |||
| Brain metastasis | 0.37 | 0.99 | |||||
| Not present | 1112 (82) | 601 (80) | 538 (61) | 211 (62) | |||
| Present | 216 (16) | 135 (18) | 330 (37) | 121 (36) | |||
| Asymptomatic ﮺ | 133 | 84 | 112 (34) | 44 (36) | |||
| Symptomatic | 83 | 51 | 208 (63) | 77 (64) | |||
| Not reported | 29 (2) | 11 (2) | 21 (2) | 7 (2) | |||
| LDH | 0.06 | 0.03 | |||||
| Normal | 1018 (75) | 591 (79) | 424 (48) | 176 (52) | |||
| Elevated | 311 (23) | 147 (20) | 443 (50) | 146 (43) | |||
| Not determined | 24 (2) | 9 (1) | 19 (2) | 17 (5) | |||
| Organ sites with metastasis | 0.35 | 0.97 | |||||
| <3 | 442 (33) | 236 (32) | 44 (5) | 18 (5) | |||
| >2 | 720 (53) | 417 (56) | 729 (82) | 262 (77) | |||
| Unknown | 195 (14) | 94 (13) | 116 (14) | 59 (18) | |||
Table 3.
Objective response per treatment group stratified per histologic subtype melanoma. The objective response rate is calculated as the sum of complete responses and partial responses.
Table 3.
Objective response per treatment group stratified per histologic subtype melanoma. The objective response rate is calculated as the sum of complete responses and partial responses.
| Immunotherapy | BRAF/MEK | |||
|---|---|---|---|---|
| SSM | NM | SSM | NM | |
| Complete response | 196 (17) | 108 (16) | 17 (2) | 16 (9) |
| Partial response | 346 (30) | 194 (30) | 362 (43) | 120 (37) |
| Stable disease | 32 (3) | 17 (3) | 63 (7) | 29 (9) |
| Progressive disease or death | 596 (51) | 336 (51) | 401 (48) | 162 (50) |
| Objective response rate | 47% | 46% | 45% | 46% |
Table 4.
Multivariable treatment-related Cox regression analysis in patients treated with immunotherapy. Significant values are highlighted in bold.
Table 4.
Multivariable treatment-related Cox regression analysis in patients treated with immunotherapy. Significant values are highlighted in bold.
| Variables | N | Hazard Ratio–95% CI | p-Value | |
|---|---|---|---|---|
| Age | 2104 | 1.00 (0.99–1.01) | 0.48 | |
| Gender | Male | 1333 | Reference | |
| Female | 771 | 0.89 (0.74–1.06) | 0.19 | |
| WHO | 0–1 | 1902 | Reference | |
| 2–4 | 79 | 1.02 (0.99–1.06) | 0.20 | |
| Treatment type | Anti-CTLA-4 | 462 | Reference | |
| Ant-PD-1/Anti-CLTA-4 | 1642 | 0.64 (0.53–0.76) | <0.01 | |
| LDH | Not elevated | 1609 | Reference | |
| Elevated | 458 | 1.27 (1.17–1.38) | <0.01 | |
| Cerebral disease | Absent | 1713 | Reference | |
| Present | 351 | 1.05 (1.01–1.11) | 0.03 | |
| Total organ sites | <3 | 678 | Reference | |
| >2 | 1137 | 1.03 (0.87–1.20) | 0.76 | |
| Melanoma | SSM | 1357 | Reference | |
| NM | 747 | 0.90 0.76–1.08) | 0.26 | |
| BRAF mutation | Absent | 1053 | Reference | |
| Present | 916 | 0.69 (0.58–0.83) | <0.01 | |
| NRAS mutation | Absent | 1112 | Reference | |
| Present | 574 | 1.16 (1.05–1.28) | <0.01 |
Table 5.
Multivariable treatment-related Cox regression analysis in patients treated with targeted therapy. Significant values are highlighted in bold.
Table 5.
Multivariable treatment-related Cox regression analysis in patients treated with targeted therapy. Significant values are highlighted in bold.
| Variable | N | Hazard Ratio–95% CI | p-Value | |
|---|---|---|---|---|
| Age | 1228 | 1.004 (0.99–1.01) | 0.08 | |
| Gender | Male | 697 | Reference | |
| Female | 531 | 0.98 (86–1.14) | 0.87 | |
| WHO | ||||
| 0–1 | 890 | Reference | ||
| 2–4 | 123 | 1.08 (1.06–1.11) | <0.01 | |
| Treatment type | BRAF mono therapy | 593 | Reference | |
| BRAF/MEKi | 635 | 0.80 (0.74–0.86) | <0.01 | |
| LDH | Not elevated | 600 | Reference | |
| Elevated | 589 | 1.24 (1.12–1.32) | <0.01 | |
| Cerebral disease | Absent | 749 | Reference | |
| Present | 451 | 1.08 (1.04–1.13) | <0.01 | |
| Total organ sites | <3 | 62 | Reference | |
| >2 | 991 | 0.94 (0.78–1.13) | 0.50 | |
| Melanoma | SSM | 889 | Reference | |
| NM | 339 | 0.92 (0.78–1.08) | 0.30 |
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Rauwerdink, D.J.W.; van Doorn, R.; van der Hage, J.; Van den Eertwegh, A.J.M.; Haanen, J.B.A.G.; Aarts, M.; Berkmortel, F.; Blank, C.U.; Boers-Sonderen, M.J.; De Groot, J.W.B.; et al. Systemic Therapy in Advanced Nodular Melanoma versus Superficial Spreading Melanoma: A Nation-Wide Study of the Dutch Melanoma Treatment Registry. Cancers 2022, 14, 5694. https://doi.org/10.3390/cancers14225694
AMA Style
Rauwerdink DJW, van Doorn R, van der Hage J, Van den Eertwegh AJM, Haanen JBAG, Aarts M, Berkmortel F, Blank CU, Boers-Sonderen MJ, De Groot JWB, et al. Systemic Therapy in Advanced Nodular Melanoma versus Superficial Spreading Melanoma: A Nation-Wide Study of the Dutch Melanoma Treatment Registry. Cancers. 2022; 14(22):5694. https://doi.org/10.3390/cancers14225694
Chicago/Turabian StyleRauwerdink, Daan Jan Willem, Remco van Doorn, Jos van der Hage, Alfonsus J. M. Van den Eertwegh, John B. A. G. Haanen, Maureen Aarts, Franchette Berkmortel, Christian U. Blank, Marye J. Boers-Sonderen, Jan Willem B. De Groot, and et al. 2022. "Systemic Therapy in Advanced Nodular Melanoma versus Superficial Spreading Melanoma: A Nation-Wide Study of the Dutch Melanoma Treatment Registry" Cancers 14, no. 22: 5694. https://doi.org/10.3390/cancers14225694
APA StyleRauwerdink, D. J. W., van Doorn, R., van der Hage, J., Van den Eertwegh, A. J. M., Haanen, J. B. A. G., Aarts, M., Berkmortel, F., Blank, C. U., Boers-Sonderen, M. J., De Groot, J. W. B., Hospers, G. A. P., de Meza, M., Piersma, D., Van Rijn, R. S., Stevense, M., Van der Veldt, A., Vreugdenhil, G., Wouters, M. W. J. M., Suijkerbuijk, K., ... Kapiteijn, E. (2022). Systemic Therapy in Advanced Nodular Melanoma versus Superficial Spreading Melanoma: A Nation-Wide Study of the Dutch Melanoma Treatment Registry. Cancers, 14(22), 5694. https://doi.org/10.3390/cancers14225694
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