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Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HR adj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: The presence of tumor-infiltrating lymphocytes (TILs) in melanoma has been linked to survival. Their predictive capability for immune checkpoint inhibition (ICI) response remains uncertain. Therefore, we investigated the association between treatment response and TILs in the largest cohort to date and analyzed if this association was independent of known clinical predictors., Methods: In this multicenter cohort study, patients who received first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were identified. TILs were scored on hematoxylin and eosin (H&E) slides of primary melanoma and pre-treatment metastases using the validated TILs-WG, Clark and MIA score. The primary outcome was objective response rate (ORR), with progression free survival and overall survival being secondary outcomes. Univariable and multivariable logistic regression and Cox proportional hazard were performed, adjusting for known clinical predictors., Results: Metastatic melanoma specimens were available for 650 patients and primary specimens for 565 patients. No association was found in primary melanoma specimens. In metastatic specimens, a 10-point increase in the TILs-WG score was associated with a higher probability of response (aOR 1.17, 95 % CI 1.07-1.28), increased PFS (HR 0.93, 95 % CI 0.87-0.996), and OS (HR 0.94, 95 % CI 0.89-0.99). When categorized, patients in the highest tertile TILs-WG score (15-100 %) compared to the lowest tertile (0 %) had a longer median PFS (13.1 vs. 7.3 months, p = 0.04) and OS (49.4 vs. 19.5 months, p = 0.003). Similar results were noted using the MIA and Clark scores., Conclusion: In advanced melanoma patients, TIL patterns on H&E slides of pre-treatment metastases, regardless of measurement method, are independently associated with ICI response. TILs are easily scored on readily available H&Es, facilitating the use of this biomarker in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Karijn P.M. Suijkerbuijk reports financial support was provided by Netherlands Organisation for Health Research and Development. Karijn P.M. Suijkerbuijk reports financial support was provided by Hanarth Fund Foundation. Karijn P.M. Suijkerbuijk reports financial support was provided by Philips. Dr. de Groot reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Dr. De Groot has advisory board relationships with BMS. Dr. Aarts has advisory board / consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer and received research grants from Merck-Pfizer and all were paid to the institution and not related to current work. Dr. Hospers has consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi and Pierre Fabre and has received research grants from Bristol Myers Squibb and Seerave and all were paid to the institution. Dr. Kapiteijn has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly and Bayer not related to current work and paid to institute, and received research grants not related to this paper from Bristol Myers Squibb, Delcath and Pierre-Fabre. Dr. Piersma had advisory board relationships with BMS, Novartis and Pierre Fabre, honoraria were paid to institution. Dr. Suijkerbuijk has consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre Novartis, Sairopa, received honoraria from Novartis, Roche, Merck Sharp and Dome and received research funding from TigaTx, Bristol Myers Squibb and Philips and all were paid to institution and not related to the study. Dr. Schrader received honoraria/research funding from Kyowa Kirin paid to the institution and not related to the study. The remaining authors of this manuscript have no conflicts of interest to disclose. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs., Methods: Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression., Results: Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HR adj 1.14; 95 %CI 1.01-1.29; HR adj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HR adj 1.32; 95 %CI 1.02-1.72) and OS (HR adj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone., Conclusions: High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GAPH reports consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, Merck Sharp and Dome, Pfizer, Novartis, Sanofi, Pierre Fabre and has received research funding from Bristol-Myers Squibb and Seerave. All paid to institution. MJBA reports consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Novartis, Merck Sharp and Dome, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas and Bayer, and received research funding from Merck-Pfizer. All paid to institution. KC reports consultancy fees from Eli Lilly AbbVie and Pfizer. ATJM has received fees from AbbVie, Actelion, CSL Behring, Experf, Novartis, and Shire and declares speaking fees from AstraZeneca, Sanofi-Aventis and Bristol-Myers Squibb. CUB reports consulting/advisory relationships with AstraZeneca, Bristol-Myers Squibb, GenMab, GSK, Lilly, Merck Sharp and Dome, Novartis, Pfizer, Pierre Fabre, Roche and Third Rock Ventures, and received research funding from 4SC, Bristol-Myers Squibb, NanoString and Novartis. All paid to institution. His is co-founder of and owns shares in Immagene BV and Signature Oncology, and is inventor on several related patents (including submitted): WO 2021/177822 A1, N2027907 and P091040NL2. SA reports consulting/advisory relationships with Merck Sharp and Dome, Sanofi, Roche, Bristol-Myers Squibb, Pfizer, Ipsen and Galapagos. All paid to institution. DP reports consultancy/advisory relationships with Pierre Fabre and Novartis. Partly paid to intstitution. EK reports consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Pierre Fabre, Immunocore and Lilly, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre-Fabre. Not related to current work and paid to institute. ML reports consultancy/advisory relationships with Bristol-Myers Squibb and Janssen-Cilag B.V. All paid to institution. AMMvdV reports consultancy/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Sanofi, Pfizer, Novartis, Roche, Eisai, Merck, Pierre Fabre and Ipsen. All paid to institution. JBAGH reports consultancy/advisory relationships with Achillus Tx, AstraZenica, BioNTech, Bristol-Myers Squibb, CureVac, GlaxoSmithKline, Imcyse, Iovance Bio, Instil Bio, Ipsen, Merck, Merck Sharp and Dome, Molecular Partners, Neogene TX, Novartis, Pfizer, PokeAcell, Roche, Sanofi, Scenic, T-Knife and TRV, and received research funding from Amgen, Bristol-Myers Squibb, BioNTech, Merck Sharp and Dome, Novartis and Sastra Cell Therapy. All paid to institution. KPMS reports consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre, Novartis, Sairopa. She received honoraria from Novartis and Merck Sharp and Dome, and research funding from TigaTx, Bristol Myers Squibb, Philips and Genmab. All paid to institution. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy., Methods: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life., Discussion: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response., Trial Registration: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022., (© 2024. The Author(s).)

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal-external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence-all at start of ICI-, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64-0.66). The range of predicted response probabilities was 7%-81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Effectivity of BRAF(/MEK) inhibitor rechallenge has been described in prior studies. However, structured data are largely lacking., Methods: Data from all advanced melanoma patients treated with BRAFi(/MEKi) rechallenge were retrieved from the Dutch Melanoma Treatment Registry. The authors analyzed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for both first treatment and rechallenge. They performed a multivariable logistic regression and a multivariable Cox proportional hazards model to assess factors associated with response and survival., Results: The authors included 468 patients in the largest cohort to date who underwent at least two treatment episodes of BRAFi(/MEKi). Following rechallenge, ORR was 43%, median PFS was 4.6 months (95% confidence interval [CI], 4.1-5.2), and median OS was 8.2 months (95% CI, 7.2-9.4). Median PFS after rechallenge for patients who discontinued first BRAFi(/MEKi) treatment due to progression was 3.1 months (95% CI, 2.7-4.0) versus 5.2 months (95% CI, 4.5-5.9) for patients who discontinued treatment for other reasons. Discontinuing first treatment due to progression and lactate dehydrogenase (LDH) levels greater than two times the upper limit of normal were associated with lower odds of response and worse PFS and OS. Symptomatic brain metastases were associated with worse survival, whereas a longer treatment interval between first treatment and rechallenge was associated with better survival. Responding to the first BRAFi(/MEKi) treatment was not associated with response or survival., Conclusions: This study confirms that patients benefit from rechallenge. Elevated LDH levels, symptomatic brain metastases, and discontinuing first BRAFi(/MEKi) treatment due to progression are associated with less benefit from rechallenge. A prolonged treatment interval is associated with more benefit from rechallenge., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Checkpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies, assessing their health-state utilities is essential and can be used for the calculation of quality-adjusted life years and for cost-effectiveness analyses. Therefore, we evaluated the health-state utilities in long-term advanced melanoma survivors., Methods: Health-state utilities were evaluated in a cohort of advanced melanoma survivors 24-36 months (N = 37) and 36-plus months (N = 47) post-ipilimumab monotherapy. In addition, the health-state utilities of the 24-36 months survivor group were assessed longitudinally, and utilities of the combined survival groups (N = 84) were compared with a matched control population (N = 168). The EQ-5D was used to generate health-state utility values, and quality-of-life questionnaires were used to establish correlations and influencing factors of utility scores., Results: Health-state utility scores were similar between the 24-36 months'- and the 36-plus months' survival group (0.81 vs 0.86; p = .22). In survivors, lower utility scores were associated with symptoms of depression (β = - .82, p = .022) and fatigue burden (β = - .29, p = .007). Utility scores did not significantly change after 24-36 months of survival, and the utilities of survivors were comparable to the matched control population (0.84 vs 0.87; p = .07)., Discussion: Our results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Few clinical trials address efficacy of adjuvant systemic treatment in patients with in-transit melanoma (ITM). This study describes adjuvant systemic therapy of ITM patients beyond clinical trials. In this study, we included stage III adjuvant-treated melanoma patients registered in the nationwide Dutch Melanoma Treatment Registry between July 2018 and December 2020. Patients were divided into three groups: nodal disease only, ITM only and ITM and nodal disease. Recurrence patterns, recurrence-free survival (RFS) and overall survival (OS) at 12-months were analyzed. In our study population of 1037 patients, 66.8% had nodal disease only, 16.7% had ITM only and 16.2% had ITM with nodal disease. RFS at 12-months was comparable in the nodal only and ITM only group (72.2% vs70.1%, P = .97) but lower in ITM and nodal disease patients (57.8%; P = .01, P < .01). Locoregional metastases occurred as first recurrence in 38.9% nodal disease only, 71.9% of ITM-only and 44.0% of ITM and nodal disease patients. Distant recurrences occurred in 42.3%, 18.8% and 36.0%, respectively (P = .02). 12-months OS was not significantly different for nodal disease only patients compared with ITM-only (94.4% vs 97.6%, P = .06) but was significantly higher for ITM-only compared with ITM and nodal disease patients (97.6% vs 91.0%, P < .01). In conclusion, we showed that in the adjuvant setting, RFS rates in ITM-only patients are similar to non-ITM, though better than in ITM and nodal disease patients. Adjuvant-treated ITM-only patients less often experience distant recurrences and have a superior OS compared with ITM and nodal disease patients., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI-treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

In phase III trials, ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grades 3-4 adverse events. Here, we report real-world safety and survival outcomes of ipilimumab plus nivolumab for advanced melanoma. Patients with advanced melanoma who received first-line ipilimumab plus nivolumab between January 1, 2015 and June 30, 2021 were selected from the Dutch Melanoma Treatment Registry. We evaluated response status at 3, 6, 12, 18, and 24 months. OS and PFS were estimated with the Kaplan-Meier method. Separate analyses were performed for patients with or without brain metastases and for patients who met the inclusion criteria of the Checkmate-067 trial. In total, 709 patients received first-line ipilimumab plus nivolumab. Three hundred sixty (50.7%) patients experienced grade 3-4 adverse events, with 211 of the (58.6%) patients requiring hospital admission. The median treatment duration was 42 days (IQR = 31-139). At 24 months, disease control was achieved in 37% of patients. Median PFS since the start of treatment was 6.6 months (95% CI: 5.3-8.7), and median OS was 28.7 months (95% CI: 20.7-42.2). CheckMate-067 trial-like patients had a 4-year OS of 50% (95% CI: 43-59). Among patients with no asymptomatic or symptomatic brain metastases, the 4-year OS probabilities were 48% (95% CI: 41-55), 45% (95% CI: 35-57), and 32% (95% CI: 23-46). Ipilimumab plus nivolumab can achieve long-term survival in advanced melanoma patients in a real-world setting, including patients not represented in the CheckMate-067 trial. However, the proportion of patients with disease control in the real world is lower compared with clinical trials., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients diagnosed with haematologic malignancies (HMs) have a higher risk of developing subsequent solid tumours, such as melanoma. Patients with HM were mostly excluded from clinical trials but potentially derive less benefit from immune checkpoint inhibitors (ICIs) due to disease- or treatment-related T- or B-cell dysfunction., Methods: All advanced melanoma patients treated with anti-PD-1-based treatment or targeted therapy between 2015 and 2021 were included from the prospective nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and melanoma-specific survival (MSS) were analysed for patients with HM (HM+) and without HM (HM-). A cox model was used to account for confounders associated with PFS and MSS., Results: In total, 4638 advanced melanoma patients received first-line anti-PD-1 monotherapy (n = 1763), ipilimumab-nivolumab (n = 800), or BRAF(/MEK) inhibitors (n = 2075). Concurrent HMs were present for 46 anti-PD1-treated patients, 11 ipilimumab-nivolumab-treated patients and 43 BRAF(/MEK)-inhibitor-treated patients. In anti-PD-1-treated patients, the median PFS was 2.8 months for HM+ and 9.9 months for HM- (p = 0.01). MSS was 41.2 months for HM+ and 58.1 months for HM- (p = 0.00086). In multivariable analysis, the presence of an HM was significantly associated with higher risk of melanoma progression (HR adj 1.62; 95% confidence interval [95% CI] 1.15-2.29; p = 0.006) and melanoma-related death (HR adj 1.74; 95% CI 1.09-2.78; p = 0.020). Median PFS and MSS for first-line BRAF(/MEK-) inhibitor-treated HM+ and HM- patients were not significantly different., Conclusions: Patients with HM and advanced melanoma show significantly worse melanoma-related outcomes when treated with ICI, but not targeted therapy, compared to patients without HM. Clinicians should be aware of potentially altered effectiveness of ICI in patients with active HM., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.vdE. has advisory relationships with Amgen, Bristol Myers Squibb, Roche, Novartis, MSD, Pierre Fabre, Sanofi, Pfizer, Ipsen, Merck and has received research study grants not related to this paper from Sanofi, Roche, Bristol Myers Squibb, Idera and TEVA and has received travel expenses from MSD Oncology, Roche, Pfizer and Sanofi and has received speaker honoraria from BMS and Novartis. J.H. has advisory relationships with Achilles Therapeutics, AstraZeneca, Bristol Myers Squibb, BioNTech, Immunocore, Iovance Biotherapeutics, Instil Bio, Ipsen, MSD, Merck Serono, Molecular Partners, Novartis, Neogene Therapeutics, Pfizer, PokeAcel, Roche/Genentech, Sanofi, T-Knife and has received research grants not related to this paper from Asher Bio, Amgen, Bristol Myers Squibb, MSD, BioNTech, Neogene Therapeutics and Novartis. All grants were paid to the institutions. C.B. has/had advisory role: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, received research funding: BMS, Novartis, NanoString, 4SC, stockownership: co-founder Immagene BV and Signature Oncology, patents (incl. submitted): WO 2021/177822 A1, N2027907, P091040NL2. M.A. has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer. Research grants Merck-Pfizer. Not related to current work and paid to institute. J.dG. has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, Novartis. G.H. consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Pierre Fabre and has received research grants not related to this paper from Bristol Myers Squibb, Seerave and were paid to the institution. E.K. has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly and Bayer, and received research grants not related to this paper from Bristol Myers Squibb and Pierre-Fabre. Not related to current work and paid to institute. R.vR. has advisory board/consultancy honoraria from Pfizer and an expert meeting fee from Roche. A.vdV. has consultancy relationships with Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, Eisai, Merck. M.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, AbbVie, received honoraria from Novartis, MSD and Roche and received research funding from BMS, Philips and TigaTx. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Predicting checkpoint inhibitors treatment outcomes in melanoma is a relevant task, due to the unpredictable and potentially fatal toxicity and high costs for society. However, accurate biomarkers for treatment outcomes are lacking. Radiomics are a technique to quantitatively capture tumour characteristics on readily available computed tomography (CT) imaging. The purpose of this study was to investigate the added value of radiomics for predicting clinical benefit from checkpoint inhibitors in melanoma in a large, multicenter cohort., Methods: Patients who received first-line anti-PD1±anti-CTLA4 treatment for advanced cutaneous melanoma were retrospectively identified from nine participating hospitals. For every patient, up to five representative lesions were segmented on baseline CT, and radiomics features were extracted. A machine learning pipeline was trained on the radiomics features to predict clinical benefit, defined as stable disease for more than 6 months or response per RECIST 1.1 criteria. This approach was evaluated using a leave-one-centre-out cross validation and compared to a model based on previously discovered clinical predictors. Lastly, a combination model was built on the radiomics and clinical model., Results: A total of 620 patients were included, of which 59.2% experienced clinical benefit. The radiomics model achieved an area under the receiver operator characteristic curve (AUROC) of 0.607 [95% CI, 0.562-0.652], lower than that of the clinical model (AUROC=0.646 [95% CI, 0.600-0.692]). The combination model yielded no improvement over the clinical model in terms of discrimination (AUROC=0.636 [95% CI, 0.592-0.680]) or calibration. The output of the radiomics model was significantly correlated with three out of five input variables of the clinical model (p < 0.001)., Discussion: The radiomics model achieved a moderate predictive value of clinical benefit, which was statistically significant. However, a radiomics approach was unable to add value to a simpler clinical model, most likely due to the overlap in predictive information learned by both models. Future research should focus on the application of deep learning, spectral CT-derived radiomics, and a multimodal approach for accurately predicting benefit to checkpoint inhibitor treatment in advanced melanoma., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AvdE has advisory relationships with Amgen, Bristol Myers Squibb, Roche, Novartis, MSD, Pierre Fabre, Sanofi, Pfizer, Ipsen, Merck and has received research study grants not related to this paper from Sanofi, Roche, Bristol Myers Squibb, Idera, and TEVA and has received travel expenses from MSD Oncology, Roche, Pfizer, and Sanofi and has received speaker honoraria from BMS and Novartis. JdG has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, Novartis. PJ has a research collaboration with Philips Healthcare and Vifor Pharma. MBS has consultancy/advisory relationships with Pierre Fabre, MSD, and Novartis. EK has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly, Bayer, EISAI, and Ipsen, and received research grants not related to this paper from Bristol Myers Squibb and Pierre Fabre. PD has consultancy/advisory relationships with Paige, Pantarei, and Samantree paid to the institution, and research grants from Pfizer, none related to current work, and paid to institute. KS has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, AbbVie and received honoraria from Novartis, MSD, and Roche and research funding from Bristol Myers Squibb, TigaTx, and Philips. TL has received research funding from Philips. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: When analysing patient survival, one is often interested in cause of death. Little is known about the presence of population mortality in advanced melanoma patients. The aim of this study was to assess population mortality after different response states in advanced melanoma patients in the Netherlands, and analyse the contribution of disease and population mortality for different age groups., Methods: We selected patients diagnosed between 2013 and 2019 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. A multi-state model with response states integrating population mortality was fitted. One-year landmark analyses were performed to assess outcomes after each response state., Results: Overall, 5119 patients were selected. Five-year probabilities of melanoma-related mortality in patients alive in complete response at one year after diagnosis increased with age, and was 17.2% (95% confidence interval: 13.0-21.4) for patients aged <65 years and 28.7% (95% confidence interval: 24.3-33.1) in patients aged ≥80 years. Population mortality only played a large role for older patients (75 years and above) alive at 1 year after diagnosis with a partial or complete response., Conclusion: Even though survival outcomes of advanced melanoma patients have improved over the last decade, the vast majority of patients still die due to melanoma-related mortality., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Sentinel lymph node biopsy (SLNB) is important for staging in patients with primary cutaneous melanoma. Did having previously undergone SLNB also affect outcomes in patients once they have progressed to metastatic melanoma in the era prior to adjuvant therapy?, Methods: Data were retrieved from the Dutch Melanoma Treatment Registry, a prospectively collected, nationwide database of patients with unresectable stage IIIC or IV (advanced) melanoma between 2012 and 2018. Melanoma-specific survival (MSS) was compared between patients with advanced cutaneous melanoma, previously treated with a wide local excision (WLE) or WLE combined with SLNB as initial treatment of their primary tumor. Cox regression analyses were used to analyze the influence of different variables on MSS., Results: In total, 2581 patients were included, of whom 1412 were treated with a WLE of the primary tumor alone and 1169 in whom this was combined with SLNB. At a median follow-up of 44 months from diagnosis of advanced melanoma, MSS was significantly longer in patients who had previously undergone SLNB {median 23 months (95% confidence interval [CI] 19-29) vs. 18 months (95% CI 15-20) for patients treated with WLE alone; p = 0.002}. However, multivariate Cox regression did not identify SLNB as an independent favorable prognostic factor for MSS after diagnosis of advanced melanoma., Conclusion: Prior to the availability of adjuvant systemic therapy, once patients have unresectable stage IIIC or IV (advanced) melanoma, there was no difference in disease outcome for patients who were or were not previously staged with SLNB., (© 2022. Society of Surgical Oncology.)

Background: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma., Methods: In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×10 9 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival., Results: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression., Conclusions: In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.)., (Copyright © 2022 Massachusetts Medical Society.)

Recent results of patients with advanced melanoma treated with first-line BRAF-MEK inhibitors in clinical trials showed 5-year survival in one-third of patients with a median overall survival (OS) of more than 2 years. This study aimed to investigate these patients' real-world survival and identify the characteristics of long-term survivors. The study population consisted of patients with advanced cutaneous melanoma with a BRAF-V600 mutated tumor who were treated with first-line BRAF-MEK inhibitors between 2013 and 2017. Long-term survival was defined as a minimum OS of 2 years from start therapy. The median progression-free survival (mPFS) and median OS (mOS) of real-world patients ( n  = 435) were respectively 8.0 (95% CI, 6.8-9.4) and 11.7 (95% CI, 10.3-13.5) months. Two-year survival was reached by 28% of the patients, 22% reached 3-year survival and 19% reached 4-year survival. Real-world patients often had brain metastases (41%), stage IV M1c disease (87%), ECOG PS ≥2 (21%), ≥3 organ sites (62%) and elevated LDH of ≥250 U/I (49%). Trial-eligible real-world patients had an mOS of 17.9 months. Patients surviving more than 2 years ( n  = 116) more often had an ECOG PS ≤1 (83%), normal LDH (60%), no brain metastases (60%), no liver metastases (63%) and <3 organ sites (60%). Long-term survival of real-world patients treated with first-line BRAF-MEK inhibitors is significantly lower than that of trial patients, which is probably explained by poorer baseline characteristics of patients treated in daily practice. Long-term survivors generally had more favorable characteristics with regard to age, LDH level and metastatic sites, compared to patients not reaching long-term survival., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: Management of checkpoint inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti-tumor necrosis factor on checkpoint-inhibitor efficacy., Objective: To determine the association of toxic effect management with progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS) in patients with advanced melanoma treated with first-line ipilimumab-nivolumab combination therapy., Design, Setting, and Participants: This population-based, multicenter cohort study included patients with advanced melanoma experiencing grade 3 and higher irAEs after treatment with first-line ipilimumab and nivolumab between 2015 and 2021. Data were collected from the Dutch Melanoma Treatment Registry. Median follow-up was 23.6 months., Main Outcomes and Measures: The PFS, OS, and MSS were analyzed according to toxic effect management regimen. Cox proportional hazard regression was used to assess factors associated with PFS and OS., Results: Of 771 patients treated with ipilimumab and nivolumab, 350 patients (median [IQR] age, 60.0 [51.0-68.0] years; 206 [58.9%] male) were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids alone, and 115 received steroids with second-line immunosuppressants. Colitis and hepatitis were the most frequently reported types of toxic effects. Except for type of toxic effect, no statistically significant differences existed at baseline. Median PFS was statistically significantly longer for patients treated with steroids alone compared with patients treated with steroids plus second-line immunosuppressants (11.3 [95% CI, 9.6-19.6] months vs 5.4 [95% CI, 4.5-12.4] months; P = .01). Median OS was also statistically significantly longer for the group receiving steroids alone compared with those receiving steroids plus second-line immunosuppressants (46.1 months [95% CI, 39.0 months-not reached (NR)] vs 22.5 months [95% CI, 36.5 months-NR]; P = .04). Median MSS was also better in the group receiving steroids alone compared with the group receiving steroids plus second-line immunosuppressants (NR [95% CI, 46.1 months-NR] vs 28.8 months [95% CI, 20.5 months-NR]; P = .006). After adjustment for potential confounders, patients treated with steroids plus second-line immunosuppressants showed a trend toward a higher risk of progression (adjusted hazard ratio, 1.40 [95% CI, 1.00-1.97]; P = .05) and had a higher risk of death (adjusted hazard ratio, 1.54 [95% CI, 1.03-2.30]; P = .04) compared with those receiving steroids alone., Conclusions and Relevance: In this cohort study, second-line immunosuppression for irAEs was associated with impaired PFS, OS, and MSS in patients with advanced melanoma treated with first-line ipilimumab and nivolumab. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in patients with melanoma but also other tumor types.

Purpose: The introduction of immune checkpoint inhibitors and targeted therapies improved the overall survival of patients with advanced melanoma. It is not known how often these costly treatments with potential serious side effects are ineffectively applied in the last phase of life. This study aimed to investigate the start of a new systemic therapy within 45 and 90 days of death in Dutch patients with advanced melanoma., Methods: We selected patients who were diagnosed with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry, and died between 2013 and 2019. Primary outcome was the probability of starting a new systemic therapy 45 and 90 days before death. Secondary outcomes were type of systemic therapy started, grade 3/4 adverse events (AEs), and the total costs of systemic therapies., Results: Between 2013 and 2019, 3,797 patients with unresectable IIIC or stage IV melanoma were entered in the registry and died. The percentage of patients receiving a new systemic therapy within 45 and 90 days before death was significantly different between Dutch melanoma centers (varying from 6% to 23% and 20% to 46%, respectively). Thirteen percent of patients (n = 146) developed grade 3/4 AEs in the last period before death. The majority of patients with an AE required hospital admission (n = 102, 69.6%). Mean total costs of systemic therapy per cohort year of the patients who received a new systemic therapy within 90 days before death were 2.3%-2.8% of the total costs spent on melanoma therapies., Conclusion: The minority of Dutch patients with metastatic melanoma started a new systemic therapy in the last phase of life. However, the percentages varied between Dutch melanoma centers. Financial impact of these therapies in the last phase of life is relatively small., Competing Interests: Rawa K. IsmailEmployment: MSD John B. HaanenStock and Other Ownership Interests: Neogene TherapeuticsConsulting or Advisory Role: MSD Oncology (Inst), Pfizer (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Roche/Genentech (Inst), Ipsen (Inst), Achilles Therapeutics (Inst), Immunocore (Inst), Sanofi (Inst), Third Rock Ventures (Inst), Neogene Therapeutics, Molecular Partners (Inst), bioNTech (Inst), T-Knife (Inst), PokeAcell (Inst), Instil Bio (Inst), Iovance Biotherapeutics (Inst)Research Funding: MSD (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Neon Therapeutics (Inst), Amgen (Inst), BioNTech (Inst), Asher Biotherapeutics (Inst) Christian U. BlankStock and Other Ownership Interests: ImmageneConsulting or Advisory Role: Roche/Genentech (Inst), MSD Oncology (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), AstraZeneca (Inst), Lilly (Inst), Pierre Fabre (Inst), GenMab (Inst), Third Rock VenturesResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), NanoString Technologies (Inst), 4SC (Inst)Patents, Royalties, Other Intellectual Property: WO 2021/177822 A1Expert Testimony: FreshfieldsTravel, Accommodations, Expenses: Bristol Myers Squibb Maureen J.B. AartsResearch Funding: Pfizer (Inst) Jan Willem B. de GrootConsulting or Advisory Role: Bristol Myers Squibb, Pierre Fabre, Servier Geke A.P. HospersConsulting or Advisory Role: Roche (Inst), MSD (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Pierre Fabre (Inst), Sanofi (Inst)Research Funding: Bristol Myers Squibb (Inst), Seerave Foundation (Inst) Ellen KapiteijnConsulting or Advisory Role: Pierre Fabre (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Lilly (Inst), Ipsen (Inst), Delcath Systems (Inst)Research Funding: BMS (Inst), Pierre Fabre (Inst) Djura PiersmaConsulting or Advisory Role: Pierre Fabre (Inst), Novartis (Inst) Astrid A.M. van der VeldtConsulting or Advisory Role: Ipsen (Inst), Roche (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD Oncology (Inst), Sanofi (Inst), Pierre Fabre (Inst), Novartis (Inst), Eisai (Inst), Merck (Inst)Research Funding: Bayer (Inst)Travel, Accommodations, Expenses: Roche, MSD Oncology, Novartis, Bayer Karijn P.M. SuijkerbuijkConsulting or Advisory Role: Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Pierre Fabre (Inst), AbbVie (Inst)Speakers' Bureau: Roche (Inst), Novartis (Inst)Research Funding: Bristol Myers Squibb Foundation (Inst), TigaTx (Inst), Philips Research (Inst) Alfonsus J.M. van den EertweghHonoraria: Bristol Myers SquibbConsulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre FabreResearch Funding: Roche, Sanofi, BMSNo other potential conflicts of interest were reported.

Purpose: Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma., Materials and Methods: All patients with advanced melanoma treated with first-line anti-PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to BRAF and NRAS status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS., Results: In total, 1764 patients received anti-PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti-PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for BRAF -mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with NRAS -mutant (4.8 months; 95% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95% CI, 3.6 to 7.1). In multivariable analysis, BRAF -mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for BRAF -mutant melanoma compared with NRAS -mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens., Conclusion: Ipilimumab-nivolumab-treated patients with BRAF -mutant melanoma display improved PFS and OS compared with patients with NRAS -mutant and double wild-type melanoma. BRAF mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma.

The COVID-19 pandemic had a severe impact on medical care. Our study aims to investigate the impact of COVID-19 on advanced melanoma care in the Netherlands. We selected patients diagnosed with irresectable stage IIIc and IV melanoma during the first and second COVID-19 wave and compared them with patients diagnosed within the same time frame in 2018 and 2019. Patients were divided into three geographical regions. We investigated baseline characteristics, time from diagnosis until start of systemic therapy and postponement of anti-PD-1 courses. During both waves, fewer patients were diagnosed compared to the control groups. During the first wave, time between diagnosis and start of treatment was significantly longer in the southern region compared to other regions (33 vs 9 and 15 days, P-value <.05). Anti-PD-1 courses were postponed in 20.0% vs 3.0% of patients in the first wave compared to the control period. Significantly more patients had courses postponed in the south during the first wave compared to other regions (34.8% vs 11.5% vs 22.3%, P-value <.001). Significantly more patients diagnosed during the second wave had brain metastases and worse performance status compared to the control period. In conclusion, advanced melanoma care in the Netherlands was severely affected by the COVID-19 pandemic. In the south, the start of systemic treatment for advanced melanoma was more often delayed, and treatment courses were more frequently postponed. During the second wave, patients were diagnosed with poorer patient and tumor characteristics. Longer follow-up is needed to establish the impact on patient outcomes., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

There is no consensus on the optimal treatment duration of anti-PD-1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti-PD-1 discontinuation, the association of treatment duration with progression and anti-PD-1 re-treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first-line anti-PD-1 monotherapy in the absence of progressive disease (n = 324). Survival was estimated after anti-PD-1 discontinuation and with a Cox model the association of treatment duration with progression was assessed. At the time of anti-PD-1 discontinuation, 90 (28%) patients had a complete response (CR), 190 (59%) a partial response (PR) and 44 (14%) stable disease (SD). Median treatment duration for patients with CR, PR and SD was 11.2, 11.5 and 7.2 months, respectively. The 24-month progression-free survival and overall survival probabilities for patients with a CR, PR and SD were, respectively, 64% and 88%, 53% and 82%, 31% and 64%. Survival outcomes of patients with a PR and CR were similar when anti-PD-1 discontinuation was not due to adverse events. Having a PR at anti-PD-1 discontinuation and longer time to first response were associated with progression [hazard ratio (HR) = 1.81 (95% confidence interval, CI = 1.11-2.97) and HR = 1.10 (95% CI = 1.02-1.19; per month increase)]. In 17 of the 27 anti-PD-1 re-treated patients (63%), a response was observed. Advanced melanoma patients can have durable remissions after (elective) anti-PD-1 discontinuation., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs., Materials and Methods: Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan-Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis., Results: Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million., Conclusion: Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma., Competing Interests: Disclosure ACJvA reports grants and personal fees from Amgen and Merck-Pfizer; and personal fees from Bristol-Myers Squibb, Novartis, MSD-Merck, Pierre Fabre, Sanofi, and 4SC, outside the submitted work. AJMvdE reports personal fees from BMS, MSD, Merck, Sanofi, Roche, Novartis, Eisai, Ipsen, Pfizer, and Pierre Fabre; and grants from Grant for clinical studies, outside the submitted work. MGF reports grants from Roche Nederland B.V., Daiichi Sankyo, Abbvie, Gilead Sciences Netherlands BV, and Astellas Pharma BV, outside the submitted work. JWBdG reports personal fees from BMS, MSD, Pierre Fabre, and Servier, outside the submitted work. JBAGH reports grants and other from BMS, MSD, Novartis, BioNTech, and Amgen; other from Achilles Tx, GSK, Immunocore, Ipsen, Merck Serono, Molecular Partners, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, and Vaximm; and personal fees from Neogene Tx, outside the submitted work. GAPH reports consulting and advisory role: Amgen, Roche, MSD, BMS, Pfizer, Novartis, Pierre Fabry, paid to the institution (UMCG); and research grant from BMS and Seerave, paid to the institution (UMCG). DP reports personal fees from BMS advisory board and Pierre Fabre advisory board, outside the submitted work. KPMS reports personal fees from Novartis, Roche, Pierre Fabre, MSD, BMS, and Abbvie, outside the submitted work. AAMvdV reports other from BMS, MSD, Merck, Sanofi, Roche, Novartis, Eisai, Ipsen, Pfizer, and Pierre Fabre, outside the submitted work. HMW reports non-financial support from Ipsen; personal fees from Roche; and personal fees and non-financial support from Astellas, outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Little is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR, a population-based registry to monitor the quality and safety of melanoma care in the Netherlands. This study aims to describe treatment patterns, relapse, and toxicity rates of adjuvant-treated melanoma patients beyond the clinical trial setting., Methods: Analyses were performed on adjuvant-treated melanoma patients included in the DMTR. Descriptive statistics were used to analyse patient-, and treatment characteristics. A baseline registration completeness analysis was performed, and an analysis on trial eligibility in clinical practice patients. Recurrence-free survival (RFS) at 12-months was estimated with the Kaplan-Meier method., Results: A total of 641 patients were treated with adjuvant anti-PD-1 therapy. RFS at 12-months was 70.6% (95% CI, 66.9-74.6) with a median follow-up of 12.8 months. Sex, stage of disease and Breslow thickness were associated with a higher hazard for RFS. Eighteen per cent of the anti-PD-1-treated patients developed grade ≥3 toxicity. Sixty-one per cent of patients prematurely discontinued anti-PD-1 therapy., Conclusion: Adjuvant anti-PD-1 treatment of resected stage III/IV melanoma in daily practice showed slightly higher toxicity rates and more frequent premature discontinuation but similar RFS rates compared to trials., Competing Interests: Conflict of interest statement AvdE has advisory relationships with Amgen, Bristol Myers Squibb, Roche, Novartis, MSD, Pierre Fabre, Sanofi, Pfizer, Ipsen, Merck and has received research study grants not related to this paper from Sanofi, Roche, Bristol Myers Squibb, Idera and TEVA and has received travel expenses from MSD Oncology, Roche, Pfizer and Sanofi and has received speaker honoraria from BMS and Novartis. MBS has consultancy/advisory relationships with Pierre Fabre, MSD and Novartis. JdG has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, Novartis. GH consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Pierre Fabre and has received research grants not related to this paper from Bristol Myers Squibb, Seerave. EK has consultancy/advisory relationships with BristolMyers Squibb, Novartis, Merck, Pierre Fabre, and received research grants not related to this paper from Bristol Myers Squibb. KS has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, Abbvie and received honoraria from Novartis, MSD and Roche. AvdV has consultancy relationships with Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, Eisai, Merck. JH has advisory relationships with Achilles Therapeutics, Bristol Myers Squibb, BioNTech, Immunocore, Ipsen, MSD, Merck Serono, Molecular Partners, Novartis, Neogene Therapeutics, PokeAcel, Pfizer, Roche/Genentech, Sanofi, T-Knife, Third Rock Ventures, 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. The funders had no role in the writing of this article or decision to submit it for publication. AvA has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC. Research grants from Amgen, Merck-Pfizer. All outside of current work and all paid to institute. MA has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer. Research grants Merck-Pfizer. Not related to current work and paid to institute. HMW has received travel expenses from Ipsen and Astellas and has received honoraria from Roche and Astellas. RvR has received expert meeting fees from Roche and advisory board fees from Pfizer. EE has received speaker honoraria from BMS, Pierre Fabre, Kyowa Kirin, and travel/conference expenses from MSD. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan-Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range [IQR] 5 - 44) and 14 months (IQR 5 - not reached), respectively (P = 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58-0.85; P < 0.001). As compared to patients with advanced and metastatic cMKP, MUP patients have superior survival in adjusted analysis, but usually present with poorer prognostic characteristics. In crude analysis, OS was comparable indicating that patients with MUP benefit at least equally from treatment with novel therapies., (© 2021. The Author(s).)

Background: The incidence of metastatic melanoma is increasing in all ages. Multiple trials with targeted drugs and immune checkpoint inhibitors showed improved survival in metastatic melanoma. However, patients aged ≥75 years are often under-represented in clinical trials, therefore raising questions on safety and efficacy of treatment., Patients and Methods: We analyzed a real-world cohort of 3054 patients with metastatic melanoma stratified for age (≤65 years, 66-74 years and ≥ 75 years), and BRAF status, providing data on treatment strategies, toxicity, and survival. Kaplan Meier curves and Cox Proportional Hazard Models were used to present overall survival (OS) and Melanoma Specific Survival (MSS)., Results: Overall, 52.2% of patients were ≤ 65 years and 18.4% of patients ≥75 years. BRAF mutated tumors were found less often in patients ≥75 years: 34.5% versus 65% in patients ≤65 years. Patients ≥75 years received systemic therapy less frequently compared to their younger counterparts independent of the BRAF status. When receiving treatment, no statistical significant difference in grade 3 or 4 toxicity was observed. Three year Overall Survival rate was 13.7% (9.1-19.3) in patients ≥75 years versus 26.7% (23.1-30.4) in patients ≤65 years, with a Hazard Ratio (HR) of 1.71 (95%CI 1.50-1.95), p < 0.001. Three year Melanoma Specific Survival was 30.4% (22.0-39.2) versus 34.0% (29.7-38.2), HR 1.26 (95% CI 1.07-1.49), p = 0.005 with an adjusted HR of 1.21 (1.00-1.47), p = 0.049., Conclusion: Patients with metastatic melanoma ≥75 years are less frequently treated, but when treated there is no statistical significant increase in toxicity and only a borderline statistical significant difference in Melanoma Specific Survival was seen, compared to younger patients., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been excluded from clinical trials., Objective: To evaluate the safety and efficacy of ICI in patients with advanced melanoma with and without AID., Design: Nationwide cohort study., Setting: The Netherlands., Patients: 4367 patients with advanced melanoma enrolled in the Dutch Melanoma Treatment Registry (DMTR) between July 2013 and July 2018 and followed through February 2019., Measurements: Patient, clinical, and treatment characteristics; irAEs of grade 3 or higher; treatment response; and survival., Results: A total of 415 patients (9.5%) had AID, categorized as rheumatologic AID ( n = 227), endocrine AID ( n = 143), inflammatory bowel disease (IBD) ( n = 55), or "other" ( n = 8). Of these, 228 patients (55%) were treated with ICI (vs. 2546 [58%] without AID); 87 were treated with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), 187 with anti-programmed cell death 1 (PD-1), and 34 with the combination. The incidences of irAEs of grade 3 or higher in patients with AID were 30% (95% CI, 21% to 41%) with anti-CTLA-4, 17% (CI, 12% to 23%) with anti-PD-1, and 44% (CI, 27% to 62%) with combination therapy; for patients without AID, the incidences were 30% (CI, 27% to 33%) ( n = 916), 13% (CI, 12% to 15%) ( n = 1540), and 48% (CI, 43% to 53%) ( n = 388), respectively. Patients with AID more often discontinued anti-PD-1 treatment because of toxicity than patients without AID (17% [CI, 12% to 23%] vs. 9% [CI, 8% to 11%]). Patients with IBD were more prone to anti-PD-1-induced colitis (6/31 = 19% [CI, 7% to 37%]) than patients with other AIDs (3% [CI, 0% to 6%]) and patients without AID (2% [CI, 2% to 3%]).The objective response rate was similar in patients with versus without AID who were treated with anti-CTLA-4 (10% [CI, 5% to 19%] vs. 16% [CI, 14% to 19%]), anti-PD-1 (40% [CI, 33% to 47%] vs. 44% [CI, 41% to 46%]), or the combination (39% [CI, 20% to 59%] vs. 43% [CI, 38% to 49%]). Survival did not differ between patients with and those without AID (median, 13 months [CI, 10 to 16 months] vs. 14 months [CI, 13 to 15 months])., Limitation: Information was limited on AID severity and immunosuppressive treatment., Conclusion: Response to ICI with anti-CTLA-4, anti-PD-1, or their combination for advanced melanoma and overall incidence of any irAEs of grade 3 or higher were similar in patients with and without preexisting AID. However, severe colitis and toxicity requiring early discontinuation of treatment occurred more frequently among patients with preexisting IBD, warranting close follow-up., Primary Funding Source: The Netherlands Organization for Health Research and Development.

Background: Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort., Methods: Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3-4 hepatitis and outcome., Results: 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44)., Conclusion: Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.

Background: The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response., Methods: The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs., Discussion: From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients., Trial Registration: The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

Background: Anti-PD-1 antibodies and BRAF/MEK inhibitors are the two main groups of systemic therapy in the treatment of BRAF V600 -mutant advanced melanoma. Until now, data are inconclusive on which therapy to use as first-line treatment. The aim of this study was to use propensity score matching to compare first-line anti-PD-1 monotherapy vs. BRAF/MEK inhibitors in advanced BRAF V600 -mutant melanoma patients., Methods: We selected patients diagnosed between 2014 and 2017 with advanced melanoma and a known BRAF V600 -mutation treated with first-line BRAF/MEK inhibitors or anti-PD-1 antibodies, registered in the Dutch Melanoma Treatment Registry. Patients were matched based on their propensity scores using the nearest neighbour and the optimal matching method., Results: Between 2014 and 2017, a total of 330 and 254 advanced melanoma patients received BRAF/MEK inhibitors and anti-PD-1 monotherapy as first-line systemic therapy. In the matched cohort, patients receiving anti-PD-1 antibodies as a first-line treatment had a higher median and 2-year overall survival compared to patients treated with first-line BRAF/MEK inhibitors, 42.3 months (95% CI: 37.3-NE) vs. 19.8 months (95% CI: 16.7-24.3) and 65.4% (95% CI: 58.1-73.6) vs. 41.7% (95% CI: 34.2-51.0)., Conclusions: Our data suggest that in the matched BRAF V600 -mutant advanced melanoma patients, anti-PD-1 monotherapy is the preferred first-line treatment in patients with relatively favourable patient and tumour characteristics.

Background: The treatment landscape has completely changed for advanced melanoma. We report survival outcomes and the differential impact of prognostic factors over time in daily clinical practice., Methods: From a Dutch nationwide population-based registry, patients with advanced melanoma diagnosed from 2013 to 2017 were analysed (n = 3616). Because the proportional hazards assumption was violated, a multivariable Cox model restricted to the first 6 months and a multivariable landmark Cox model from 6 to 48 months were used to assess overall survival (OS) of cases without missing values. The 2017 cohort was excluded from this analysis because of the short follow-up time., Results: Median OS of the 2013 and 2016 cohort was 11.7 months (95% confidence interval [CI]: 10.4-13.5) and 17.7 months (95% CI: 14.9-19.8), respectively. Compared with the 2013 cohort, the 2016 cohort had superior survival in the Cox model from 0 to 6 months (hazard ratio [HR] = 0.55 [95% CI: 0.43-0.72]) and in the Cox model from 6 to 48 months (HR = 0.68 [95% CI: 0.57-0.83]). Elevated lactate dehydrogenase levels, distant metastases in ≥3 organ sites, brain and liver metastasis and Eastern Cooperative Oncology Group performance score of ≥1 had stronger association with inferior survival from 0 to 6 months than from 6 to 48 months. BRAF-mutated melanoma had superior survival in the first 6 months (HR = 0.50 [95% CI: 0.42-0.59])., Conclusion(s): Prognosis for advanced melanoma in the Netherlands has improved from 2013 to 2016. Prognostic importance of most evaluated factors was higher in the first 6 months after diagnosis. BRAF-mutated melanoma was only associated with superior survival in the first 6 months., Competing Interests: Conflict of interest statement AvdE reports advisory relationships with Amgen, Bristol-Myers Squibb, Roche, Novartis, MSD, and Pierre-Fabre. AvA reports consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, and 4SC and research grants not related to this paper from Amgen, BMS, and Novartis. JdG reports personal fees outside the submitted work from Bristol-Myers Squibb, Roche, Pierre-Fabre, Servier, and MSD, Novartis. GH reports consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, and Novartis and research grants not related to this paper from Bristol-Myers Squibb, and Seerave. EK has consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Novartis, Roche, Merck, Pierre-Fabre, EISAI, Bayer, and Genzyme-Sanofi and research grants not related to this paper from Novartis and Bristol-Myers Squibb. KS advisory relationships with Bristol-Myers Squibb, Roche, Novartis, MSD, and Pierre-Fabre. AvdV reports consultancy relationships with Bristol-Myers Squibb, MSD, Roche, Novartis, Pierre-Fabre, Pfizer, Sanofi, Ipsen, and Eisai. JH reports advisory relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celsius Therapeutics, GSK, Immunocore, Ipsen, MSD, Merck Serono, Novartis, Neon Therapeutics, Pfizer, Roche/Genentech, Sanofi, and Seattle Genetics and research grants not related to this paper from Novartis, Bristol-Myers Squibb, MSD, and Neon Therapeutics. All grants were paid to the institutions. The funders had no role in the writing of this article or decision to submit it for publication., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Postapproval trials and patient registries have their pros and cons in the generation of postapproval data. No direct comparison between clinical outcomes of these data sources currently exists for advanced melanoma patients. We aimed to investigate whether a patient registry can complement or even replace postapproval trials. Postapproval single-arm clinical trial data from the Medicines Evaluation Board and real-world data from the Dutch Melanoma Treatment Registry were used. The study population consisted of advanced melanoma patients with brain metastases treated with targeted therapies (BRAF- or BRAF-MEK inhibitors) in the first line. A Cox hazard regression model and a propensity score matching (PSM) model were used to compare the two patient populations. Compared to patients treated in postapproval trials (n = 467), real-world patients (n = 602) had significantly higher age, higher ECOG performance status, more often ≥3 organ involvement and more symptomatic brain metastases. Lactate dehydrogenase levels were similar between both groups. The unadjusted median overall survival (mOS) in postapproval clinical trial patients was 8.7 (95% CI, 8.1-10.4) months compared to 7.2 (95% CI, 6.5-7.7) months (P < 0.01) in real-world patients. With the Cox hazard regression model, survival was adjusted for prognostic factors, which led to a statistically insignificant difference in mOS for trial and real-world patients of 8.7 (95% CI, 7.9-10.4) months compared to 7.3 (95% CI, 6.3-7.9) months, respectively. The PSM model resulted in 310 matched patients with similar survival (P = 0.9). Clinical outcomes of both data sources were similar. Registries could be a complementary data source to postapproval clinical trials to establish information on clinical outcomes in specific subpopulations., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The aim of this study was to evaluate treatment patterns and overall survival (OS) of patients with BRAFV600 wild-type and BRAFV600-mutant advanced melanoma in the Netherlands., Methods: We selected patients of 18 years and over, diagnosed between 2016 and 2017 with unresectable stage IIIC or IV melanoma, registered in the Dutch Melanoma Treatment Registry. To assess the association of BRAFV600-mutation status with OS we used the Cox proportional-hazards model., Results: A total of 642 BRAFV600 wild-type and 853 mutant patients were included in the analysis. Median OS did not differ significantly between both groups, 15.2 months (95% confidence interval [CI]: 13.2-19.2) versus 20.6 months (95% CI: 18.3-25.0). Survival rates at 6 and 12 months were significantly lower for BRAFV600 wild-type patients compared with BRAFV600-mutant patients, 72.0% (95% CI: 68.6-75.6) and 56.0% (95% CI: 52.2-60.0) versus 83.4% (95% CI: 80.9-85.9) and 65.7% (95% CI: 62.6-69.0). Two-year survival was not significantly different between both groups, 41.1% (95% CI: 37.2-45.3) versus 47.0% (95% CI: 43.6-60.6). Between 0 and 10 months, BRAFV600 wild-type patients had a decreased survival with a hazard ratio for OS of 2.00 (95% CI: 1.62-2.46) but this effect disappeared after 10 months. At 12 months, BRAFV600-mutant patients had started with second-line systemic treatment more often compared with BRAFV600 wild-type patients (50% vs. 19%)., Conclusion: These results suggest that advanced BRAFV600 wild-type melanoma patients have worse survival than BRAFV600-mutated patients during the first 10 months after diagnosis because of less available treatment options., Competing Interests: J.B.H. has advisory relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celsius Therapeutics, GSK, Immunocore, Ipsen, MSD, Merck Serono, Novartis, Neon Therapeutics, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics and has received research grants not related to this paper from Novartis, Bristol-Myers Squibb, MSD, Neon Therapeutics. All grants were paid to the institutions. C.U.B. has advisory relationships with, Bristol-Myers Squibb, Genmab, GSK, Lilly, MSD, Roche, Novartis, Pfizer and grant support by BMS, Novartis, and NanoString. J.-W.B.d.G. has received personal fees outside the submitted work from Bristol-Myers Squibb, Roche, Pierre Fabre, Servier, MSD, Novartis. G.A.P.H. has consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, BMS. She received honoraria from Novartis, Pierre Fabre, and Roche and has received research grants not related to this paper from Bristol-Myers Squibb, Seerave. A.A.M.v.d.V. has consultancy relationships with Bristol-Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, Eisai. E.K. has consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Novartis, Roche, Merck, Pierre Fabre, EISAI, Bayer, Genzyme-Sanofi and received research grants not related to this paper from Novartis and Bristol-Myers Squibb. K.P.M.S. has consulting/advisory relationships with BMS and MSD. She received honoraria from Novartis, Pierre Fabre, and Roche. A.J.M.v.d.E. has consulting/advisory relationships with BMS, Roche, MSD, and Novartis. He received a study grant from Roche. The funders had no role in the writing of this article or decision to submit it for publication. The other authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer., Material and Methods: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines., Results: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7 vs . 89.8, difference (diff) = -5.80, p =.005), role (83.5 vs. 90, diff = -5.97, p =.02), cognitive (83.7 vs. 91.9, diff = -8.05, p =.001), and social functioning (86.5 vs. 95.1, diff = -8.49, p = <.001) and had a higher symptom burden of fatigue (23.0 vs. 15.5, diff = 7.48, p =.004), dyspnea (13.3 vs. 6.7, diff = 6.47 p =.02), diarrhea (7.9 vs. 4.0, diff = 3.78, p =.04), and financial impact (10.5 vs. 2.5, diff = 8.07, p =.001) than matched controls. Group differences were indicated as clinically relevant., Discussion: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.

The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune- or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE-006 and CHECKMATE-067/-066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan-Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population-based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long-term survival is possible. The prognosis of ineligible patients with advanced melanoma in real-world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now., Methods: Risk ratios of severe (grade ≥3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry., Results: 111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RR adj ) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RR adj 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs., Conclusion: In patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found., Competing Interests: Competing interests: CUB reports receiving commercial research grants from Novartis, Bristol-Myers 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. AJMvdE reports receiving commercial research grants from Bristol-Myers Squibb; reports receiving speakers bureau honoraria from Bristol-Myers Squibb and Novartis; and is an unpaid consultant/advisory board member for Bristol-Myers Squibb, Novartis, MSD, Pierre Fabre and AMGEN. JWdG is a paid consultant for Bristol-Myers Squibb and MSD. GAH is an unpaid consultant/advisory board member for Bristol-Myers Squibb, MSD, Roche and Novartis. AAMvdV is a paid consultant for Bristol-Myers Squibb, MSD, Novartis, Roche, Pfizer, Eisai, Ipsen, Pierre Fabre, Sanofi and Bayer. JBAGH is a paid consultant for AIMM, Neon Therapeutics, Immunocore, Vaximm and Neogene Therapeutics, and reports receiving commercial research grants from Bristol-Myers Squibb, MSD, Novartis and Neon Therapeutics. EK is a paid advisory board member for Bristol-Myers Squibb, Novartis, Merck/MSD and Pierre Fabre, and reports receiving commercial research grants from Bristol-Myers Squibb. KPMS reports receiving speakers bureau honoraria from Novartis and Roche, and is an unpaid consultant/advisory board member for Novartis, Roche, MSD, Pierre Fabre and Bristol-Myers Squibb., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

The efficacy of anti-programmed death-1 (PD-1) monotherapy for advanced melanoma has been established, but it is unknown to what extent patients benefit in the real world. In this observational study with nationwide population-based data from the Dutch Melanoma Treatment Registry, we analyzed real-world outcomes of first-line anti-PD-1 monotherapy in advanced melanoma patients diagnosed in 2015 to 2016. Overall survival (OS) was estimated with the Kaplan-Meier method. Competing risks analysis was used to estimate probabilities for second-line treatment, with death as competing risk. With a Cox model, the association of factors with OS was estimated. Patients who received anti-PD-1 monotherapy (n=550) had a median age of 65 years and 502 (95%) patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, 383 (70%) had normal lactate dehydrogenase (LDH), 370 (67%) had stage IV-M1c disease, and in 441 (81%), brain metastases were absent. The median OS was 24 months [95% confidence interval (CI): 20-30 mo]. The median OS of patients normally eligible for phase III trial participation was 31 months (95% CI: 23-not estimable). The BRAF mutation was associated with superior OS. ECOG PS of ≥1, symptomatic brain metastases, and liver metastases were associated with inferior OS and, together with elevated LDH, with death before second-line treatment. Patients with a complete response had a 2-year OS probability from first reported complete response of 92% (95% CI: 86%-99%). Real-world advanced melanoma patients in the Netherlands have benefitted from anti-PD-1 monotherapy. ECOG PS ≥1, symptomatic brain metastasis, liver metastasis, and elevated LDH are important prognostic factors for survival. The additional information that this study provides could help to improve more effective use in the real world.

Background: Mucosal melanoma (MM) is rare and has a poor prognosis. Since 2011, new effective treatments are available for advanced melanoma. It is unclear whether patients with mucosal melanoma equally benefit from these new treatments compared with patients with cutaneous melanoma (CM)., Methods: Patients with advanced MM and CM diagnosed between 2013 and 2017 were included from a nationwide population-based registry - the Dutch Melanoma Treatment Registry. Overall survival (OS) was estimated with the Kaplan-Meier method (also for a propensity score-matched cohort). A Cox model was used to analyse the association of possible prognostic factors with OS., Results: In total, 120 patients with MM and 2960 patients with CM were included. Median OS was 8.7 months and 14.5 months, respectively. Patients with MM were older (median age 70 versus 65 years) and more often female (60% versus 41%), compared with CM. In total, 77% and 2% of the MM patients were treated with first-line immunotherapy and targeted therapy, respectively, compared with 49% and 33% of the CM patients. In contrast to CM, OS for MM did not improve for patients diagnosed in 2015-2017, compared with 2013-2014. ECOG performance score ≥1 (HR = 1.99 [1.26-3.15; p = 0.003]) and elevated LDH level (HR = 1.63 [0.96-2.76]; p = 0.069) in MM were associated with worse survival., Conclusions: Within the era of immune and targeted therapies, prognosis for patients with advanced MM has not improved as much as for CM. Collaboration is necessary to enlarge sample size for research to improve immunotherapeutic strategies and identify targetable mutations., Competing Interests: Conflict of interest statement M.C.T.v.Z., F.L.B., M.I.E.v.P., L.C.d.W., M.W.J.M.W., M.J.B.S., M.J.B.A., F.W.P.J.v.d.B., D.P., R.S.v.R., A.J.t.T., G.V., J.v.d.H. have no conflicts of interest to disclose. A.J.M.v.d.E. reports having advisory relationships with Amgen, Bristol-Myers Squibb, Roche, Novartis, MSD, and Pierre Fabre. J.W.B.d.G. reports receiving personal fees outside the submitted work from Bristol-Myers Squibb, Roche, Pierre Fabre, Servier, MSD, Novartis. G.A.P.H. reports having consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis and receiving research grants not related to this paper from Bristol-Myers Squibb, and Seerave. E.H.W.K. reports having consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Novartis, Roche, Merck, Pierre Fabre, EISAI, Bayer, Genzyme-Sanofi and receiving research grants not related to this paper from Novartis and Bristol-Myers Squibb. K.P.M.S. reports having advisory relationships with Bristol-Myers Squibb, Roche, Novartis, MSD, and Pierre Fabre. A.A.M.v.d.V. reports having consultancy relationships with Bristol-Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, and Eisai. J.B.A.G.H. reports having advisory relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celsius Therapeutics, GSK, Immunocore, Ipsen, MSD, Merck Serono, Novartis, Neon Therapeutics, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics and receiving research grants not related to this paper from Novartis, Bristol-Myers Squibb, MSD, Neon Therapeutics. All grants were paid to the institutions. The funders had no role in the writing of this article or decision to submit it for publication. Authors have full control of all primary data. They agree to allow the journal to review the data if requested., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown., Experimental Design: Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analyzed whether toxicity management affected survival in these patients., Results: A total of 1,250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab, and 85 combination therapy. A total of 312 patients (25%) developed severe (grade ≥3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared with 15 months for patients without severe toxicity [hazard ratio (HR adj ) = 0.77; 95% confidence interval (CI), 0.63-0.93]. Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF ± steroids for steroid-refractory toxicity compared with patients who were managed with steroids only (HR adj = 1.61; 95% CI, 1.03-2.51), with a median OS of 17 and 27 months, respectively., Conclusions: Patients experiencing severe ICI toxicity have a prolonged OS. However, this survival advantage is abrogated when anti-TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy. See related commentary by Weber and Postow, p. 2085 ., (©2020 American Association for Cancer Research.)

The aim of this population-based study was to identify the factors associated with clinical outcomes in vemurafenib-treated patients and to evaluate outcomes across subgroups of patients with different risk profiles. Data were retrieved from the Dutch Melanoma Treatment Registry. Time to next treatment (TTNT) and overall survival (OS) of all metastatic melanoma patients who received vemurafenib between 2012 and 2015 were assessed using Kaplan-Meier estimates. A risk score was developed on the basis of all prognostic factors associated with TTNT and OS derived from multivariable Cox regression analyses. Patients were stratified according to the presence of prognostic risk factors by counting the number of factors, ranging from 0 to 6. A total of 626 patients received vemurafenib with a median follow-up of 35.8 months. The median TTNT and OS were 4.7 months [95% confidence intervals (CI): 4.4-5.1] and 7.3 months (95% CI: 6.6-8.0). The strongest prognostic factors were serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance score, number of organ sites involved and brain metastases. Patients with a favourable risk profile (no risk factors) had a median TTNT and OS of 7.1 (95% CI: 5.8-8.5) and 15.4 months (95% CI: 10.0-20.9). The median OS more than halved for patients with greater than or equal to 2 risk factors compared with patients with no risk factors. The clinical outcomes of vemurafenib in metastatic melanoma patients with a favourable risk profile are comparable with the results of the trials. Combining prognostic factors into a risk score could be valuable to stratify patients into favourable and poor-prognosis groups.

There is limited evidence on the costs associated with ipilimumab. We investigated healthcare costs of all Dutch patients with advanced cutaneous melanoma who were treated with ipilimumab. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry. Costs were determined by applying unit costs to individual patient resource use. A total of 807 patients who were diagnosed between July 2012 and July 2015 received ipilimumab in Dutch practice. The mean (median) episode duration was 6.27 (4.61) months (computed from the start of ipilimumab until the start of a next treatment, death, or the last date of follow-up). The average total healthcare costs amounted to &OV0556;81 484, but varied widely (range: &OV0556;18 131-&OV0556;160 002). Ipilimumab was by far the most important cost driver (&OV0556;73 739). Other costs were related to hospital admissions (&OV0556;3323), hospital visits (&OV0556;1791), diagnostics and imaging (&OV0556;1505), radiotherapy (&OV0556;828), and surgery (&OV0556;297). Monthly costs for resource use other than ipilimumab were &OV0556;1997 (SD: &OV0556;2629). Treatment-naive patients (n=344) had higher total costs compared with previously-treated patients (n=463; &OV0556;85 081 vs. &OV0556;78 811). Although patients with colitis (n=106) had higher costs for resource use other than ipilimumab (&OV0556;11 426) compared with patients with other types of immune-related adverse events (n=90; &OV0556;9850) and patients with no immune-related adverse event (n=611; &OV0556;6796), they had lower total costs (&OV0556;76 075 vs. &OV0556;87 882 and &OV0556;81 480, respectively). In conclusion, this nation-wide study provides valuable insights into the healthcare costs of advanced cutaneous melanoma patients who were treated with ipilimumab in clinical practice. Most of the costs were attributable to ipilimumab, but the costs and its distribution varied considerably across subgroups.

Phase III trials with ipilimumab showed an improved survival in patients with metastatic melanoma. We evaluated the use and safety of ipilimumab, and the survival of all patients with metastatic cutaneous melanoma (N=807) receiving ipilimumab in real-world clinical practice in The Netherlands using data from the Dutch Melanoma Treatment Registry. Patients who were registered between July 2012 and July 2015 were included and analyzed according to their treatment status: treatment-naive (N=344) versus previously-treated (N=463). Overall, 70% of treatment-naive patients and 62% of previously-treated patients received all four planned doses of ipilimumab. Grade 3 and 4 immune-related adverse events occurred in 29% of treatment-naive patients and 21% of previously-treated patients. No treatment-related deaths occurred. Median time to first event was 5.4 months [95% confidence interval (CI): 4.7-6.5 months] in treatment-naive patients and 4.4 months (95% CI: 4.0-4.7 months) in previously-treated patients. Median overall survival was 14.3 months (95% CI: 11.6-16.7 months) in treatment-naive patients and 8.7 months (95% CI: 7.6-9.6 months) in previously-treated patients. In both patient groups, an elevated lactate dehydrogenase level (hazard ratio: 2.25 and 1.70 in treatment-naive and previously-treated patients, respectively) and American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and 1.83, respectively) were negatively associated with overall survival. These real-world outcomes of ipilimumab slightly differed from outcomes in phase III trials. Although phase III trials are crucial for establishing efficacy, real-world data are of great added value enhancing the generalizability of outcomes of ipilimumab in clinical practice.

Objective: To evaluate treatment strategies and survival of patients with unresectable stage IIIc or IV melanoma since the 2012 introduction of new drugs in the Netherlands., Design: Prospective cohort study., Method: We analysed data from the Dutch Melanoma Treatment Registry (DMTR) regarding patients diagnosed with unresectable stage IIIc or IV melanoma in the period of 1 July 2012 to 31 December 2015. We estimated survival times using the Kaplan-Meier method. The relationship between year of diagnosis and survival was estimated using Cox regression analysis, adjusted for age, WHO performance status, lactate dehydrogenase values, stage, brain metastases and distant metastases., Results: Out of 2,768 registered patients, approximately three-quarters received systemic therapy. This treatment was subject to change every year. Median survival was 10.7 months (95% CI: 9.6-13.2) in 2012 and 13.8 months (95% CI: 11.8-15.6) in 2015. Median survival for patients receiving systemic therapy was 17.1 months in 2015. 2-year survival in this period increased from 23% to 40%. Patients diagnosed in 2015 had better survival than patients of 2014 (hazard ratio (HR) 0.82; 95% CI: 0.73-0.93). This was also true for patients receiving systemic therapy (HR: 0.79; 95% CI: 0.69-0.91)., Conclusion: Fast availability of new drugs, initiated by the then minister of VWS (health, welfare and sport) and the professional organisation, has thoroughly changed treatment of unresectable stage IIIc and IV melanoma. Data from the DMTR indicate safe use of these new drugs in daily practice and improved survival of advanced-melanoma patients in recent years.

Background: In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure the safety and quality of melanoma care in the Netherlands. This article describes the design and objectives of the DMTR and presents some results of the first 2 years of registration., Methods: The DMTR documents detailed information on all Dutch patients with unresectable stage IIIc or IV melanoma. This includes tumour and patient characteristics, treatment patterns, clinical outcomes, quality of life, healthcare utilisation, informal care and productivity losses. These data are used for clinical auditing, increasing the transparency of melanoma care, providing insights into real-world cost-effectiveness and creating a platform for research., Results: Within 1 year, all melanoma centres were participating in the DMTR. The quality performance indicators demonstrated that the BRAF inhibitors and ipilimumab have been safely introduced in the Netherlands with toxicity rates that were consistent with the phase III trials conducted. The median overall survival of patients treated with systemic therapy was 10.1 months (95% confidence interval [CI] 9.1-11.1) in the first registration year and 12.7 months (95% CI 11.6-13.7) in the second year., Conclusion: The DMTR is the first comprehensive multipurpose nationwide registry and its collaboration with all stakeholders involved in melanoma care reflects an integrative view of cancer management. In future, the DMTR will provide insights into challenging questions regarding the definition of possible subsets of patients who benefit most from the new drugs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)