Despite the improved survival rates of patients with advanced stage melanoma since the introduction of ICIs, many patients do not have (long-term) benefit from these treatments. There is evidence... Show moreDespite the improved survival rates of patients with advanced stage melanoma since the introduction of ICIs, many patients do not have (long-term) benefit from these treatments. There is evidence that the exposome, an accumulation of host-extrinsic factors including environmental influences, could impact ICI response. Recently, a survival benefit was observed in patients with BRAF wild-type melanoma living in Denmark who initiated immunotherapy in summer as compared to winter. As the Netherlands lies in close geographical proximity to Denmark and has comparable seasonal differences, a Dutch validation cohort was established using data from our nationwide melanoma registry. In this study, we did not observe a similar seasonal difference in overall survival and are therefore unable to confirm the Danish findings. Validation of either the Dutch or Danish findings in (combined) patient cohorts from other countries would be necessary to determine whether this host-extrinsic factor influences the response to ICI-treatment. Show less
Zeijl, M.C.T. van; Breeschoten, J. van; Wreede, L.C. de; Wouters, M.W.J.M.; Hilarius, D.L.; Blank, C.U.; ... ; Eertwegh, A.J.M. van den 2023
Background: In phase III trials, ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grade 3-4 adverse events (AEs). Here, we... Show moreBackground: In phase III trials, ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grade 3-4 adverse events (AEs). Here, we report real-world safety and survival outcomes of ipilimumab plus nivolumab for advanced melanoma.Methods: Patients with advanced melanoma who received first-line ipilimumab plus nivolumab between 1-1-2015 and 30-6-2021 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.Results: In total, 709 patients received first-line ipilimumab plus nivolumab. Three hundred sixty (50.7%) patients experienced grade 3-4 AEs with 211 of them (58.6%) patients requiring hospital admission. 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 36% (95%CI: 27-48).Conclusion: 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 to clinical trials. Show less
The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanomathat develop brain metastases (BM) remains unpredictable. In this study, we aimed to identifyprognostic factors... Show moreThe efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanomathat develop brain metastases (BM) remains unpredictable. In this study, we aimed to identifyprognostic factors in patients with melanoma BM who are treated with ICIs. Data from advancedmelanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained fromthe Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment ofBM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potentialclassifiers and overall survival (OS) as the response variable. In total, 1278 patients were included.Most patients were treated with ipilimumab–nivolumab combination therapy (45%). The survivaltree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. Thestrongest clinical parameter associated with survival in advanced melanoma patients with BM wasthe serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomaticBM had the worst prognosis. The clinicopathological classifiers identified in this study can contributeto optimizing clinical studies and can aid doctors in giving an indication of the patients’ survivalbased on their baseline and disease characteristics. Show less
BackgroundCheckpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies,... Show moreBackgroundCheckpoint 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.MethodsHealth-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.ResultsHealth-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 (beta = - .82, p = .022) and fatigue burden (beta = - .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).DiscussionOur results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores. Show less
BackgroundPatients 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...Show moreBackgroundPatients 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.MethodsAll 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.ResultsIn 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 (HRadj 1.62; 95% confidence interval [95% CI] 1.15–2.29; p = 0.006) and melanoma-related death (HRadj 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.ConclusionsPatients 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. Show less
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... Show moreSince 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. Show less
Breeschoten, J. van; Eertwegh, A.J.M. van den; Hilarius, D.L.; Haanen, J.B.; Blank, C.U.; Aarts, M.J.B.; ... ; Wreede, L.C. de 2023
IntroductionWhen 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... Show moreIntroductionWhen 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.MethodsWe 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.ResultsOverall, 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.ConclusionEven 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. Show less
Simple Summary: BRAF/MEK therapy and anti-PD-1 therapy have shown better recurrence-free survival of stage III melanoma in patients with BRAF V600 mutations in clinical trials. However, little is... Show moreSimple Summary: BRAF/MEK therapy and anti-PD-1 therapy have shown better recurrence-free survival of stage III melanoma in patients with BRAF V600 mutations in clinical trials. However, little is known about how these therapies compare to each other in everyday practice. The aim of our study was to describe the toxicity and survival of patients treated with BRAF/MEK therapy and anti-PD-1 therapy in daily practice. We demonstrated that grade >= 3 toxicity occurred in 11.5% of patients and was the most common cause of early treatment discontinuation (71.1%). We also show that at 12 months, patients treated with BRAF/MEK therapy have less progression than those treated with anti-PD-1 therapy. However, this is no longer the case at 18 months. Adjuvant BRAF/MEK- and anti-PD-1 inhibition have significantly improved recurrence-free survival (RFS) compared to placebo in resected stage III BRAF-mutant melanoma. However, data beyond the clinical trial setting are limited. This study describes the toxicity and survival of patients treated with adjuvant BRAF/MEK inhibitors and compares outcomes to adjuvant anti-PD-1. For this study, stage III BRAF V600 mutant cutaneous melanoma patients treated with adjuvant BRAF/MEK-inhibition or anti-PD-1 were identified from the Dutch Melanoma Treatment Registry. BRAF/MEK- and anti-PD-1-treated patients were matched based on propensity scores, and RFS at 12 and 18 months were estimated. Between 1 July 2018 and 31 December 2021, 717 patients were identified. Of these, 114 patients with complete records were treated with BRAF/MEK therapy and 532 with anti-PD-1. Comorbidities (p = 0.04) and geographical region (p < 0.01) were associated with treatment choice. In 45.6% of BRAF/MEK-treated patients, treatment was prematurely discontinued. Grade >= 3 toxicity occurred in 11.5% of patients and was the most common cause of early discontinuation (71.1%). At 12 and 18 months, RFS in BRAF/MEK-treated patients was 85% and 70%, compared to 68% and 68% in matched anti-PD-1-treated patients (p = 0.03). In conclusion, comorbidities and geographical region determine the choice of adjuvant treatment in patients with resected stage III BRAF-mutant melanoma. With the currently limited follow-up, BRAF/MEK-treated patients have better RFS at 12 months than matched anti-PD-1-treated patients, but this difference is no longer observed at 18 months. Therefore, longer follow-up data are necessary to estimate long-term effectiveness. Show less
