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
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
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... Show moreBACKGROUND 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 5x10(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. Show less
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... Show moreIMPORTANCE: 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 tumor types. Show less
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... Show moreBackground: 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 (83.7vs. 89.8, difference (diff) = -5.80,p=.005), role (83.5vs.90, diff = -5.97,p=.02), cognitive (83.7vs.91.9, diff = -8.05,p=.001), and social functioning (86.5vs.95.1, diff = -8.49,p= <.001) and had a higher symptom burden of fatigue (23.0vs.15.5, diff = 7.48,p=.004), dyspnea (13.3vs.6.7, diff = 6.47p=.02), diarrhea (7.9vs.4.0, diff = 3.78,p=.04), and financial impact (10.5vs.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. Show less
Boekhout, A.H.; Hauptmann, M.; Eertwegh, A.J.M. van den; Hospers, G.A.P.; Groot, J.W.B. de; Aarts, M.J.B.; ... ; Blank, C.U. 2017
