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... Show morePURPOSE: 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. Show less
Background: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint... Show moreBackground: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint inhibitors in patients with stage III and IV AM and compare them to cutaneous melanoma (CM). Methods: We included patients with advanced AM and CM treated with first-line anti -programmed cell death (PD)-1 monotherapy or ipilimumab-nivolumab registered in the prospective nationwide Dutch Melanoma Treatment Registry. Objective response rates, progression free survival (PFS) and overall survival (OS) were calculated. A Cox proportional hazard model was used to assess the prognostic factors with PFS and OS. Results: In total, 2058 patients (88 AM and 1970 CM) with advanced melanoma were included. First-line objective response rates were 34% for AM versus 54% for CM in the advanced anti-PD-1 cohort and 33% for AM versus 53% for CM in the advanced ipilimumab-nivolumab cohort. The Median PFS was significantly shorter for anti-PD-1 treated AM patients (3.1 months; 95%CI: 2.8-5.6) than patients with CM (10.1 months; 95%CI: 8.5-12.2) (P < 0.001). In patients with advanced melanoma, AM was significantly associated with a higher risk of progression (HRadj 1.63; 95%CI: 1.26-2.11 ; P < 0.001) and death (HRadj 1.54; 95%CI: 1.15-2.06; P Z 0.004) than CM. Conclusions: This study shows lower effectiveness of anti-PD-1 monotherapy and ipilimumab-nivolumab in AM, with lower response rates, PFS and OS than CM. This group of patients should be prioritised in the development of alternative treatment strategies. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
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,... Show moreBackground: 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. (C) 2021 The Authors. Published by Elsevier Ltd. Show less
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... Show moreThe 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. Show less
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... Show moreThere 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. Show less
Simple Summary: The survival of advanced melanoma patients has improved significantly over the last decade due to the introduction of new systemic therapies. It is unknown whether survival outcomes... Show moreSimple Summary: The survival of advanced melanoma patients has improved significantly over the last decade due to the introduction of new systemic therapies. It is unknown whether survival outcomes of advanced melanoma patients differ between melanoma centers in the Netherlands. This research aimed to assess center variation in treatments and 2-year survival probabilities of advanced melanoma patients diagnosed between 2013 and 2017 in the Netherlands. Significant center variation in 2-year survival probabilities of patients diagnosed in 2014-2015 was observed after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. This study shows the added value of quality monitoring with a national registry that enables the study of variation between centers.Background: To assure a high quality of care for patients treated in Dutch melanoma centers, hospital variation in treatment patterns and outcomes is evaluated in the Dutch Melanoma Treatment Registry. The aim of this study was to assess center variation in treatments and 2-year survival probabilities of patients diagnosed between 2013 and 2017 in the Netherlands. Methods: We selected patients diagnosed between 2013 and 2017 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. Centers' performance on 2-year survival was evaluated using Empirical Bayes estimates calculated in a random effects model. Treatment patterns of the centers with the lowest and highest estimates for 2-year survival were compared. Results: For patients diagnosed between 2014 and 2015, significant center variation in 2-year survival probabilities was observed even after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. Conclusion: Our data suggest that between 2014 and 2015, after correcting for patient case-mix, significant variation in 2-year survival probabilities between Dutch melanoma centers existed. The use of new systemic therapies could partially explain this variation. In 2013 and between 2016 and 2017, no significant variation between centers existed. Show less
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.... Show moreBackground: 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. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Kooij, M.K. van der; Dekkers, O.M.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Boers-Sonderen, M.J.; Groot, J.W.B. de; ... ; Kapiteijn, E. 2021
Simple Summary Melanoma is a malignant form of skin cancer. The overall survival of patients with advanced stages of disease were initially low. Fortunately, in recent years systemic treatment with... Show moreSimple Summary Melanoma is a malignant form of skin cancer. The overall survival of patients with advanced stages of disease were initially low. Fortunately, in recent years systemic treatment with immunotherapy has prolonged survival. We set out to answer the question whether men and women with advanced melanoma differ in prognostic factors, tumor-response to immunotherapy, and treatment-related adverse events. All patients in the Netherlands were registered between July 2013 and July 2018. We showed that although clinical and tumor characteristics differ, the safety profile of immunotherapy is comparable. Furthermore, overall, a 10% survival advantage for women was seen. Following immunotherapy there was no survival difference. Recent meta-analyses show conflicting data on sex-dependent benefit following systemic treatment for advanced melanoma patients. We examined the nationwide Dutch Melanoma Treatment Registry (July 2013-July 2018), assessing sex-dependent differences in advanced melanoma patients (stage IIIC/IV) with respect to clinical characteristics, mutational profiles, treatments initiated, grade 3-4 adverse events (AEs), treatment responses, and mortality. We included 3985 patients, 2363 men (59%) and showed that although men and women with advanced melanoma differ in clinical and tumor characteristics, the safety profile of immune checkpoint inhibition (ICI) is comparable. The data suggest a 10% survival advantage for women, mainly seen in patients >= 60 years of age and patients with BRAF V600 mutant melanoma. Following ICI there was no survival difference. Show less
Glas, N.A. de; Bastiaannet, E.; Bos, F. van den; Mooijaart, S.P.; Veldt, A.A.M. van der; Suijkerbuijk, K.P.M.; ... ; Kapiteijn, E.W. 2021
Simple Summary: Trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included in these trials.... Show moreSimple Summary: Trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included in these trials. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma. We included 2216 patients aged >= 65 years from the Dutch Melanoma Treatment Registry and described outcomes of immunotherapy. The study showed that responses and severe side effects did not differ from previously reported younger populations and randomized trials, even in the oldest patients and in patients with other diseases. However, patients aged >= 75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. We therefore conclude that immunotherapy seems to have similar effects in older patients compared to younger patients, but the impact of less severe toxicity on quality of life should be further studied as older patients are more likely to discontinue treatment.Background: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma and to identify predictors of outcome. Methods: We included patients aged >= 65 years with metastatic melanoma from the Dutch Melanoma Treatment Registry. We described the reasons for hospital admissions and treatment discontinuation. Additionally, we assessed predictors of toxicity and response using logistic regression models and survival using Cox regression models. Results: We included 2216 patients. Grade >= 3 toxicity was not associated with age, comorbidities or WHO status. Patients aged >= 75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. Response rates were similar to previous trials (40.3% and 43.6% in patients aged 65-75 and >= 75, respectively, for anti-PD1 treatment) and did not decrease with age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity. Conclusion: Response rates and toxicity outcomes of checkpoint inhibitors did not change with increasing age or comorbidity. However, the impact of grade I-II toxicity on quality of life deserves further study as older patients discontinue treatment more frequently. Show less
Kooij, M.K. van der; Suijkerbuijk, K.P.M.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Blank, C.U.; Boers-Sonderen, M.J.; ... ; Kapiteijn, E. 2021
Background: Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been... Show moreBackground: 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. Show less
Verver, D.; Grunhagen, D.J.; Akkooi, A.C.J. van; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Eertwegh, A.J.M. van den; ... ; Veldt, A.A.M. van der 2021
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,... Show moreMelanoma 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. Show less
Mulder, E.E.A.P.; Joode, K. de; Litiere, S.; Tije, A.J. ten; Suijkerbuijk, K.P.M.; Boers-Sonderen, M.J.; ... ; Veldt, A.A.M. van der 2021
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.... Show moreBackground 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.MethodsThe 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 24months 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.DiscussionFrom 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 registrationThe 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. Show less
Biewenga, M.; Kooij, M.K. van der; Wouters, M.W.J.M.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Groot, J.W.B. de; ... ; Kapiteijn, E. 2021
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... Show moreBackground 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. Show less
Breeschoten, J. van; Wouters, M.W.J.M.; Wreede, L.C. de; Hilarius, D.H.; Haanen, J.B.; Blank, C.U.; ... ; Eertwegh, A.J.M. van den 2021
Objective: The aim of this study was to evaluate treatment patterns and overall survival (OS) of patients with BRAF(V600) wild-type and BRAF(V600)-mutant advanced melanoma in the Netherlands.... Show moreObjective: The aim of this study was to evaluate treatment patterns and overall survival (OS) of patients with BRAF(V600) wild-type and BRAF(V600)-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 BRAF(V600)-mutation status with OS we used the Cox proportional-hazards model. Results: A total of 642 BRAF(V600) 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 BRAF(V600) wild-type patients compared with BRAF(V600)-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, BRAF(V600) 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, BRAF(V600)-mutant patients had started with second-line systemic treatment more often compared with BRAF(V600) wild-type patients (50% vs. 19%). Conclusion: These results suggest that advanced BRAF(V600) wild-type melanoma patients have worse survival than BRAF(V600)-mutated patients during the first 10 months after diagnosis because of less available treatment options. Show less
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... Show moreBackground: 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. (C) 2020 Elsevier Ltd. All rights reserved. Show less
Ismail, R.K.; Sikkes, N.O.; Wouters, M.W.J.M.; Hilarius, D.L.; Pasmooij, A.M.G.; Eertwegh, A.J.M. van den; ... ; Boer, A. de 2021
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... Show morePostapproval 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 (c) 2020 The Author(s). Published by Wolters Kluwer Health, Inc. Show less
Breeschoten, J. van; Wouters, M.W.J.M.; Hilarius, D.L.; Haanen, J.B.; Blank, C.U.; Aarts, M.J.B.; ... ; Eertwegh, A.J.M. van den 2021
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... Show moreBackground 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 85.4% (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. Show less
