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Item does not contain fulltext 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.

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 tar-geted therapy between 2015 and 2021 were included from the prospective nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and melanoma-specific sur-vival (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 mono -therapy (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 pa-tients, 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.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.(c) 2023 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/).

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BACKGROUND: 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.PATIENTS AND METHODS: 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.RESULTS: 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 17.3 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 CONCLUSION: 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.

Additional file 1.

Since the publication of this paper, the authors have noticed an error in the Abstract where the value for the 2-year overall survival

Doel Evaluatie van de behandelstrategieën en overleving van patiënten met irresectabel melanoom stadium IIIc of IV sinds de introductie van nieuwe geneesmiddelen in 2012 in Nederland. Opzet Prospectieve cohortstudie. Methode Wij analyseerden gegevens uit de Dutch Melanoma Treatment Registry (DMTR) van patiënten die in de periode 1 juli 2012-31 december 2015 waren gediagnosticeerd met irresectabel melanoom stadium IIIc of IV. We schatten de overlevingsduur met de Kaplan-Meier-methode. De relatie tussen jaar van diagnose en overleving werd geschat met Cox-regressieanalyse, gecorrigeerd voor leeftijd, ‘WHO performance status’, lactaatdehydrogenasewaarde, tumorstadium, hersenmetastasen en afstandsmetastasen. Resultaten Van de geregistreerde 2768 patiënten kreeg ongeveer driekwart systemische therapie; deze behandeling was elk jaar aan verandering onderhevig. De mediane overlevingsduur was 10,7 maanden (95%-BI: 9,6-13,2) in 2012 en 13,8 maanden (95%-BI: 11,8-15,6) in 2015; de mediane overlevingsduur voor systemisch behandelde patiënten was 17,1 maanden in 2015. De 2- jaarsoverleving nam in deze periode toe van 23 tot 40%. Patiënten gediagnosticeerd in 2015 hadden een betere overleving dan patiënten uit 2014 (hazardratio (HR): 0,82; 95%-BI: 0,73-0,93). Dit effect gold ook voor patiënten die werden behandeld met systemische therapie (HR: 0,79; 95%-BI: 0,69-0,91). Conclusie De snelle beschikbaarheid van nieuwe geneesmiddelen, die door de toenmalige minister van VWS en de beroepsgroep is geïnitieerd, heeft de behandeling van patiënten met irresectabel melanoom stadium IIIc of IV ingrijpend veranderd. De gegevens uit de DMTR duiden op een veilig gebruik van deze nieuwe geneesmiddelen in de dagelijkse praktijk en een verbetering van de overleving van patiënten met gevorderd melanoom in de afgelopen jaren.

Doel Evaluatie van de behandelstrategieën en overleving van patiënten met irresectabel melanoom stadium IIIc of IV sinds de introductie van nieuwe geneesmiddelen in 2012 in Nederland. Opzet Prospectieve cohortstudie. Methode Wij analyseerden gegevens uit de Dutch Melanoma Treatment Registry (DMTR) van patiënten die in de periode 1 juli 2012-31 december 2015 waren gediagnosticeerd met irresectabel melanoom stadium IIIc of IV. We schatten de overlevingsduur met de Kaplan-Meier-methode. De relatie tussen jaar van diagnose en overleving werd geschat met Cox-regressieanalyse, gecorrigeerd voor leeftijd, ‘WHO performance status’, lactaatdehydrogenasewaarde, tumorstadium, hersenmetastasen en afstandsmetastasen. Resultaten Van de geregistreerde 2768 patiënten kreeg ongeveer driekwart systemische therapie; deze behandeling was elk jaar aan verandering onderhevig. De mediane overlevingsduur was 10,7 maanden (95%-BI: 9,6-13,2) in 2012 en 13,8 maanden (95%-BI: 11,8-15,6) in 2015; de mediane overlevingsduur voor systemisch behandelde patiënten was 17,1 maanden in 2015. De 2- jaarsoverleving nam in deze periode toe van 23 tot 40%. Patiënten gediagnosticeerd in 2015 hadden een betere overleving dan patiënten uit 2014 (hazardratio (HR): 0,82; 95%-BI: 0,73-0,93). Dit effect gold ook voor patiënten die werden behandeld met systemische therapie (HR: 0,79; 95%-BI: 0,69-0,91). Conclusie De snelle beschikbaarheid van nieuwe geneesmiddelen, die door de toenmalige minister van VWS en de beroepsgroep is geïnitieerd, heeft de behandeling van patiënten met irresectabel melanoom stadium IIIc of IV ingrijpend veranderd. De gegevens uit de DMTR duiden op een veilig gebruik van deze nieuwe geneesmiddelen in de dagelijkse praktijk en een verbetering van de overleving van patiënten met gevorderd melanoom in de afgelopen jaren.

Background The effect of extended adjuvant aromatase inhibition in hormone receptor-positive breast cancer after sequential endocrine therapy of tamoxifen followed by an aromatase inhibitor for a 5-year treatment period still needs clarification. To address this issue, we began the DATA study to assess different durations of anastrozole therapy after tamoxifen. Methods DATA was a prospective, randomised, open-label, multicentre, phase 3 study done in 79 hospitals in the Netherlands. We randomly assigned postmenopausal women with hormone receptor-positive early breast cancer with no signs of disease recurrence after 2–3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole treatment (1 mg orally once a day) in a 1:1 ratio. We used TENALEA (Trans European Network for Clinical Trials Services) for the randomisation procedure. Stratification factors were nodal status, hormone receptor status, HER2 status, and tamoxifen treatment duration. The primary study endpoint of this analysis was disease-free survival starting beyond 3 years after randomisation (adapted disease-free survival). Here we report the final analysis from the DATA trial, which is registered with ClinicalTrials.gov, number NCT00301457. Findings Between June 28, 2006, and Aug 10, 2009, we screened 1912 patients of whom 955 were assigned to the 3-year group and 957 to the 6-year anastrozole treatment group. 1860 patients were eligible (931 in the 6-year group and 929 in the 3-year group) and 1660 were disease free 3 years after randomisation. The 5-year adapted disease-free survival was 83·1% (95% CI 80·0–86·3) in the 6-year group and 79·4% (76·1–82·8) in the 3-year group (hazard ratio [HR] 0·79 [95% CI 0·62–1·02]; p=0·066). Patients in the 6-year treatment group had more adverse events than those in the 3-year treatment group, including all-grade arthralgia or myalgia (478 [58%] of 827 in the 6-year treatment group vs 438 [53%] of 833 in the 3-year treatment group) and osteopenia or osteoporosis (173 [21%] vs 137 [16%]). Interpretation We cannot recommend the use of extended adjuvant aromatase inhibition after 5 years of sequential endocrine therapy in all postmenopausal women with hormone receptor-positive breast cancer. Funding AstraZeneca.

In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3′-deoxy-3’L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.

Background: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. Methods: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. Discussion: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. Trial registration:Clinicaltrials.govidentifier: NCT02414750. Registered 10 April 2015, retrospectively registered.