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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/).

Checkpoint inhibition has emerged as a promising therapeutic strategy for several types of cancer. Immune-related adverse effects (irAEs) commonly involve the endocrine system. Distinguishing endocrine side effect-related symptoms from disease progression or treatment-related toxicity can be challenging. If not recognized in time, endocrine irAEs may be life-threatening. As the use of checkpoint inhibitors is expected to increase, there is a need for more awareness of endocrine irAEs amongst health care professionals. We describe three cases that illustrate the importance of timely recognition, patient education and the management of endocrinopathies. Two patients who were treated with the checkpoint inhibitor ipilimumab developed hypophysitis and subsequent episodes of hypocortisolism. These cases underline both the frequency of diagnostic delay and the importance of patient education with regard to glucocorticoid stress dosage. The third patient presented with diabetes mellitus after administration of nivolumab. A multidisciplinary approach is warranted to ensure optimal care for patients with endocrine irAEs.

In the original publication of the article the following abstract and keywords were inadvertently omitted. Abstract Background In this study the toxicity and efficacy of an irradiated autologous tumor cell vaccine (ATV) co-injected with a class-B CpG oligodeoxynucleotide (CpG-B) and GMCSF, followed by systemic CpG-B and IFN-α administration, were examined in patients with metastatic renal cell carcinoma (mRCC). Methods A single-arm Phase II trial was conducted, in which patients with mRCC were intradermally injected with a minimum of three whole-cell vaccines containing 0.7–1.3 × 107 irradiated autologous tumor cells (ATC), admixed with 1 mg CpG-B and 100 μg GM-CSF, followed by bi-weekly s.c. injections with 8 mg CpG-B and s.c. injections with 6 MU IFN-α three times per week. Results Fifteen patients were treated according to the protocol. Treatment was well tolerated. Objective clinical responses occurred in three patients, including one longterm complete response. Disease stabilization occurred in another three patients. Positive delayed type hypersensitivity (DTH) responses to ATC were absent before treatment but present in 13 out of 15 patients during treatment. Immune monitoring revealed activation of plasmacytoid dendritic cells, non-classical monocytes and up-regulation of both PD-1 and CTLA4 on effector T cells upon treatment. Moreover, a pre-existing ex vivo IFN-γ response to ATC was associated with clinical response. Conclusions ATV combined with systemic CpG-B and IFN-α is tolerable, safe, immunogenic and able to elicit antitumor responses in patients with mRCC. Immune activation and treatment-induced up-regulation of PD-1 and CTLA4 on circulating T cells further suggest an added benefit of combining this approach with immune checkpoint blockade. Keywords Autologous tumor cell vaccination · CpG-B · IFN-alpha · GM-CSF · Metastatic renal cell cancer.

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.

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.

BACKGROUND. Abiraterone Acetate (AA) and Enzalutamide (Enz) are effective hormonal treatments in mCRPC patients. Retrospective studies suggested clinical cross-resistance between Enz and AA. However, 12.8-39.1% of patients previously treated with docetaxel (Doc) and AA do respond to Enz. These responders have not been characterized. METHODS. 102 Enz treated mCRPC patients after AA and Doc treatment were included in this study. Differences in patient characteristics and previous treatment outcomes between PSA responders and non-responders on Enz were evaluated. RESULTS. Median Progression-Free Survival was 12.2 weeks (95% CI 11.7-14.3) and Overall Survival 43.5 weeks (95% CI 37.4-61.2). There were 26 (25%) Enz-responders and 76 (75%) non-responders. Significant higher percentages of Gleason scores >= 8 and PSA doubling times (PSA-DT) = 40 (68 patients) revealed significant differences in baseline PSA levels, PSA-DT = 8 and IAE's between Enz responders and non-responders. CONCLUSIONS. PSA response to Enz after previous AA and Doc treatment was associated with a longer IAE, a higher Gleason score and a PSA-DT