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Objective: Immune checkpoint inhibitors (ICIs) are revolutionary in oncology but may cause immune-related (IR) side effects, such as hypophysitis. Treatment with anti-PD-(L)1, anti-CTLA-4 or anti-CLTA-4/PD-1 may induce hypophysitis, but little is known about the differences in clinical presentation or need for different treatment. We analyzed the differences of anti-PD-(L)1, anti-CTLA-4 and anti-CTLA-4/PD-1 induced hypophysitis., Methods: retrospective analysis of 67 patients (27 anti-PD-(L)1, 6 anti-CLTA-4 and 34 anti-CTLA-4/PD-1 induced hypophysitis)., Results: The median time between starting ICIs and IR-hypophysitis was longer after anti-PD(L)-1) therapy (22 weeks versus 11 and 14 weeks after anti-CTLA-4 and anti-CTLA-4/PD-1 therapy, respectively). The majority of patients (>90%), presented with atypical complaints such as fatigue, nausea, and muscle complaints. Headache, TSH or LH/FSH deficiency were more common in anti-CTLA-4 and anti-CLTA-4/PD-1 versus anti-PD-(L)1 induced hypophysitis (83% and 58% versus 8%, 67% and 41% versus 11%, and 83% and 48% versus 7%, respectively). Pituitary abnormalities on MRI (hypophysitis or secondary empty sella syndrome) were only seen in patients receiving anti-CTLA-4 or anti-CTLA-4/PD-1 therapy. Recovery from TSH, LH/FSH and ACTH deficiency was described in 92%, 70% and 0% of patients after a mean period of 14 and 104 days, respectively, and did not differ between patients who did or did not receive high-dose steroids., Conclusion: The clinical presentation of IR-hypophysitis varies depending on the type of ICIs. MRI abnormalities were only seen in anti-CTLA-4 or anti-CTLA-4/PD-1 induced hypophysitis. Endocrine recovery is seen for LH/FSH and TSH deficiency but not for ACTH deficiency, irrespective of the corticosteroid dose., Competing Interests: KS has consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre Novartis, Sairopa, received honoraria from Novartis, Roche, Merck Sharp and Dome and received research funding from TigaTx, Bristol Myers Squibb and Philips. HS has received research funding from Pfizer Quality Improvement Grant and travel plus accommodation costs for an international meeting from Rhythm Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 van der Leij, Suijkerbuijk, van den Broek, Valk, Dankbaar and van Santen.)

PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients., (© 2024. The Author(s).)

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 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., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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. 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., Methods: The 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 24 months 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., Discussion: From 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 Registration: The 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.

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 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 65.4% (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.

The efficacy of anti-programmed death-1 (PD-1) monotherapy for advanced melanoma has been established, but it is unknown to what extent patients benefit in the real world. In this observational study with nationwide population-based data from the Dutch Melanoma Treatment Registry, we analyzed real-world outcomes of first-line anti-PD-1 monotherapy in advanced melanoma patients diagnosed in 2015 to 2016. Overall survival (OS) was estimated with the Kaplan-Meier method. Competing risks analysis was used to estimate probabilities for second-line treatment, with death as competing risk. With a Cox model, the association of factors with OS was estimated. Patients who received anti-PD-1 monotherapy (n=550) had a median age of 65 years and 502 (95%) patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, 383 (70%) had normal lactate dehydrogenase (LDH), 370 (67%) had stage IV-M1c disease, and in 441 (81%), brain metastases were absent. The median OS was 24 months [95% confidence interval (CI): 20-30 mo]. The median OS of patients normally eligible for phase III trial participation was 31 months (95% CI: 23-not estimable). The BRAF mutation was associated with superior OS. ECOG PS of ≥1, symptomatic brain metastases, and liver metastases were associated with inferior OS and, together with elevated LDH, with death before second-line treatment. Patients with a complete response had a 2-year OS probability from first reported complete response of 92% (95% CI: 86%-99%). Real-world advanced melanoma patients in the Netherlands have benefitted from anti-PD-1 monotherapy. ECOG PS ≥1, symptomatic brain metastasis, liver metastasis, and elevated LDH are important prognostic factors for survival. The additional information that this study provides could help to improve more effective use in the real world.