Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab - study protocol.

BACKGROUND: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. METHODS: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. DISCUSSION: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.

The meaning of screening: detection of brain metastasis in the adjuvant setting for stage III melanoma.

BACKGROUND: The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is considered in patients with completely resected stage III melanoma before the start of adjuvant treatment. The aim of this study was to assess the yield of screening for BM in these patients. MATERIALS AND METHODS: A single-center cohort study was carried out in the Erasmus MC, Rotterdam, The Netherlands, a large tertiary referral center for patients with melanoma. Eligible patients with complete resection of stage III melanoma and a screening MRI of the brain, made within 12 weeks after resection and before adjuvant treatment (programmed cell death protein 1 inhibitors, dabrafenib-trametinib), available between 1 August 2018 and 1 January 2021, were included. RESULTS: A total of 202 patients were included. Eighteen (8.9%) of 202 patients had extracranial metastasis at screening. Two (1.1%) of the remaining 184 patients had BM at screening, resulting in a switch from adjuvant treatment to ipilimumab-nivolumab. At a median follow-up of 21.2 months, BM was detected in another 4 (2.4%) of 166 patients who started with adjuvant treatment. CONCLUSIONS: The yield of screening MRI of the brain is low after complete resection of stage III melanoma, before the start of adjuvant treatment. Therefore, routine screening MRI is not recommended in this setting.

Cost-effectiveness of adjuvant systemic therapies for patients with high-risk melanoma in Europe: a model-based economic evaluation.

BACKGROUND: The introduction of adjuvant systemic treatment has significantly improved recurrence-free survival in patients with resectable high-risk melanoma. Adjuvant treatment with immune checkpoint inhibitors and targeted therapy, however, substantially impacts health care budgets, while the number of patients with melanoma who are treated in the adjuvant setting is still increasing. To evaluate the socioeconomic impact of the three adjuvant treatments, a cost-effectiveness analysis (CEA) was carried out. MATERIALS AND METHODS: Data were obtained from the three pivotal registration phase III clinical trials on the adjuvant treatment of patients with resected high-risk stage III in melanoma (KEYNOTE-054, CheckMate 238, and COMBI-AD). For this CEA, a Markov model with three health states (no evidence of disease, recurrent/progressive disease, and death) was applied. From a societal perspective, different adjuvant strategies were compared according to total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. To evaluate model uncertainty, sensitivity analyses (deterministic and probabilistic) were carried out. RESULTS: In the adjuvant setting, total costs (per patient) were €168 826 for nivolumab, €194 529 for pembrolizumab, and €211 110 for dabrafenib-trametinib. These costs were mainly determined by drug acquisition costs, whereas routine surveillance costs varied from €126 096 to €134 945. Compared with routine surveillance, LYs improved by approximately 1.41 for all therapies and QALYs improved by 2.02 for immune checkpoint inhibitors and 2.03 for targeted therapy. This resulted in incremental cost-effectiveness ratios of €21 153 (nivolumab), €33 878 (pembrolizumab), and €37 520 (dabrafenib-trametinib) per QALY gained. CONCLUSIONS: This CEA compared the three EMA-approved adjuvant systemic therapies for resected stage III melanoma. Adjuvant treatment with nivolumab was the most cost-effective, followed by pembrolizumab. Combination therapy with dabrafenib-trametinib was the least cost-effective. With the increasing number of patients with high-risk melanoma who will be treated with adjuvant treatment, there is an urgent need to reduce drug costs while developing better prognostic and predictive tools to identify patients who will benefit from adjuvant treatment.

Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial.

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.

Validation of a clinicopathological and gene expression profile model for sentinel lymph node metastasis in primary cutaneous melanoma.

BACKGROUND: The Clinicopathological and Gene Expression Profile (CP-GEP) model was developed to accurately identify patients with T1-T3 primary cutaneous melanoma at low risk for nodal metastasis. OBJECTIVES: To validate the CP-GEP model in an independent Dutch cohort of patients with melanoma. METHODS: Patients (aged ≥ 18 years) with primary cutaneous melanoma who underwent sentinel lymph node biopsy (SLNB) between 2007 and 2017 at the Erasmus Medical Centre Cancer Institute were eligible. The CP-GEP model combines clinicopathological features (age and Breslow thickness) with the expression of eight target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, CXCL8 and MLANA). Using the pathology result of SLNB as the gold standard, performance measures of the CP-GEP model were calculated, resulting in CP-GEP high risk or low risk for nodal metastasis. RESULTS: In total, 210 patients were included in the study. Most patients presented with T2 (n = 94, 45%) or T3 (n = 70, 33%) melanoma. Of all patients, 27% (n = 56) had a positive SLNB, with nodal metastasis in 0%, 30%, 54% and 16% of patients with T1, T2, T3 and T4 melanoma, respectively. Overall, the CP-GEP model had a negative predictive value (NPV) of 90·5% [95% confidence interval (CI) 77·9-96.2], with an NPV of 100% (95% CI 72·2-100) in T1, 89·3% (95% CI 72·8-96·3) in T2 and 75·0% (95% CI 30·1-95·4) in T3 melanomas. The CP-GEP indicated high risk in all T4 melanomas. CONCLUSIONS: The CP-GEP model is a noninvasive and validated tool that accurately identified patients with primary cutaneous melanoma at low risk for nodal metastasis. In this validation cohort, the CP-GEP model has shown the potential to reduce SLNB procedures in patients with melanoma.