Thyroid-Like Ophthalmopathy in a Euthyroid Patient Receiving Ipilimumab

Abstract

A 68-year-old lady with metastatic malignant melanoma was treated with Ipilimumab. She presented to Eye Casualty unable to move her eyes. Physical examination confirmed ophthalmoplegia and identified proptosis bilaterally. Radiological imaging showed bilateral enlargement of all the extra-ocular muscles suggestive of thyroid eye disease. Laboratory investigations found this patient to be euthyroid. A diagnosis of thyroid-like orbitopathy secondary to Ipilimumab therapy was made. Thyroid function tests should be performed for all patients prior to their commencement of Ipilimumab. Thyroid-like eye disease may develop in patients treated with Ipilimumab even if they remain euthyroid.     

The proportion of circulating CD45RO+CD8+ memory T cells is correlated with clinical response in melanoma patients treated with ipilimumab

BackgroundImmune checkpoint blockade (ICB) has been a breakthrough in the treatment of metastatic melanoma. But with only about 20–40% long-term responders and severe side-effects in about 12–17%, finding predictive markers for treatment response is of great interest.MethodsWe prospectively assessed clinical data, haematologic parameters and freshly isolated peripheral blood mononuclear cells of 30 patients treated with ipilimumab (n = 21) and pembrolizumab (n = 9) prior to the first 4 cycles with ICB and before the first tumour assessment.ResultsWe discovered that the baseline levels of CD45RO⁺CD8⁺ T cells significantly differed among the patients. Thirteen (43%) of our patients had normal baseline levels of CD45RO⁺CD8⁺ T cells, whereas 17 (57%) patients were low on CD45RO⁺CD8⁺ T cells. The baseline levels of CD45RO⁺CD8⁺ T cells correlated significantly with the response to ipilimumab but not pembrolizumab. Patients with baseline levels of lower/equal 25% of CD45RO⁺CD8⁺ T cells did not respond to treatment with ipilimumab. Phenotyping the CD8⁺ T cells in patients treated with ipilimumab revealed an activated HLA-DR⁺CD25⁻ phenotype, implying antigen non-specific stimulation. The levels of the HLA-DR⁺CD25⁻CD8⁺ T cells were significantly higher in patients with a normal baseline of CD45RO⁺CD8⁺ T cells and even increased significantly during treatment. Furthermore, proliferation of melanoma antigen recognized by T cells 1 (MART-1)-specific CD8⁺ T cells was not observed. Patients with normal baseline levels of CD45RO⁺CD8⁺ T cells showed a significant longer overall survival when treated with ipilimumab but not pembrolizumab.ConclusionPatients with normal baseline levels of CD45RO⁺CD8⁺ T cells respond significantly more frequently to treatment with ipilimumab and the CD8⁺ T cells appear to be antigen non-specifically activated. The baseline level of CD45RO⁺CD8⁺ T cells represents a promising factor as biomarker for the prediction of the response to ipilimumab.     

The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients

The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C–IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node–positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.     

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma

BackgroundThe anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy.Patients and methodsA multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed.ResultsIn total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively.ConclusionsIpilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients.     

Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: Analysis of 60 Japanese patients

Background

Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching.

Adjuvant ipilimumab in stage III melanoma: New landscape,new questions

The recently reported significant prolongation of overall survival with ipilimumab as adjuvant in high-risk stage III melanoma patients represents an important event in the adjuvant treatment landscape. The European Organisation for Research and Treatment of Cancer 18071 trial demonstrated a 28% reduction in risk of death in patients treated with ipilimumab at 10 mg/kg (hazard ratio for death, 0.72; 95.1% CI, 0.58−0.88; P = 0.001) compared with placebo. All end-points—recurrence-free survival (RFS), distant-metastasis-free survival (DMFS) and overall survival (OS)—showed similar benefits. Survival rates at 5 years in ipilimumab-treated patients were OS 11%, DMFS 9% and RFS 11% higher than in placebo-treated patients. Global Health quality-of-life scores were not significantly different between treatment arms, in spite of significant adverse event rates that resulted in only 42% of patients receiving more than four doses of ipilimumab and only 28.9% of patients going beyond 1 year of treatment. Grades 3–4 immune-related adverse events occurred in 41.6% of ipilimumab-treated patients and in 2.7% of placebo-treated patients. One can speculate on dose and duration of treatment, as well as on the requirement for complete lymph-node dissection in sentinel-node-positive patients. The remaining role of interferons will be discussed regarding differences in sensitivity profiles—such as in ulcerated melanoma versus non-ulcerated melanoma—and access to new drugs. Ongoing trials with targeted agents and with anti programmed cell death protein 1 (anti-PD-1) agents may bring significant additional results in the next few years that will redefine how we treat stage III patients. Overall, pricing of new treatments will determine access and whether patients will actually benefit from new treatment options.     

Health-related quality of life results from the phase III CheckMate 067 study

BackgroundNivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067.Patients and methodsHRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated.ResultsNivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause.ConclusionThese results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.Study numberNCT01844505.