Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.
Abstract Purpose: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown. Methods: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined. Results: Forty-seven patients were identified from 12 centres. The response rate to [...]
Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma.
Abstract Purpose: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes. Patients and methods: Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary [...]
Multi-trait genetic analysis identifies auto-immune loci associated with cutaneous melanoma.
Abstract Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be [...]
Antitumor Activity of Ipilimumab or BRAF ± MEK Inhibition After Pembrolizumab in Patients With Advanced Melanoma: Analysis from KEYNOTE-006.
Abstract Background: Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized. Patients and methods: In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled. Results: At data cut-off (4 December 2017), median follow-up was 46.9 [...]
Acute bilateral phrenic nerve neuropathy causing hypercapnic respiratory associated with checkpoint inhibitor immunotherapy.
Abstract We present two cases of acute hypercapnic respiratory failure due to diaphragmatic dysfunction secondary to bilateral phrenic nerve paralysis, in patients who were receiving immunotherapy for melanoma. Bilateral diaphragmatic paralysis is an uncommon cause of acute or sub-acute hypercapnic respiratory failure which causes severe breathlessness, orthopnoea and potentially death. Immune checkpoint inhibitors are now standard of care in several solid organ malignancies. However, their use is associated with a risk of developing autoimmune toxicities, which includes mononeuritis. Our two cases demonstrate the potential difficulties in recognising acute hypercapnic respiratory failure and diagnosis of the rare disorder of bilateral [...]
Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition – A Descriptive Observational Retrospective Multicenter Analysis.
Abstract Introduction: Immune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia. Methods: This multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, [...]
High-Dimensional Single-Cell Transcriptomics in Melanoma and Cancer Immunotherapy
Abstract Recent advances in single-cell transcriptomics have greatly improved knowledge of complex transcriptional programs, rapidly expanding our knowledge of cellular phenotypes and functions within the tumour microenvironment and immune system. Several new single-cell technologies have been developed over recent years that have enabled expanded understanding of the mechanistic cells and biological pathways targeted by immunotherapies such as immune checkpoint inhibitors, which are now routinely used in patient management with high-risk early-stage or advanced melanoma. These technologies have method-specific strengths, weaknesses and capabilities which need to be considered when utilising them to answer translational research questions. Here, we provide guidance [...]
Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy
Abstract Background: Immune checkpoint inhibitors (ICIs) are approved to treat multiple cancers. Retrospective analyses demonstrate acceptable safety of ICIs in most patients with autoimmune disease, although disease exacerbation may occur. Psoriasis vulgaris is a common, immune-mediated disease, and outcomes of ICI treatment in patients with psoriasis are not well described. Thus we sought to define the safety profile and effectiveness of ICIs in patients with pre-existing psoriasis. Methods: In this retrospective cohort study, patients from eight academic centers with pre-existing psoriasis who received ICI treatment for cancer were evaluated. Main safety outcomes were psoriasis exacerbation and immune-related adverse events (irAEs). We [...]
Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006.
Abstract Objective: Patients with melanoma and early stable disease (SD) with pembrolizumab have unclear prognosis. We present post hoc analyses of long-term outcomes for patients with early SD, partial response (PR) or complete response (CR) with pembrolizumab. Patients and methods: Patients who received pembrolizumab in the KEYNOTE-001 and KEYNOTE-006 studies and had SD, PR or CR at weeks 12 or 24 were included. Results: Of 294 patients in the week 12 analysis, 107 (36.4%) had SD at week 12, of whom 7 (6.5%) had a best overall response of CR, 43 (40.2%) had PR and 57 (53.3%) had SD. Forty-eight-month overall survival [...]
Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy.
Abstract Background: Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events (irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients. Methods: Institutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab. Results: Twenty-two patients were identified. Two were [...]