Hyperglycemia in patients treated with immune checkpoint inhibitors: key clinical challenges and multidisciplinary consensus recommendations.
Abstract Immune checkpoint inhibitors (ICIs) have an expanding role in the management of numerous cancers. Hyperglycaemia is commonly seen in patients treated with ICIs. However, the differential diagnosis for hyperglycaemia is broad, and incorrect diagnosis can have serious consequences. Herein we review the available literature on causes of hyperglycaemia in ICI treated patients and expert guidelines on management and provide an updated synthesis of expert multidisciplinary recommendations. Our key recommendations are as follows: Intensity of screening for hyperglycaemia should be based on a patient's risk level, including assessment of factors such as corticosteroid use, pre-existing diabetes, baseline HbA1c and [...]
Immune Checkpoint Inhibitors for Patients With Preexisting Autoimmune Neurologic Disorders.
Abstract Importance: Immune checkpoint inhibitors (ICIs) are efficacious in many cancer types but can produce immune-related adverse events (irAEs). As such, patients with preexisting autoimmune disorders are often excluded from clinical trials, although subsequent studies have shown that many of these patients have acceptable ICI tolerance. The safety and efficacy of ICIs among patients with preexisting neurologic autoimmune disorders (NAIDs) is not well characterized. Objective: To evaluate the safety and clinical outcomes associated with ICI therapy among patients with NAIDs. Design, setting, and participants: This multicenter retrospective cohort study included patients with cancer who were treated with ICIs between October 2013 and [...]
Efficacy of adjuvant therapy in patients with stage IIIA cutaneous melanoma.
Abstract Background: Patients with resected American Joint Committee on Cancer eighth edition (AJCC v8) stage IIIA melanoma have been underrepresented in clinical trials of adjuvant drug therapy. The benefit of adjuvant targeted therapy and immunotherapy in this population is unclear. Patients and methods: In this multicentre, retrospective study, patients with stage IIIA melanoma (AJCC v8) who received adjuvant pembrolizumab or nivolumab [anti-programmed cell death protein 1 (PD-1)], BRAF/MEK-targeted therapy dabrafenib + trametinib (TT) or no adjuvant treatment [observation (OBS)] were included. Recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and toxicity rates were examined. Results: A total of 628 patients from 34 centres [...]
Prognostic and predictive value of gastric acid suppressants in the EORTC 1325/KEYNOTE-054 randomized phase III trial of pembrolizumab vs placebo in resected stage III melanoma.
Abstract Background The gut microbiome plays a pivotal role in regulating immunity. Gastric acid suppressants (GAS) are known to alter the gut microbiome and might therefore modify response to immunotherapy in cancer patients. We estimated associations of GAS with recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in the EORTC 1325/KEYNOTE-054 trial. Methods Patients with resected stage III melanoma were randomized to receive 200 mg of pembrolizumab or placebo. Pembrolizumab prolonged RFS and DMFS (reported elsewhere). We used Cox models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between GAS at baseline, and RFS and [...]
Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Long-term follow-up, crossover, and rechallenge with pembrolizumab in the phase III KEYNOTE-716 study.
Abstract Background: Adjuvant pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB/IIC melanoma in KEYNOTE-716. Results of a post hoc 4-year analysis are reported, including progression/recurrence-free survival 2 (PRFS2). Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks (part 1). RFS was the primary end point; DMFS was secondary. Patients with recurrence following placebo or 17 cycles of pembrolizumab could cross over to or be rechallenged with pembrolizumab (part 2). Results: Median follow-up (n = 976) was 52.8 months (range, 39.4-64.8). RFS (HR, 0.62 [95 % CI, 0.50-0.78]) [...]
Characterizing Chronic Cutaneous Immune-Related Adverse Events Following Immune Checkpoint Inhibitors.
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Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma.
Abstract Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront [...]
Clinical outcomes and management following progressive disease with anti-PD-(L)1 therapy in patients with advanced Merkel Cell Carcinoma.
Abstract Aim: Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management. Method: This is a multi-centre international retrospective cohort study with data collected up to May 2023 from 17 centres across 6 countries. Outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy. Results: One-hundred and eighty-five advanced MCC patients received anti-PD-(L)1 therapy. At median [...]
Prognostic and predictive value of metformin in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma.
Abstract Background: Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial. Methods: Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months [...]
Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance.
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