Characterization of the treatment-naive immune microenvironment in melanoma with BRAF mutation
Abstract Background: Patients with BRAF-mutant and wild-type melanoma have different response rates to immune checkpoint blockade therapy. However, the reasons for this remain unknown. To address this issue, we investigated the precise immune composition resulting from BRAF mutation in treatment-naive melanoma to determine whether this may be a driver for different response to immunotherapy. Methods: In this study, we characterized the treatment-naive immune context in patients with BRAF-mutant and BRAF wild-type (BRAF-wt) melanoma using data from single-cell RNA sequencing, bulk RNA sequencing, flow cytometry and immunohistochemistry (IHC). Results: In single-cell data, BRAF-mutant melanoma displayed a significantly reduced infiltration of CD8+ T cells and macrophages but also increased B cells, natural [...]
Combined immunotherapy with nivolumab and ipilimumab with and without sequential or concomitant stereotactic radiotherapy in patients with melanoma brain metastasis: An international retrospective study.
Abstract Background: Ipilimumab plus nivolumab (COMBO) is the standard treatment in patients with asymptomatic melanoma brain metastases (MBM). We report a retrospective study aiming to assess the outcome of patients with MBM treated with COMBO with or without sequential/concomitant stereotactic radiotherapy (SRT). Methods: MBM patients treated with COMBO with or without SRT have been retrieved: demographics, steroid treatment, Central Nervous System [CNS]-related symptoms, BRAF status, radiotherapy (yes/no and timing) or surgery, number of MBM, maximum diameter of metastasis, overall response rate (ORR), progression-free (PFS) and overall survival (OS) have been analyzed. Results: 453 patients were included: 190 received [...]
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 [...]
Nivolumab plus relatlimab in advanced melanoma: RELATIVITY-047 4-year update.
Abstract Background: In phase 2/3 randomized RELATIVITY-047, nivolumab plus relatlimab demonstrated a statistically significant improvement in progression-free survival (PFS), a clinically meaningful but not statistically significant improvement in overall survival (OS), and a numerically higher objective response rate (ORR) versus nivolumab alone in patients with previously untreated advanced melanoma. Methods: Descriptive 4-year updated analyses in patients treated with nivolumab 480 mg plus relatlimab 160 mg fixed-dose combination versus nivolumab 480 mg intravenously every 4 weeks are presented. Primary endpoint was PFS by blinded independent central review (BICR). Other endpoints included melanoma-specific survival (MSS). Results: At 45.3 months' minimum follow-up, nivolumab plus relatlimab [...]
Do BRAF-targeted therapies have a role in the era of immunotherapy?
Abstract Over half of cutaneous melanomas have BRAF mutations, with this mutation being more prevalent in younger patients who often present with more aggressive disease. BRAF-targeted therapy and checkpoint inhibitor immunotherapy have led to marked improvements in outcomes for patients with BRAF-mutant melanoma. Despite these advances, novel combinatorial strategies are vital given that more than half of advanced melanoma patients will still die due to melanoma. Translational evidence has suggested potential immunostimulatory effects of BRAF-targeted therapies, yet their combination with immunotherapy has shown limited clinical success. The pathways that lead to acquired resistance to targeted therapy, which may confer [...]
Federated deep learning enables cancer subtyping by proteomics.
Abstract Artificial intelligence applications in biomedicine face major challenges from data privacy requirements. To address this issue for clinically annotated tissue proteomic data, we developed a Federated Deep Learning (FDL) approach (ProCanFDL), training local models on simulated sites containing data from a pan-cancer cohort (n=1,260) and 29 cohorts held behind private firewalls (n=6,265), representing 19,930 replicate data-independent acquisition mass spectrometry (DIA-MS) runs. Local parameter updates were aggregated to build the global model, achieving a 43% performance gain on the hold-out test set (n=625) in 14 cancer subtyping tasks compared to local models, and matching centralized model performance. The approach's [...]
Patient-reported outcomes with adjuvant nivolumab versus placebo after complete resection of stage IIB/C melanoma in the randomized phase 3 CheckMate 76 K trial.
Abstract Background: In the phase 3 CheckMate 76 K trial, adjuvant nivolumab significantly improved recurrence-free survival and distant metastasis-free survival versus placebo in patients with resected stage IIB/C melanoma. We report patient-reported outcomes from CheckMate 76 K. Methods: Change from baseline to week 53 in health-related quality of life (HRQoL), as measured using the EORTC QLQ-C30 and EQ-5D-5L utility index and visual analog scale (VAS), was compared between treatment groups using linear mixed-effect models. Time to confirmed deterioration (TTCD) in HRQoL was assessed using Cox regression. Bother from side effects, as measured by the FACIT-GP5, was descriptively compared between treatment groups. [...]