Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial
Abstract Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial assessed 790 patients with resected stage IIB/C melanoma randomized 2:1 (stratified by tumor category) to nivolumab 480 mg or placebo every 4 weeks for 12 months. The primary endpoint was investigator-assessed recurrence-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS) and safety. At 7.8 months of minimum follow-up, nivolumab significantly improved RFS versus placebo (hazard ratio (HR) = 0.42; 95% confidence interval (CI): 0.30-0.59; P < 0.0001), with 12-month RFS of 89.0% [...]
Lag-3 expression and clinical outcomes in metastatic melanoma patients treated with combination anti-lag-3 + anti-PD-1-based immunotherapies
Abstract Lymphocyte-activation gene-3 (LAG-3), an immune checkpoint receptor, negatively regulates T-cell function and facilitates immune escape of tumors. Dual inhibition of LAG-3 and programmed cell death receptor-1 (PD-1) significantly improved progression-free survival (PFS) in metastatic melanoma patients compared to anti-PD-1 therapy alone. Investigating the utility of LAG-3 expression as a biomarker of response to anti-LAG-3 + anti-PD-1 immunotherapy is of great clinical relevance. This study sought to evaluate the association between baseline LAG-3 expression and clinical outcomes following anti-LAG-3 and anti-PD-1-based immunotherapy in metastatic melanoma. LAG-3 immunohistochemistry (clone D2G4O) was performed on pre-treatment formalin-fixed, paraffin-embedded metastatic melanoma specimens from [...]
Uncovering the complex relationship between balding, testosterone and skin cancers in men
Abstract Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to greater exposure to ultraviolet radiation or indicate a role for androgenic pathways in the pathogenesis of skin cancers. We dissected this relationship via Mendelian randomization (MR) analyses, using genetic data from recent male-only meta-analyses of cutaneous melanoma (12,232 cases; 20,566 controls) and keratinocyte cancers (KCs) (up to 17,512 cases; >100,000 controls), followed by stratified MR analysis by body-sites. We found strong associations between MPB and the risk of KC, but not with androgens, [...]
Long-Term Outcomes and Persistent Toxicities Following BRAF/MEK Inhibitor Therapy for Advanced Melanoma.
Abstract Background: Recent studies have shown that approximately 20% of patients have 4-5 year progression free survival (PFS) on BRAF/MEK inhibitors. The long-term safety and efficacy in these patients with more durable responses have not been studied. Methods: This retrospective multicenter cohort study assessed response, progression, and adverse events in patients from eight institutions in four countries with >4-year PFS following BRAF/MEK inhibitors. Results: Among 146 patients, 112 (76.7%) remained progression-free at median follow-up of 7.8 years from treatment start; 131 (89.7%) were alive. Among progressors (n = 34), 21 (62%) were on treatment at progression. Among those who discontinued treatment for [...]
COLUMBUS-AD: phase III study of adjuvant encorafenib + binimetinib in resected stage IIB/IIC BRAF V600-mutated melanoma
Abstract Stage IIB/IIC melanoma has a high risk of recurrence after surgical resection. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-programmed cell death protein 1 (PD-1) antibodies significantly improve recurrence-free survival versus placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF MEK inhibitor therapy showed benefits in high-risk stage III and advanced disease; however, its role in patients with fully resected stage BRAF-mutated IIB/IIC melanoma is still unknown. Here we describe the rationale and design of the ongoing randomized, placebo-controlled COLUMBUS-AD trial, the first study [...]
Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results
Abstract Purpose: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma. Methods: Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and [...]
Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results.
Abstract Purpose: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma. Methods: Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and [...]
Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections.
Abstract Background: Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1-5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. Methods: Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and [...]
Single cell profiling of tumour biopsies and heterogeneity in response of dedifferentiated melanoma
Abstract Background: Patients with advanced BRAFV600-mutant melanoma can be treated with immune checkpoint inhibitors or combination BRAF/MEK inhibitors. The sequence of these therapies can influence response to second-line treatment. Patients who progress on first-line PD1 blockade have poorer outcomes on BRAF/MEK inhibitors compared to patients who are treatment-naïve. Thus, defining the molecular features that are modified by therapy and that influence subsequent treatment responses require thorough characterization. Methods: In this study, tumor biopsies from five BRAF-mutant melanoma patients progressing on anti-PD1 (PROG) and five BRAF-mutant treatment-naïve (NAÏVE) patients were dissociated and treated ex vivo with BRAF/MEK inhibitors (dabrafenib+trametinib (DT)) before flow cytometry profiling [...]
Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-Risk Resected Melanoma.
Abstract Importance: Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. Objective: To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. Design, setting, and participants: This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation [...]