Analysis of treatment-free survival of patients with advanced melanoma receiving nivolumab as monotherapy or in combination with relatlimab in RELATIVITY-047
Abstract Background: Treatment-free survival (TFS; time spent free of systemic anticancer therapy) is increasingly used to support traditional endpoints. TFS was previously evaluated in patients with advanced melanoma treated with nivolumab plus ipilimumab. This analysis compared TFS for nivolumab plus relatlimab and nivolumab monotherapy in patients with advanced melanoma. Methods: Data were from 714 patients in the phase 2/3 RELATIVITY-047 trial (ClinicalTrials.gov identifier: NCT03470922). TFS was defined as the difference in restricted mean event times between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic anticancer therapy initiation or death. TFS was further partitioned into time with [...]
Randomized, double-blind, phase III LEAP-003 study of first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab for unresectable or metastatic melanoma
Abstract Background: Lenvatinib plus pembrolizumab demonstrated antitumor activity in advanced melanoma after prior anti-programmed cell death protein or ligand 1 [PD-(L)1] therapy in LEAP-004. Here, we report results from LEAP-003 (NCT03820986) which evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in unresectable advanced melanoma. Participants and methods: Participants with unresectable stage III or IV melanoma, previously untreated with PD-(L)1 inhibitors were randomly assigned 1 : 1 to pembrolizumab 200 mg intravenously every 3 weeks plus either lenvatinib 20 mg or placebo orally once daily. Dual primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review and [...]
Predictive Performance of the Clinicopathologic Gene Expression Profile (CP-GEP) in Identifying Cutaneous Melanoma Patients for Whom Sentinel Lymph Node Biopsy is Unnecessary: A Systematic Review and Meta-Analysis
Abstract Context & aim: Sentinel lymph node biopsy (SLNB) is an invasive procedure that detects microscopic nodal metastasis, crucial for accurate staging and optimal management. In melanoma, most patients who undergo the procedure have no sentinel lymph node (SLN) metastasis detected. The CP-GEP model (Merlin Assay) was developed to identify patients who do not have SLN metastases and who may therefore safely forgo SLNB, based upon clinicopathologic and gene expression features of the primary tumour. While the Merlin Assay has been validated by independent cohorts with relatively moderate sample sizes, this meta-analysis aims to assess the overall predictive performance of [...]
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 [...]