Adjuvant nivolumab and relatlimab in stage III/IV melanoma: the randomized phase 3 RELATIVITY-098 trial
Abstract Based on RELATIVITY-047, nivolumab plus relatlimab is approved for advanced melanoma. Here, to address a current unmet need for more efficacious adjuvant regimens for completely resected melanoma, the phase 3, double-blind RELATIVITY-098 trial compared adjuvant nivolumab plus relatlimab to nivolumab after complete resection of stage III/IV melanoma. Patients were randomized 1:1 to receive nivolumab 480 mg plus relatlimab 160 mg (n = 547) or nivolumab 480 mg (n = 546) intravenously every 4 weeks for ≤1 year; safety populations totaled 543 and 545 patients, respectively. The primary endpoint was recurrence-free survival (RFS), and the key secondary was overall [...]
A dynamic recurrence risk prediction tool for adjuvant therapy in stage III melanoma
Abstract Background: Prognosis for AJCC stage III melanoma varies significantly. Adjuvant therapies, including pembrolizumab, nivolumab, and dabrafenib/trametinib, have markedly reduced recurrence risk, as shown in pivotal trials (Keynote-054, CheckMate-238, and Combi-AD). Despite these advancements, clinicians lack tools to dynamically assess recurrence risk across the patient journey. Patients and methods: Using pooled individual patient data (IPD) from Kaplan-Meier curves of these trials, we developed a tool to dynamically estimate relapse-free survival (RFS) and distant metastasis-free survival (DMFS) over time. Conditional survival analyses incorporated AJCC-8 substages, treatment regimens, and recurrence data. Results: The analysis included 2206 patients (IIIA: 174, IIIB: 768, IIIC: 1169, IIID: [...]
Sites of metastases before systemic treatment influence progression patterns and survival in stage IV melanoma patients
Abstract Background: Metastatic sites influence response rates to immune checkpoint inhibitors (ICI) and survival, suggesting anatomical locations impact treatment outcomes. This study examines how baseline metastatic sites affect progression patterns and survival in melanoma patients receiving first-line ICI or BRAF/MEK inhibitors (BRAF/MEKi). Methods: Metastatic site presence and lesion counts at baseline and progression were captured chronologically for 347 ICI-treated and 210 BRAF/MEKi-treated patients using a novel graph representation. This novel approach enabled systematic comparison of progression patterns post-therapy failure across patients by providing a standardized representation of patterns of progression in patients with distinct clinical histories. Associations of baseline metastatic sites [...]
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 [...]
The Development and Evaluation of a Convolutional Neural Network for Cutaneous Melanoma Detection in Whole Slide Images
Abstract Context: The current melanoma staging system does not account for 26% of the variance seen in melanoma-specific survival, therefore our ability to predict patient outcome is not fully elucidated. Morphology may be of greater significance than in other solid tumors, with Breslow thickness remaining the strongest prognostic indicator despite being subject to high levels of interobserver variation. The application of convolutional neural networks to whole slide images affords objective morphologic metrics, which may reveal new insights into patient prognosis. Objective: To develop and evaluate a convolutional neural network for invasive cutaneous melanoma detection in whole slide images for [...]
Nodal radioactivity after lymphoscintigraphy as a guide to sentinel node-positivity in melanoma patients
Abstract Objective: To determine how often the sentinel node (SN) with the highest gamma count after lymphoscintigraphy was metastasis-free in SN-positive melanoma patients. Background: SN biopsy (SNB) is a standard staging procedure for patients with primary cutaneous melanoma. After pre-operative radiotracer injection, intra-operative gamma counts are used, with blue dye localization, to guide SN retrieval. Sometimes only the "hottest" nodes are removed, but the reliability of predicting SN-positivity on the basis of a node's gamma count is uncertain. Methods: Patients who had a SNB and in whom ≥2 SNs were removed, at least one of which contained metastatic melanoma, were identified from [...]
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 [...]