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 [...]
Correction: Validation of the Melanoma Institute of Australia’s Sentinel Lymph Node Biopsy Risk Prediction Tool for Cutaneous Melanoma
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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 [...]
DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance
Abstract Purpose: Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival. Materials and methods: InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of [...]
Updated pan-tumor guidelines for neoadjuvant scoring of pathologic response: a joint SITC and INMC effort
Abstract Background: Practice-changing clinical trials for novel therapeutic regimens administered in the neoadjuvant setting have been reported for multiple cancer types, bringing this treatment strategy to the forefront for patients with high-risk surgically resectable disease. Previously, tumor-type- or therapy-type-specific scoring systems were used for pathologic response assessment. The goal of this effort is to update, harmonize, and standardize the emerging system(s) for pathologic response assessment and data capture. Materials and methods: Leaders in pathology, oncology, and surgery, including those from the Society for Immunotherapy of Cancer's Pan-tumor Harmonization of Pathologic Response Assessment (PATHdata) efforts and the International Neoadjuvant Melanoma Consortium (INMC), [...]
Pathological response calculation assessment remains accurate with reduced tumor bed examination following neoadjuvant immunotherapy in clinically detectable stage III melanoma
Abstract Background: Neoadjuvant immunotherapy produces event-free survival advantage over adjuvant therapy for patients with surgically resectable macroscopic stage IIIB/C/D melanoma. Pathological response, determined as percentage residual viable tumor (% RVT), provides critical prognostic information and informs management decisions. Here, we assessed accuracy of %RVT calculation when reduced tumor bed (TB) was examined and leverage these results proposing streamlined protocols for pathological examination. Patients and methods: Comprehensive histopathological examination was carried out on 134 patient specimens after neoadjuvant immunotherapy with ipilimumab and nivolumab. Impact on %RVT when evaluating less TB than recommended by the initial International Neoadjuvant Melanoma Consortium (INMC) protocol was [...]
Uptake of health economic evaluations alongside clinical trials in Australia: an observational study
Abstract Background: Australia's clinical trials sector is highly productive with continued sector investment needed to enhance research impact. Generating economic evidence alongside trials has the potential to facilitate the implementation of trial results into practice. Ascertaining the use of health economic evaluations alongside clinical trials can assist in determining whether clinical trials fully realize and operationalize their potential to change policy and practice. The aims of this study were to ascertain the uptake of health economic evaluations alongside Australian-led clinical trials and explore associations between uptake and trial characteristics. Methods: This observational study comprised a descriptive analysis of clinical trials registries, [...]
Study protocol of a randomised phase II trial of concurrent stereotactic body radiotherapy with immunotherapy versus immunotherapy alone in patients with 1-5 extracranial melanoma oligometastases (AXIOM)
Abstract Background: Immunotherapy has significantly improved survival in patients with metastatic melanoma, achieving objective response rates of 45-60% and long-term survival. However, there is scope and a need to further improve outcomes. Preclinical and early clinical data suggest synergistic effects between stereotactic body radiotherapy (SBRT) and checkpoint inhibitor immunotherapy with an acceptable safety profile. Methods: AXIOM is a phase II, multicentre, randomised trial designed to evaluate the effectiveness and safety of upfront SBRT to all radiologically identified metastasis with immunotherapy over historical immunotherapy alone (standard of care) in patients with 1-5 extracranial melanoma oligometastases. The sample size calculation is based on [...]
Oncoplastic surgery for cutaneous head and neck cancers: A novel technique combining wide excision, local flap reconstruction and sentinel node biopsy
Abstract Background and purposes: Sentinel node biopsy (SNB) procedures in the head and neck (H&N) region can be technically demanding due to anatomic and size constraints. Often, node procurement is attempted through small incisions, making identification of crucial anatomy difficult. Given the primary site may be close to the sentinel nodes (SN), a local flap can be designed for the dual purpose of gaining access to the sentinel node field through raising the flap while facilitating repair of the primary site resulting in superior aesthetic outcomes. We detail our technique hereof. Subjects studied and methods: A review of consecutive patients undergoing [...]