Targeted therapy for rare BRAF-mutated melanoma: Updated multicenter analysis and launch of a publicly accessible online outcome database.

Introduction: While BRAF-/MEK-inhibitor therapy is well established in V600E/K-mutated melanoma, the efficacy in advanced melanoma with rare BRAF mutations remains uncertain. This is an updated analysis of an international data collection including 49 new patients, accompanied by development of a publicly accessible global database.

Patients And Methods: A retrospective analysis was conducted at 20 international cancer centers, evaluating 143 patients with rare BRAF V600 (V600-nonE/K; 48 %) and non-V600 (52 %) mutations.

Phase 2, Open-Label, Multicenter Study of Nelitolimod in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naive Advanced Melanoma.

Purpose: Nelitolimod (previously SD-101) is a toll-like receptor 9 agonist. We assessed whether intratumoral nelitolimod plus pembrolizumab potentiates antitumor activity in patients with advanced melanoma who had not previously received anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy.

Patients And Methods: Patients with advanced melanoma who were naive to anti-PD-1/PD-L1 therapy received either nelitolimod 2 mg injected into 1-4 lesions or nelitolimod 8 mg injected weekly into a single lesion for 4 weekly doses, then every 3 weeks.

Testicular Function After Immune-Checkpoint Inhibitors Treatment.

Objective: To investigate the effects of immune-checkpoint inhibitors (ICIs) on spermatogenesis and testicular endocrine function in reproductive-age men with melanoma.

Design: Prospective, mixed longitudinal and cross-sectional cohort study.

Patients: Twenty-nine men aged 19-46 years undergoing ICI therapy for melanoma at two Australian centres between 2019 and 2024.

Pretreatment and on-treatment ctDNA and tissue biomarkers predict recurrence in patients with stage IIIB-D/IV melanoma treated with adjuvant immunotherapy: CheckMate 915.

Purpose: CheckMate 915 (NCT03068455) compared adjuvant nivolumab monotherapy versus combination nivolumab+ipilimumab in patients with resected stage III/IV melanoma. This exploratory analysis was performed to identify biomarkers that correlate with benefit from adjuvant immunotherapy.

Patients And Methods: 1,844 patients received nivolumab 480 mg every 4 weeks or nivolumab 240 mg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.

Unraveling Relatlimab-Specific Biology Using Biomarker Analyses in Patients with Advanced Melanoma in RELATIVITY-047.

Purpose: Administration of the lymphocyte activation gene 3 (LAG-3) inhibitor relatlimab (RELA) and the PD-1 inhibitor nivolumab (NIVO) significantly prolonged progression-free survival (PFS) versus NIVO alone in patients with advanced melanoma treated in RELATIVITY-047. This report describes correlative analyses of biospecimens collected within that trial to better understand the mechanisms of action and identify patients who could benefit from treatment with NIVO + RELA.

Patients And Methods: Pre- and on-treatment peripheral blood samples from 563 patients were analyzed using flow cytometry for changes in 77 prespecified immune cell populations and using immunoassay for peripheral IFNγ.

Discovery and Validation of an Ancillary Genomic Test of Malignancy for Primary Melanocytic Tumors.

Purpose: Pathologic diagnosis of melanocytic tumors can be difficult and prone to error. More accurate ancillary tools are needed. We present a genomic model for distinguishing benign (nevi) from malignant (melanoma) melanocytic skin tumors.

Pre-Amplification of Cell-Free DNA: Balancing Amplification Errors with Enhanced Sensitivity.

Circulating tumour DNA (ctDNA) is a promising biomarker for personalised oncology. However, its clinical utility is limited by detection sensitivity, particularly in early-stage disease. T-Oligo Primed Polymerase Chain Reaction (TOP-PCR) is a commercial amplification approach utilising an efficient "half-adapter" ligation design and a single-primer-based PCR strategy.

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.

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.

Nivolumab plus relatlimab in advanced melanoma: RELATIVITY-047 4-year update.

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).

Combined immunotherapy with nivolumab and ipilimumab with and without sequential or concomitant stereotactic radiotherapy in patients with melanoma brain metastasis: An international retrospective study.

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.

Federated Deep Learning Enables Cancer Subtyping by Proteomics.

Unlabelled: 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 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 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 with local models and matching centralized model performance.

Hyperglycemia in patients treated with immune checkpoint inhibitors: key clinical challenges and multidisciplinary consensus recommendations.

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.

Immune Checkpoint Inhibitors for Patients With Preexisting Autoimmune Neurologic Disorders.

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.

Clinical validation of droplet digital PCR assays in detecting BRAF-mutant circulating tumour DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomised phase 3 trial.

Background: Cell-free, circulating tumour DNA (ctDNA) is an established measure of minimal residual disease; however, it is not utilised in melanoma management. We investigated whether ctDNA measurements could predict survival outcomes during adjuvant targeted therapy or placebo treatment in stage III melanoma, thereby identifying patients at high risk and low risk of recurrence.

Methods: Analytically validated mutation-specific droplet digital PCR assays were used to measure BRAF or BRAF ctDNA in patients aged 18 years or older who were enrolled in the COMBI-AD trial, which was a double-blind, randomised, phase 3 study of oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) combination therapy versus two matched placebos in resected BRAF-mutant stage III melanoma.

Longitudinal Analysis Reveals Dynamic Changes in Histopathologic Features in Responders to Neoadjuvant Treatment in a Stage III BRAF-Mutant Melanoma Cohort.

Despite advances in systemic therapies, cutaneous melanoma remains a highly deadly disease. Patients with high-risk stage III melanoma have a significant likelihood of recurrence following surgery. Although adjuvant immunotherapy has been the standard of care, recent evidence demonstrates that neoadjuvant immunotherapy is more effective for higher-risk stage III patients, showing superior survival outcomes compared with adjuvant immunotherapy.

Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Long-term follow-up, crossover, and rechallenge with pembrolizumab in the phase III KEYNOTE-716 study.

Background: Adjuvant pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB/IIC melanoma in KEYNOTE-716. Results of a post hoc 4-year analysis are reported, including progression/recurrence-free survival 2 (PRFS2).

Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks (part 1).

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.

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.

FDG-PET associations with pathological response and survival with neoadjuvant immunotherapy for melanoma.

Background: Neoadjuvant immunotherapy has become the new standard of care for stage III melanoma. This study sought to describe the metabolic changes seen with fludeoxyglucose-18-positron emission tomography (FDG-PET) following neoadjuvant immunotherapy in patients with melanoma and explore associations with pathological response and recurrence-free survival (RFS).

Methods: Data from patients with macroscopic stage III nodal melanoma treated with neoadjuvant checkpoint inhibitor therapy were pooled from five melanoma centers.

Safety and efficacy of immune checkpoint therapy for the treatment of patients with cardiac metastasis: a multicenter international retrospective study.

Background: Data on the safety profiles and clinical outcomes of patients with solid tumors and cardiac metastasis treated with immune checkpoint inhibitors (ICIs) are limited.

Methods: This is an international multicenter retrospective study of patients with cancer and cardiac metastasis at baseline. Patients who had received ≥1 dose of ICI were included.

Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma.

Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma.

Ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases (ABC): 7-year follow-up of a multicentre, open-label, randomised, phase 2 study.

Background: Patients with melanoma brain metastases respond well to immunotherapy, but long-term comparative survival data are scarce. We aimed to assess the efficacy of ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases at 7 years.

Methods: This open-label, randomised, phase 2 study was conducted at four sites (two research institute cancer centres and two university teaching hospitals) in Australia.