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 [...]
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 [...]
Longitudinal Analysis Reveals Dynamic Changes in Histopathologic Features in Responders to Neoadjuvant Treatment in a Stage III BRAF-Mutant Melanoma Cohort.
Abstract 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. This has led to an immediate paradigm shift in clinical practice toward neoadjuvant therapy for this cohort. The NeoTrio clinical trial assessed the efficacy of sequential or combination BRAF-targeted therapy with anti-programmed cell death-1 in the neoadjuvant setting. However, research on [...]
Transforming Clinical Trials in Skin Cancer Research: Exploring the Potential of Flexible and Innovative Designs.
Abstract Over the past 2 decades, innovations in trial design have significantly advanced the field of clinical research. Methodological developments, such as adaptive designs, basket trials, umbrella trials, and platform trials, along with technological advancements such as virtual studies have proven effective in tackling complex research questions and managing resource constraints. These approaches enable prospectively planned modifications to trial designs and facilitate addressing multiple research questions within a single infrastructure, with technological advancements such as virtual studies enhancing accessibility, efficiency, and patient engagement. These designs can also integrate biomarker information or risk-prediction scores to enhance the efficacy of future [...]
FDG-PET associations with pathological response and survival with neoadjuvant immunotherapy for melanoma.
Abstract 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. All patients underwent baseline and preoperative FDG-PET and CT assessments, and all had surgery. Pathological response was determined using the International Neoadjuvant Melanoma Consortium criteria, radiological response using Response Evaluation Criteria in Solid [...]
Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma.
Abstract 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. We hypothesized that upfront [...]
Clinical outcomes and management following progressive disease with anti-PD-(L)1 therapy in patients with advanced Merkel Cell Carcinoma.
Abstract Aim: Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management. Method: This is a multi-centre international retrospective cohort study with data collected up to May 2023 from 17 centres across 6 countries. Outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy. Results: One-hundred and eighty-five advanced MCC patients received anti-PD-(L)1 therapy. At median [...]
G9a Inhibition Enhances Checkpoint Inhibitor Blockade Response in Melanoma.
Abstract Purpose: G9a histone methyltransferase exerts oncogenic effects in several tumor types and its inhibition promotes anticancer effects. However, the impact on checkpoint inhibitor blockade response and the utility of G9a or its target genes as a biomarker is poorly studied. We aimed to examine whether G9a inhibition can augment the efficacy of checkpoint inhibitor blockade and whether LC3B, a G9a target gene, can predict treatment response. Experimental design: Clinical potential of LC3B as a biomarker of checkpoint inhibitor blockade was assessed using patient samples including tumor biopsies and circulating tumor cells from liquid biopsies. Efficacy of G9a inhibition to enhance checkpoint [...]
Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance.
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An updated review of immune checkpoint inhibitors in cutaneous oncology: Beyond melanoma.
Abstract Over the last decade, immune checkpoint inhibitors (ICIs) have been established as an integral component of the contemporary anticancer armamentarium. In dermatology, ICIs are most established as treatment of advanced melanoma. However, emerging evidence has demonstrated that their utility in cutaneous oncology extends to a variety of other non-melanoma malignancies. This review provides an update of the evidence from clinical trials, real world analyses, and translational research over the last three years in cutaneous malignancies beyond melanoma. Special focus is presented on areas warranting further evaluation - including populations underrepresented in or excluded from clinical trials; new and [...]