Prospective tumour mutation burden and neoantigen profiling predicts immunotherapy response in metastatic melanoma
Abstract Tumour mutation burden (TMB) is a promising biomarker in predicting immunotherapy response, yet its reproducibility across target panels needs to be established. This study assessed the reproducibility of TMB estimates in melanoma using TruSight Oncology 500 across two laboratories and compared these results with the FoundationOne CDx and QIAseq TMB IO panels. High concordances in TMB estimation, mutation calls, and BRAF and N/K/HRAS hotspot variants were observed between platforms. In a cohort of 198 pre-treatment biopsies from patients treated with immune checkpoint inhibitors, high TMB (≥10 mut/Mb) was associated with significantly improved response and progression-free survival (PFS), while [...]
Real-world evaluation of the use of melanoma risk prediction tools by clinicians in Australia: a mixed methods study
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Prednisolone modulates CD8⁺ and regulatory T-cell activity to dampen response to immune checkpoint inhibitor therapy in melanoma
Abstract Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma, yet their efficacy is limited by high-grade immune-related adverse events that often require treatment with systemic corticosteroids. Although corticosteroids are widely used, their impact on anti-tumor immunity remains poorly defined. Using an ICI-responsive murine melanoma model, we show that tapered systemic prednisolone administered after three cycles of combined anti-CTLA4 and anti-PD1 therapy compromises ICI-mediated tumor control, leading to delayed progression in one-third of initially responding animals. Mechanistically, prednisolone selectively suppressed CD8+ effector T-cell activation in tumor-draining lymph nodes and in the circulation, while expanding activated regulatory T-cells. These [...]
Sclerosus Associated With Immune Checkpoint Inhibitor Therapy: A Case Series of 11 Patients
Abstract There have only been a limited number of case reports that have described vulval lichen sclerosus in patients receiving immune checkpoint inhibitor (ICI) therapy. We describe 11 cases of vulval lichen sclerosus in patients with melanoma treated with ICIs, and in nine of these cases, the lichen sclerosus symptoms began after ICI commencement. This represents the largest reported series to date and highlights the need for clinician awareness of this potential immune-related adverse effect. Read Full Paper
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 after 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 [...]
GLUT1 expression, lymphocyte distribution and CD3+ T-cell metabolic subsets as predictive markers of response to immunotherapy in advanced melanoma
Abstract Background: Glycolysis, commonly used by malignant tumors for energy production, results in acidification of the tumor microenvironment (TME) through the secretion and accumulation of lactic acid. Acidosis is a potent inhibitor of immune cell function and may therefore affect T-cell infiltration and the efficacy of immunotherapy. This study aimed to characterize the metabolic tumor microenvironment and its association with lymphocyte distribution in patients with advanced melanoma treated with immune checkpoint blockade (ICB) therapies. Methods: Pre-treatment formalin-fixed, paraffin-embedded metastatic melanoma specimens from 45 patients treated with anti-PD-1 ± anti-CTLA-4 ICB were included in this study. Patients with progression-free survival (PFS) ≥ [...]
Immune signature-based uncoupling of checkpoint inhibitor efficacy and toxicity
Abstract Personalized escalation and de-escalation of immune checkpoint inhibitor (ICI) regimens may help to overcome upfront resistance and mitigate the risk for immune-related adverse events (irAEs). Here, we examined the association between pathological response and irAEs per ICI regimen. Meta-analysis of neoadjuvant ICI trials in melanoma illustrated a pattern of increased toxicity and efficacy with the addition and/or higher dosing of anti-CTLA-4 to anti-PD-1. We subgrouped anti-PD-1, low-dose anti-CTLA-4 + anti-PD-1, high-dose anti-CTLA-4 + anti-PD-1, and anti-PD-1 + anti-LAG-3 cohorts according to the baseline interferon-gamma (IFN-γ) signature and analyzed these for response and toxicity rates. Whereas in IFN-γ high [...]
The Prognostic Significance of Tumoral Melanosis
Abstract Background: Tumoral melanosis (TM) is a histological term to describe a nodular aggregation of macrophages containing melanin pigment (melanophages) that is devoid of viable melanocytes. It is most often identified in skin, where it may be appreciated clinically as a pigmented lesion; however, it can also be found in other organs such as lymph nodes. The presence of TM is usually thought to signify the presence of a regressed melanoma or other pigmented tumor. Until recently, it was a relatively uncommon finding; however, with the use of effective systemic therapies against melanoma, its occurrence in histological specimens is more [...]
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 [...]