Uveal Melanoma UK national guidelines: 2023 update.

UK Guidelines for the management of uveal melanoma (UM) were first published in 2015 using an evidence-based systematic approach. The primary aim of this guideline was to optimise patient care by providing recommendations based on the best available scientific evidence. The resulting guideline reflected the strengths and weaknesses of the available evidence, made recommendations that were clinically impactful around prognostication, surveillance, and treatment for patients with primary lesions and metastatic disease.

RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE).

Purpose: Effective treatment options for melanoma after immune checkpoint blockade failure are limited. RP1 (vusolimogene oderparepvec) is a herpes simplex virus type 1-based oncolytic immunotherapy, here evaluated in combination with nivolumab in anti-PD-1-failed melanoma.

Methods: Patients had advanced melanoma that had confirmed progression on anti-PD-1 (≥8 weeks, last prior treatment).

Methodology for generating chorioallantoic membrane patient-derived xenograft (CAM-PDX) models of pleural mesothelioma and performing preclinical imaging for the translation of cancer studies and drug screening.

Background: Pleural mesothelioma is a cancer of the lung lining associated with asbestos exposure. Platinum/pemetrexed chemotherapy has been used for many years but provides little benefit and, despite recent immunotherapy advances, prognosis remains poor underpinning the need for development of novel therapeutics or drug repurposing. Fertilized hens' eggs provide a rapid and cost-effective alternative to murine models of pleural mesothelioma which are commonly used in preclinical studies, with chorioallantoic membrane (CAM) xenografts being a partial replacement for mouse flank xenografts.

Evolution of the tumor immune landscape during treatment with tebentafusp, a T cell receptor-CD3 bispecific.

Metastatic uveal melanoma is an aggressive disease with poor outcome, which is refractory to immune checkpoint inhibitors. A T cell receptor (TCR)-based CD3 bispecific, tebentafusp, delivers clinical benefit in patients with metastatic uveal melanoma. Understanding the molecular basis for the anti-tumor activity of tebentafusp in an indication where checkpoint inhibitors are ineffective could aid in identification of other solid tumor indications where CD3 bispecifics may serve an unmet need.

An Open-label, Randomized Study of Melphalan/Hepatic Delivery System Versus Best Alternative Care in Patients with Unresectable Metastatic Uveal Melanoma.

Background: Metastatic uveal melanoma (mUM) has a poor prognosis, with liver metastases typically presenting a therapeutic challenge. Melphalan/Hepatic Delivery System (Melphalan/HDS) is a drug/medical device combination used for liver-directed treatment of unresectable mUM patients. This study assessed efficacy and safety of Melphalan/HDS versus best alternative care (BAC).

Tebentafusp, a T cell engager, promotes macrophage reprogramming and in combination with IL-2 overcomes macrophage immunosuppression in cancer.

Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring in approximately half of the patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), is a therapeutic shown to improve overall survival (OS) in HLA-A*02:01 adult patients with mUM. Here we investigate the impact of tumor-associated macrophages (TAM) on ImmTAC activity.

Meeting Report From the 2023 Cure Ocular Melanoma (CURE OM) Global Science Meeting, Philadelphia, PA, November 2023.

The 2023 Cure Ocular Melanoma (CURE OM) Global Science Meeting was held in Philadelphia on November 6, 2023. There is increased awareness and dedicated research in uveal melanoma (UM), but unmet needs remain in the prevention, detection, and treatment of UM. The purpose of this meeting was to provide an international forum for the exchange of research ideas, to allow for discussion of basic science as well as clinical research on UM, and to gather input about advocacy and patient needs.

Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer.

Background: Pre-clinical studies suggest AZD1775, a WEE1 kinase inhibitor, potentiates the activity of various chemotherapeutic agents.

Methods: WISTERIA was a prospective, parallel two-group, open-label, dose-finding, phase I clinical trial. Eligible patients had histologically confirmed oral, laryngeal, or hypopharyngeal squamous cell carcinoma, ECOG performance status 0/1, and aged ≥18-to-≤70 years.

Long-term survival follow-up for tebentafusp in previously treated metastatic uveal melanoma.

Background: Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM.

Patients And Methods: Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+.

A three-arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel in metastatic uveal melanoma.

Aims: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel.

Oestrogen Receptor Positive Metastatic Eccrine Porocarcinoma: A Case Report and Review of Anti-Oestrogen Therapy in Rare Cancers.

Introduction: Rare cancers, in aggregate, represent a significant burden of disease in oncology and remain therapeutically challenging to manage due to a lack of clinical trials. Eccrine porocarcinoma is a rare cutaneous sweat-gland malignancy for which there remains no standard approach to metastatic disease.

Case Presentation: We describe a patient diagnosed with metastatic disease, confirmed on bone biopsy; pathological analysis further revealed this was oestrogen receptor positive.

Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.

Background: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug.

Methods: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level.

Sensitivity and Specificity of Different Prognostic Systems in Guiding Surveillance for Metastases in Uveal Melanoma.

Uveal melanoma (UM) metastasises in ~50% of patients, most frequently to the liver. Surveillance imaging can provide early detection of hepatic metastases; however, guidance regarding UM patient risk stratification for surveillance is unclear. This study compared sensitivity and specificity of four current prognostic systems, when used for risk stratification for surveillance, on patients treated at the Liverpool Ocular Oncology Centre (LOOC) between 2007-2016 ( = 1047).

Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions.

BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification.

Unlabelled: The nuclear deubiquitylase BRCA1-associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mutation (w-) and a promoter trap (KO) into human mesothelial cells. BAP1w-/KO MeT5A cells express less BAP1 protein and phenocopy key aspects of BAP1 loss in MPM.

Advances in the clinical management of uveal melanoma.

Melanomas arising in the uveal tract of the eye are a rare form of the disease with a biology and clinical phenotype distinct from their more common cutaneous counterparts. Treatment of primary uveal melanoma with radiotherapy, enucleation or other modalities achieves local control in more than 90% of patients, although 40% or more ultimately develop distant metastases, most commonly in the liver. Until January 2022, no systemic therapy had received regulatory approval for patients with metastatic uveal melanoma, and these patients have historically had a dismal prognosis owing to the limited efficacy of the available treatments.

The Chick Embryo Xenograft Model for Malignant Pleural Mesothelioma: A Cost and Time Efficient 3Rs Model for Drug Target Evaluation.

Malignant pleural mesothelioma (MPM) has limited treatment options and poor prognosis. Frequent inactivation of the tumour suppressors , and may differentially sensitise tumours to treatments. We have established chick chorioallantoic membrane (CAM) xenograft models of low-passage MPM cell lines and protocols for evaluating drug responses.

Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial.

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308).

Phase I Study of Safety, Tolerability, and Efficacy of Tebentafusp Using a Step-Up Dosing Regimen and Expansion in Patients With Metastatic Uveal Melanoma.

Purpose: This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM).

Methods: In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D.

Genetic variants associated with mandibular osteoradionecrosis following radiotherapy for head and neck malignancy.

Background/aim: Utilising radiotherapy in the management of head and neck cancer (HNC) often results in long term toxicities. Mandibular osteoradionecrosis (ORN) represents a late toxicity associated with significant morbidity. We aim to identify a panel of common genetic variants which can predict ORN to aid development of personalised radiotherapy protocols.

Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB-IVM1c melanoma.

Background: Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response.

Methods: In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response.

Results: Of 112 enrolled patients, 111 received ≥1 dose of T-VEC.