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).

Preferences for multi-cancer tests (MCTs) in primary care: discrete choice experiments of general practitioners and the general public in England.

Background: Multi-Cancer tests (MCTs) hold potential to detect cancer across multiple sites and some predict the origin of the cancer signal. Understanding stakeholder preferences for MCTs could help to develop appealing MCTs, encouraging their adoption.

Methods: Discrete Choice Experiments (DCEs) conducted online in England.

CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade.

Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8 T cell gene expression.

A Phase Ia/b study of MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in patients with RAS mutant advanced colorectal cancer (MErCuRIC).

Background: Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients.

A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers.

Background: Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials.

Longitudinal Genomic Analysis to Fine-tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients with BRAFV600-Mutant Metastatic Melanoma.

Purpose: LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study, assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma.

Patients And Methods: Adults with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) treatment-naïve or pretreated received encorafenib plus binimetinib (part I/run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; part II).

Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms.

Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment.

The role of circulating tumor DNA in melanomas of the uveal tract.

Melanoma of the uveal tract or uveal melanoma (UM) originates from melanocytes of the eye and is the most common intraocular malignancy in adults. Despite considerable advances in diagnostic procedures and treatments, prognosis remains poor in those with advanced disease. Accordingly, although current treatments have an excellent local disease control rate, approximately 50% of patients develop metastatic relapse within 10 years.

Tissue-resident natural killer cells support survival in pancreatic cancer through promotion of cDC1-CD8 T activity.

The immunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC) prevents tumor control and strategies to restore anti-cancer immunity (i.e. by increasing CD8 T-cell activity) have had limited success.

Estimating Long-Term Survivorship Rates Among Patients With Resected Stage III/IV Melanoma: Analyses From CheckMate 238 and European Organization for Research and Treatment of Cancer 18071 Trials.

Purpose: Standard-of-care treatments for patients with resected stage III/IV melanoma include the immuno-oncology (IO) agents nivolumab (NIVO) and ipilimumab (IPI). This study used mixture cure models (MCMs) to estimate cure rates among patients treated with NIVO or IPI in the phase III CheckMate 238 (ClinicalTrials.gov identifier: NCT02388906) and European Organization for Research and Treatment of Cancer (EORTC) 18071 (ClinicalTrials.

Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma.

Purpose: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma.

Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination.

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody.

Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study.

Background: In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4).

Methods: In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1.

A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAF mutant advanced melanoma (INTERIM).

Background: BRAF+MEK inhibitors extend life expectancy of patients with BRAF mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen.

Using nominal group technique to identify the planning considerations for UK Armed Forces medical personnel delivering defence engagement first aid training activities.

Introduction: Defence Medical Services personnel regularly deploy overseas to deliver training activities as part of defence engagement (DE) to positively influence partners and others. There remains scope for medical planners to enhance our understanding of how to optimally use medical staff and assets for DE. We aimed to develop a tool to improve planning for DE activities delivering first aid training.

Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound.

Background: The dense stroma of pancreatic ductal adenocarcinomas is a major barrier to drug delivery. To increase the local drug diffusion gradient, high doses of chemotherapeutic agent doxorubicin can be released from thermally-sensitive liposomes (ThermoDox®) using ultrasound-mediated hyperthermia at the tumour target. PanDox is designed as a Phase 1 single centre study to investigate enhancing drug delivery to adult patients with non-operable pancreatic ductal adenocarcinomas.

Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment.

Bispecific T-cell engagers (BiTEs) redirect endogenous T-cell populations to cells expressing tumour-associated antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of BiTE therapy.

A population-scale temporal case-control evaluation of COVID-19 disease phenotype and related outcome rates in patients with cancer in England (UKCCP).

Patients with cancer are at increased risk of hospitalisation and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the SARS-CoV-2 phenotype evolution in patients with cancer since 2020 has not previously been described. We therefore evaluated SARS-CoV-2 on a UK populationscale from 01/11/2020-31/08/2022, assessing case-outcome rates of hospital assessment(s), intensive care admission and mortality.

Tumor monocyte content predicts immunochemotherapy outcomes in esophageal adenocarcinoma.

For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage.

Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

Background: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care.

Methods: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales.

Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study.

Background: Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.