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Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4–12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies. • The efficacy of immunotherapy for melanoma in-transit metastases is unknown. • An international multicenter retrospective cohort study. • Systemic immunotherapy is an effective treatment for melanoma in-transit metastases. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is a zoonosis like most of the great plagues sculpting human history, from smallpox to pandemic influenza and human immunodeficiency virus. When viruses jump into a new species the outcome of infection ranges from asymptomatic to lethal, historically ascribed to "genetic resistance to viral disease." People have exploited these differences for good and bad, for developing vaccines from cowpox and horsepox virus, controlling rabbit plagues with myxoma virus and introducing smallpox during colonization of America and Australia. Differences in resistance to viral disease are at the core of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) crisis, yet our understanding of the mechanisms in any interspecies leap falls short of the mark. Here I review how the two key parameters of viral disease are countered by fundamentally different genetic mechanisms for resistance: (1) virus transmission, countered primarily by activation of innate and adaptive immune responses; and (2) pathology, countered primarily by tolerance checkpoints to limit innate and adaptive immune responses. I discuss tolerance thresholds and the role of CD8 T cells to limit pathological immune responses, the problems posed by tolerant superspreaders and the signature coronavirus evasion strategy of eliciting only short‐lived neutralizing antibody responses. Pinpointing and targeting the mechanisms responsible for varying pathology and short‐lived antibody were beyond reach in previous zoonoses, but this time we are armed with genomic technologies and more knowledge of immune checkpoint genes. These known unknowns must now be tackled to solve the current COVID‐19 crisis and the inevitable zoonoses to follow. [ABSTRACT FROM AUTHOR]

Background  Perineural spread (PNS) is a marker of aggressiveness and has been shown to occur in cranial nerves due to advanced mucosal and cutaneous head and neck cancer. Receptors CXC chemokine receptor 4 (CXCR4) and programmed cell death-1 (PD-1) have been shown to be overexpressed in a variety of cancers with PNS, with the inhibition of these pathways offering a potential future treatment. Methods  Retrospective immunohistochemical staining for the CXCR4 and PD-1 receptors was performed on 28 head and neck specimens that demonstrated PNS from January 2017 to August 2017, at Royal Brisbane and Women's Hospital, Brisbane, Australia. Results  CXCR4 staining was positive in 52 and 60% of the squamous cell carcinoma (SCC) and adenoid cystic carcinoma PNS specimens, respectively. Cutaneous SCC tumors with no PNS stained positively in 33%. No significant staining for PD-1 in peritumoral lymphocytes or tumor specimens was seen. Conclusion  CXCR4 is overexpressed in advanced skin cancer and head and neck tumors that demonstrated PNS to large cranial nerves. Overall, these results provide strong support for using CXCR4 as a biomarker and further investigation of immunotherapeutic agents that could inhibit tumor progression via targeting CXCR4 expression. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To characterize the outcomes of patients with nonmelanoma solid tumors receiving anti‐PD‐1 immunotherapy not funded by the Australian Pharmaceutical Benefits Scheme. Methods: Medical records of patients with metastatic nonmelanoma tumor diagnoses treated with anti‐PD‐1 (self‐funded pembrolizumab or nivolumab through an access program) from January 1, 2014, to December 31, 2016, at Peter MacCallum Cancer Centre, were retrospectively reviewed. Events after December 31, 2016, were censored. Results: Of 47 patients identified, 27 (57%) had lung cancer. Twenty‐six had compassionate access to nivolumab (24 lung, one renal, one gastroesophageal with possible new lung primary). Median overall survival was 5.7 months. Eleven (23%) achieved a partial response; none had complete response. Twenty (43%) had disease progression on first imaging; 16 (48%) of these continued treatment beyond radiological progression, with three achieving subsequent partial responses. Ten (21%) were not re‐staged mostly due to rapid deterioration or death. At 6 and 12 months, nine (20%) and two (4%) remained on treatment, respectively. Five (12%) discontinued treatment due to immune‐related toxicities. Of 34 patients who died, 71% received treatment within the last month of life; 38% died in an acute hospital. None of 25 patients with poor Eastern Cooperative Oncology Group performance scores of 2–4 responded. Conclusion: The response rates and overall survival of patients with NSCLC, renal carcinoma and triple negative breast cancer of good performance status receiving anti‐PD‐1 therapy outside of a clinical trial are consistent with clinical trial data. However, patients with poor ECOG performance status are unlikely to respond. Careful patient selection and counseling about the potential outcomes of self‐funding treatment in this setting is needed. [ABSTRACT FROM AUTHOR]

Background: Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations., Methods: PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m 2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy., Discussion: This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response., Trial Registration: Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189 , registered 8 October 2019., (© 2022. The Author(s).)

Purpose: Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population., Methods: Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks., Results: Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3-28.9)., Conclusion: Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02492789., Competing Interests: Jason Lickliter and Mark Voskoboynik are employees of Nucleus Network (Australia). Jianjun Zou, Lianshan Zhang and Stacey Luo are employees of Jiangsu Hengrui Medicine Co. Ltd (China). Michael Lahn, Andrea Mannucci and Catello Somma were or are employees of Incyte Biosciences International Sarl (Switzerland). Howard Kallender is employee of Incyte Corporation (USA). Michael Millward and Tarek Meniawy are employees of Linear Clinical Research (Australia). Hui K. Gan reports receiving honoraria from speaker bureau of Bristol-Myers Squibb, Ignyta, Eisai and Merck Serono and is a consultant/advisory board member of AbbVie and Bristol-Myers Squibb. Andrea Mannucci has ownership interests (including stock, patents, etc.) at Incyte Biosciences International Sarl (Switzerland). Michael Millward has been or currently is a member of consultant/advisory board of Merck Sharp & Dohme, Novartis, Bristol-Myers Squib, Roche, AstraZeneca, and Pfizer, and has received travel support from Bristol-Myers Squibb and Roche. Adnan Nagrial is a member of consultant/advisory board of Bristol-Myers Squibb, Merck Sharpe Dohme, Astra Zeneca and Roche, and reports receiving speaking fees from Bristol-Myers Squibb, Merck Sharpe Dohme and Roche. Andreas Behren receives research support from Incyte (Switzerland) for the RO assay. Michael Lahn has ownership interests (including stock, patents, etc.) at Incyte Biosciences International Sarl (Switzerland), AstraZeneca and Eli Lilly. Surein Arulananda reports receiving personal fees from Merck Sharpe Dohme, Astra Zeneca, Roche and Boehringer-Ingelheim. Pablo Fernandez Penas is member of advisory committee (AC) or lecture (L, only educational, non-promotional lectures) of Janssen (AC, L), Lilly (AC, L), Abbvie (AC, L), Novartis (AC, L), UCB (L), MSD (AC), La Roche Posay (L), Merck (AC, L), Roche (AC, L), Amgen (L), Sun Pharma (AC, L), Sanofi (AC), Leo (AC, L), Avene (L), Celgene (AC), Galderma (L) and Schering Plough (L), and reports receiving clinical trial supports from Boehringer Ingelheim, Pfizer, CSL, OncoSec, Lilly, CBP, Abbvie, miRagen, Galderma, Regeneron, BMS, Eisai, Jiangsu Hengrui, Sun Pharma, Novartis, UCB, Leo, Janssen, Arena, Akaal Pharma, Roche, Xoma, Kyowa Hakko Kirin, GSK, Amgen and Merck Sharpe Dohme. No potential conflicts of interest were disclosed by other authors., (© 2020 Lickliter et al.)

Background: The treatment response to new immunotherapy in advanced melanoma patients remains varied between individuals. Immune-related cutaneous side effects might have prognostic value., Objective: To determine whether development of ≥1 of the 3 immune-mediated cutaneous events (eczema, lichenoid reaction, or vitiligo-like depigmentation) is associated with improved progression-free survival., Methods: A cohort study of adults with stage IIIC-IV melanoma treated with pembrolizumab or nivolumab during May 1, 2012-February 1, 2018, at Westmead Hospital, Sydney, Australia. Treatment response was based on iRECIST version 1.1., Results: In total, 82 patients of an average age of 59.9 years were included. Median follow-up was 40.7 months; 33 patients had ≥1 target skin reaction. Skin reactions developed in one-third of individuals by 6 months. At any given time, the instantaneous risk of disease progression and death was lower for individuals who had ≥1 cutaneous adverse event (CAE) develop. Compared with individuals with no CAE, the hazard ratio for disease progression and death for individuals who had ≥1 CAE develop was 0.46 (95% confidence interval 0.23-0.91; P = .025) by the time-dependent Cox proportional hazards model., Limitations: Single-center study., Conclusion: This study demonstrates an association between the development of ≥1 of 3 CAEs and improved progression-free survival in this cohort of patients., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)