Real-world experience of immune checkpoint inhibitors in patients with solid tumours in the Top End of the Northern Territory, Australia from 2016 to 2021: a retrospective observational cohort study.

BACKGROUND: Use of immune checkpoint inhibitors is growing, but clinical trial data may not apply to Indigenous patients or patients living in remote areas. AIMS: To provide real-world incidence of immune-related adverse events (irAE) in the Top End of the Northern Territory and compare incidence between demographic subgroups. METHODS: This retrospective, observational, cohort study collected data from electronic records of patients living in the Top End with solid organ cancer treated with immunotherapy between January 2016 and December 2021. The primary outcome was cumulative incidence of any-grade and severe irAE. Secondary outcomes were overall survival, treatment duration and reason for treatment discontinuation. RESULTS: Two hundred and twenty-six patients received immunotherapy. Forty-eight (21%) lived in a remote or very remote area, and 36 (16%) were Indigenous. Cumulative incidence of any-grade irAE was 54% (122/226 patients); incidence of severe irAE was 26% (59/226 patients). Rates were similar between Indigenous and non-Indigenous patients of any-grade (42% vs 56%, P = 0.11) and severe (11% vs 18%, P = 0.29) irAE. However, Indigenous patients had shorter treatment duration, more frequently discontinued treatment due to patient preference and appeared to have shorter median overall survival than non-Indigenous patients (17.1 vs 30.4 months; hazard ratio (HR) = 1.5, 95% confidence interval (CI) = 0.92-2.66). There was no difference in mortality between remote and urban patients (median overall survival 27.5 vs 30.2 months; HR = 1.1, 95% CI = 0.7-1.7). CONCLUSIONS: Rates of irAE in our cohort are comparable to those in the published literature. There was no significant difference in any-grade or severe irAE incidence observed between Indigenous and non-Indigenous patients.

The molecular characteristics of non-small cell lung cancer in the Northern Territory's Top End.

AIM: Indigenous Australians with lung cancer have poorer survival than non-Indigenous Australians. The reasons for the disparity are not fully understood and this study hypothesized that there may be a difference in the molecular profiles of tumors. The aim of this study, therefore, was to describe and compare the characteristics of non-small cell lung cancer (NSCLC) in the Northern Territory's Top End, between Indigenous and non-Indigenous patients, and describe the molecular profile of tumors in the two groups. METHODS: A retrospective review was conducted of all adults with a new diagnosis of NSCLC in the Top End from 2017 to 2019. Patient characteristics assessed were Indigenous status, age, sex, smoking status, disease stage, and performance status. Molecular characteristics assessed were epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B (BRAF), ROS proto-oncogene 1 (ROS1), Kirsten rat sarcoma viral oncogene homolog (KRAS), mesenchymal-epithelial transition (MET), human epidermal growth factor receptor 2 (HER2), and programmed death-ligand 1 (PD-L1). Student's t-test and Fisher's Exact Test were used in the statistical analysis. RESULTS: There were 152 patients diagnosed with NSCLC in the Top End from 2017-2019. Thirty (19.7%) were Indigenous and 122 (80.3%) were non-Indigenous. Indigenous patients compared to non-Indigenous patients were younger at diagnosis (median age 60.7 years versus 67.1 years, p = 0.00036) but were otherwise similar in demographics. PD-L1 expression was similar between Indigenous and non-Indigenous patients (p = 0.91). The only mutations identified among stage IV non-squamous NSCLC patients were EGFR and KRAS but testing rates and overall numbers were too small to draw conclusions about differences in prevalence between Indigenous and non-Indigenous patients. CONCLUSION: This is the first study to investigate the molecular characteristics of NSCLC in the Top End.

CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective.

CDK4/6 inhibitors have become game-changers in the treatment of estrogen receptor-positive (ER+) breast cancer, and in combination with endocrine therapy are the standard of care first-line treatment for ER+/HER2-negative advanced breast cancer. Although CDK4/6 inhibitors prolong survival for these patients, resistance is inevitable and there is currently no clear standard next-line treatment. There is an urgent unmet need to dissect the mechanisms which drive intrinsic and acquired resistance to CDK4/6 inhibitors and endocrine therapy to guide the subsequent therapeutic decisions. We will review the insights gained from preclinical studies and clinical cohorts into the diverse mechanisms of CDK4/6 inhibitor action and resistance, and highlight potential therapeutic strategies in the context of CDK4/6 inhibitor resistance.

Oral Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer: Advances, Challenges, and Current Status.

Several endocrine therapies are currently available for the treatment of estrogen receptor (ER) positive breast cancer, but the clinical benefit of these agents is limited by endocrine therapy drug resistance. A common mechanism of endocrine therapy resistance is ESR1 mutations. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has activity against ESR1 mutant tumors but requires intramuscular injection and has poor bioavailability that precludes optimal drug dosing. This led to the development of second-generation SERDs which are potent and have improved oral bioavailability and pharmacokinetics. Several of these oral SERDs are now in phase III trials in both the early and advanced ER positive breast cancer settings. This review summarizes the background of oral SERD development, the current status and future perspectives.

Immune checkpoint inhibitor-induced myocarditis, myositis, myasthenia gravis and transaminitis: a case series and review.

Immune checkpoint inhibitors have been incorporated into the treatment of various malignancies. An increasing body of literature is reporting rare but potentially fatal adverse events associated with these agents. In this case series, the authors report the clinical features and outcomes of seven patients who received immune checkpoint inhibitors for different solid organ malignancies and developed a tetrad of immune-related myocarditis, myositis, myasthenia gravis and transaminitis. Herein the authors review the literature and describe the current diagnostic and management approach for this overlapping syndrome. The authors' series highlights the importance of a high index of clinical suspicion, prompt comprehensive investigations, early multidisciplinary team involvement and initiation of immunosuppressive therapy when immune-related adverse events are suspected.

Cancer immunotherapy is used in the treatment of different cancer types. Immunotherapy activates the immune system to detect and attack cancer cells, but side effects may arise from the immune system inadvertently attacking normal tissues and organs. The increased use of immunotherapy has led to an increase in the reporting of rare but potentially life-threatening treatment-related side effects. In this case series, the authors report the clinical features and outcomes of seven patients who developed inflammation of the heart, muscles, nerve and muscle junctions and liver following treatment with immunotherapy. The authors review the scientific literature and discuss the current understanding of and management approach to this rare syndrome. The authors' report highlights the importance of a high degree of clinical suspicion, prompt comprehensive testing to confirm diagnosis, early involvement of experts from different specialties and early initiation of treatment in the management of this unique syndrome.

Corynebacterium diphtheriae-infective endocarditis in a patient with an atrial septal defect closure device.

An 18-year-old woman presented to our institution with fever, bilateral flank pain, headache and photophobia. She had a previous atrial septal defect (ASD) closure device inserted at the age of 9 years. Blood cultures on admission were positive for Corynebacterium diphtheriae, and transoesophageal echocardiogram (TOE) revealed an echodensity associated with the ASD closure device, most consistent with a vegetation. She was treated for infective endocarditis with 6 weeks of intravenous benzylpenicillin, and follow-up TOE showed resolution of the echodensity. To our knowledge, no cases of C. diphtheriaeendocarditis of an ASD closure device have previously been reported.