Medicine (St Vincent's) - Research Publications
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ItemPhase 2 Study of Cemiplimab in Patients with Advanced Cutaneous Squamous Cell Carcinoma (CSCC): Longer Follow-Up(National Society for Cutaneous Medicine, 2020-10-27)Abstract not available.
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ItemCemiplimab Improves Health-Related Quality of Life (HRQoL) and Reduces Pain in Patients with Advanced Cutaneous Squamous Cell Carcinoma (CSCC): Results from a Post Hoc Exploratory Analysis of a Phase 2 Clinical Trial(National Society for Cutaneous Medicine, 2021-01-01)Abstract not available.
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ItemNo Preview AvailableChallenges in data linkage - experiences from an upper gastrointestinal cancer data linkage study(OXFORD UNIV PRESS, 2021-09)Abstract Background Linked, population-level data is valuable for mapping patterns of care and evaluating health service utilisation, particularly in difficult-to-reach populations. Upper gastrointestinal (UGI) cancers have a dismal prognosis, creating difficulties engaging patients in research. The utility of a linked dataset in this population is of high value. Methods Key objectives included identifying the operational and feasibility issues associated with linking Australian state-based administrative and registry data for understanding health service utilisation in UGI cancers. Datasets pertained to hospital admissions, radiotherapy, community health, primary care, palliative care, Medicare and Pharmaceutical Benefits Schedule’s and UGI cancers. Results From a logistical perspective, data access request approval processes varied, with some requiring consent to be sought from individual services contributing data. The availability of unique person-level identifying information varied widely. Additionally, the time period of data capture differed between and within datasets, limiting the quality of the linked data. Significant costs were associated with linking with primary care and Medicare and Pharmaceutical Benefits Schedule’s. Federal dataset linkage required at least a one-year waiting period. Conclusions Whilst in theory data linkage is a powerful mechanism for obtaining population-level data, in reality, there are many logistical and financial barriers to linking multiple datasets. Consequently, critical data, which has the potential to inform policy and improve patient outcomes, cannot be procured. Key messages Logistical and financial challenges are associated with linking administrative and registry datasets for research, limiting the potential of data linkage.
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ItemNo Preview Available
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ItemA PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORS(OXFORD UNIV PRESS INC, 2020-12)Abstract
BACKGROUND
Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens.METHODS
Following cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2.RESULTS
Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC.CONCLUSIONS
Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation. -
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ItemAutologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: an international, multi-centre propensity-score-matched study(WILEY, 2020-12)High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are used as consolidation in first remission (CR1) in some centres for untreated, transformed indolent B-cell lymphoma (Tr-iNHL) but the evidence base is weak. A total of 319 patients with untreated Tr-iNHL meeting prespecified transplant eligibility criteria [age <75, LVEF ≥45%, no severe lung disease, CR by positron emission tomography or computed tomography ≥3 months after at least standard cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) intensity front-line chemotherapy] were retrospectively identified. Non-diffuse large B-cell lymphoma transformations were excluded. About 283 (89%) patients had follicular lymphoma, 30 (9%) marginal-zone lymphoma and six (2%) other subtypes. Forty-nine patients underwent HDC/ASCT in CR1, and a 1:2 propensity-score-matched cohort of 98 patients based on age, stage and high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBL-DH) was generated. After a median follow-up of 3·7 (range 0·1-18·3) years, ASCT was associated with significantly superior progression-free survival [hazard ratio (HR) 0·51, 0·27-0·98; P = 0·043] with a trend towards inferior overall survival (OS; HR 2·36;0·87-6·42; P = 0·1) due to more deaths from progressive disease (8% vs. 4%). Forty (41%) patients experienced relapse in the non-ASCT cohort - 15 underwent HDC/ASCT with seven (47%) ongoing complete remission (CR); 10 chimeric antigen receptor-modified T-cell (CAR-T) therapy with 6 (60%) ongoing CR; 3 allogeneic SCT with 2 (67%) ongoing CR. Although ASCT in CR1 improves initial duration of disease control in untreated Tr-iNHL, the impact on OS is less clear with effective salvage therapies in this era of CAR-T.
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ItemLupus Low Disease Activity State and Reduced Direct Health Care Costs in Patients With Systemic Lupus Erythematosus(WILEY, 2020-09)OBJECTIVE: Treat-to-target end points for systemic lupus erythematosus (SLE) have been assessed for their impact on damage accrual and flare, but whether they have an impact on the high health care utilization and costs in SLE has not been studied. The purpose of this study was to examine our hypothesis that the recently described lupus low disease activity state (LLDAS) would be associated with reduced health care cost. METHODS: Data from a single tertiary hospital longitudinal SLE cohort were assessed. Baseline demographics, disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K], physician global assessment [PhGA], and flare index), and medication use were evaluated, and direct health care utilization and cost data were obtained from hospital information systems. LLDAS was defined as previously published: briefly, SLEDAI-2K ≤4 with no new activity, PhGA ≤1, prednisolone ≤7.5 mg/day, and optimal standard immunosuppressive agents. Analysis was performed using multivariable linear regression. RESULTS: Two hundred SLE patients, contributing 357.8 person-years of observation, were included. A history of lupus nephritis was present in 42% of patients, and damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index >0) was present at study commencement in 57.3% of patients. The mean ± SD annual direct medical cost per patient was US$7,413 ± 13,133/year. In multivariable analysis, increased cost was associated with the presence of baseline organ damage (41.7% increase; P = 0.009) and corticosteroid use (>7.5-15 mg/day: 55.7% increase; P = 0.02; and >15 mg/day: 202% increase; P < 0.001). In contrast, spending ≥50% of the observation period in LLDAS was associated with a 25.9% reduction in annual direct medical cost (P = 0.04). CONCLUSION: Greater time spent in LLDAS was associated with significantly reduced direct hospital health care costs among patients with SLE.
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ItemPEMBROLIZUMAB PLUS LENVATINIB VS CHEMOTHERAPY AND LENVATINIB MONOTHERAPY FOR RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA THAT PROGRESSED ON PLATINUM THERAPY AND IMMUNOTHERAPY: LEAP-009(BMJ PUBLISHING GROUP, 2020-11)Background Pembrolizumab alone and in combination with platinum-based chemotherapy have become standard first-line treatment options for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), and there is a growing unmet need for safe and efficacious treatment options for R/M HNSCC that has progressed on or after platinum-based chemotherapy and immunotherapy. Data from Study 111/KEYNOTE-146 showed promising antitumor activity and acceptable safety for the PD-1 inhibitor pembrolizumab given in combination with the multikinase inhibitor lenvatinib in patients with metastatic HNSCC.1 LEAP-009 (NCT04428151), a global, randomized, open-label, phase 2 trial, will assess the efficacy and safety of pembrolizumab in combination with lenvatinib versus SOC chemotherapy, as well as the efficacy and safety of lenvatinib monotherapy, in patients with R/M HNSCC that has progressed after platinum-based chemotherapy and a PD-(L)1 inhibitor. Methods Eligible patients are adults with histologically confirmed, locally incurable R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx, disease progression at any time during or after platinum-containing chemotherapy (with or without cetuximab), disease progression within 12 weeks from the last dose of treatment with ≥2 doses of a PD-(L)1 inhibitor, measurable disease based on RECIST v1.1 as confirmed by BICR, ECOG performance status of 0 or 1, and no major blood vessel invasion/infiltration. Patients will be randomized 3:3:2 to pembrolizumab (200 mg IV Q3W for up to 35 cycles) plus lenvatinib (20 mg orally once daily), investigator’s choice of SOC chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine), or lenvatinib monotherapy (24 mg orally once daily). Randomization will be stratified by PD-L1 tumor proportion score (<50% versus ≥50%) and ECOG performance status (0 versus 1). Treatment will continue until centrally verified disease progression, unacceptable toxicity, or decision to withdraw. Patients in the chemotherapy and lenvatinib monotherapy arms may be eligible to receive pembrolizumab plus lenvatinib upon disease progression. The primary endpoint is ORR according to modified RECIST v1.1 as assessed by BICR. Secondary endpoints include PFS, OS, DOR, and safety. Interim futility analysis will be conducted for the lenvatinib monotherapy arm. Tumor imaging by CT or MRI will be performed 6 weeks after randomization, every 6 weeks through year 1, and every 9 weeks thereafter. Safety will be monitored throughout the study and for 30 days after treatment end (90 days for serious AEs if no new anticancer treatment is initiated, and at any time if the AE is considered treatment-related). Recruitment is ongoing; Planned enrollment is ~400 patients. Results N/A Conclusions N/A Trial Registration ClinicalTrials. gov Identifier, NCT04428151 Ethics Approval The study and protocol were approved by the Institutional Review Board or ethics committee at each site. Consent All patients provided written informed consent to participate in the clinical trial. Reference Matthew H Taylor, Chung-Han Lee, Vicky Makker, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol 2020;38(11):1154–1163.
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ItemSUN-127 Diagnostic Challenges Associated with the Rising Incidence of Endocrine Toxicity in the Era of Combination Immunotherapy(The Endocrine Society, 2020-05-08)Abstract Background: Immune checkpoint blockade is now established as standard of care in several malignancies. Trials involving combined cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) blockade demonstrate improved tumour responses in melanoma but at the cost of severe grade 3-4 immune related adverse events (irAEs) in 55%, and endocrine irAEs in up to 10% [1]. Immune-mediated damage to endocrine glands can be a diagnostic and management challenge. We aimed to review the incidence, biochemical evolution and imaging findings of endocrine toxicity related to combined anti CTLA-4 and anti-PD-1 therapy. Methods: We undertook a retrospective chart review of patients who received combined ipilimumab and nivolumab for metastatic melanoma at a tertiary referral centre between 2016-2019. We recorded onset and duration of abnormal biochemistry in endocrine irAEs, reviewed all available MRI images for pituitary size (mm) and appearance and 18-F FDG PET images for features of hypophysitis, thyroiditis and pancreatitis. Results: 162 patients received combination therapy. At least one irAE was recorded in 135 patients (83%), 100 (62%) required glucocorticoids, and 84 (52%) had an unplanned hospital presentation due to irAEs. Thyroiditis occurred in 50 (30.9%), with median time to onset of 30.9 days (range 1-234 days). 35 cases were identified with routine biochemistry performed every 4-6 weeks. TSH receptor antibody was measured in 13 patients and all were negative. 29 (58%) developed permanent hypothyroidism. Central cortisol deficiency was documented in 31 (19%) with a median time to diagnosis of 67.5 days (range 5-286). 4 cases were diagnosed on routine biochemistry and 14 presented with symptoms prompting investigation. 13 were diagnosed after routine neuroimaging demonstrated a pituitary abnormality, and a further 27 patients without the clinical syndrome had features of hypophysitis on neuroimaging. New onset diabetes occurred in 3 people, in which pancreatic inflammation on imaging was found in 2. A further 3/5 patients with an asymptomatic elevated lipase were found to have abnormal pancreatic imaging. In one patient with no features of endocrine or exocrine failure, there was a significant increase in FDG uptake and a subsequent loss of pancreatic volume. Conclusion: We report real world incidence of endocrine irAEs with combination immunotherapy. Routine biochemistry leads to the detection of some but not all cases. Early recognition and avoidance of unplanned presentations remains a challenge. Opportunistic assessment of endocrine gland appearance on routine imaging studies may provide useful early diagnostic information. Reference: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. (2015) 1:23-34. 10.1056/NEJMoa1504030