Co-designing strategies to improve advance care planning among people from culturally and linguistically diverse backgrounds with cancer: iCanCarePlan study protocol.

BACKGROUND: Advance care planning (ACP) describes the process of supporting individuals at any age or stage of health to consider and share their personal values, life goals, and preferences regarding future health care. Engaging in ACP is associated with better-quality of care in which people receive care in lines with their wishes, values and preferences. Direct translations of ACP guides and resources do not attend to the considerable inter- and intra-ethnic variations in cultural and religious or spiritual beliefs that shape preferences among people from culturally and linguistically diverse (CALD) backgrounds. ICanCarePlan is a three-year project that aims to determine the prevalence of ACP documentation among people from CALD backgrounds with cancer, identify resources available and their use to support ACP among CALD communities, identify barriers and facilitators of person-centred ACP, and to develop, through co-design with consumers and clinicians, approaches that enhance the process ACP for people from CALD backgrounds. METHOD: A mixed-method sequential approach will be used comprising of four studies. Study one is retrospective medical record review of approximately 1500 medical records to establish the prevalence of ACP documentation among CALD patient records in cancer services. Study two is a document analysis synthesising the resources available in the Australian health system to support ACP. Study three is a qualitative study with healthcare staff and consumers to explore barriers and enablers of person-centred ACP. Evidence generated from studies one to three will inform the conduct of co-design with stakeholders to develop approaches to improve ACP processes among CALD communities. Language, technical and financial support for meaningful involvement with consumers from CALD backgrounds throughout this project is outlined. A plan for distress management is also made due to sensitive nature of the topic. The research project has also established a project steering group consisting of three consumer members who are from CALD backgrounds. DISCUSSION: The project will address a national priority issue for a growing population of CALD communities in Australia. The project will provide novel evidence of ACP among CALD communities and novel strategies developed with stakeholders to enhance uptake and experiences of ACP.

Comparison of Prognostic Scores in Early Phase Clinical Trials: A 10-year Single Centre Australian Experience.

BACKGROUND/AIM: Early phase clinical trials (EPCTs) assess the tolerability of novel anti-cancer therapeutics in patients with advanced malignancy. Patient selection is important given the modest clinical benefit and time commitments for trials. Prognostic scores have been developed to facilitate identification of high-risk patients. This study aimed to compare five prognostic scores to predict survival for patients on an EPCT. PATIENTS AND METHODS: We performed a retrospective review of patients enrolled in EPCT at Liverpool Hospital, Sydney, from 2013 to 2023. Demographic, biochemical, and survival data were collected from electronic medical records. The score from five prognostic scoring systems (Royal Marsden hospital, MD Anderson Cancer centre, Gustave Roussy Immune, MD Anderson Immune Checkpoint Inhibitor and Princess Margaret Hospital Index) were calculated. Overall survival was measured using the Kaplan-Meier method and predictive discrimination was assessed using Harrell's c-index. RESULTS: A total of 218 patients across 36 EPCTs were included. The median overall survival was 9.8 months with 22% of patients dying in less than 90 days. Seventeen to thirty-four percent of patients were categorised as high-risk. The MDACC score obtained the highest predictability for overall survival for the whole cohort (c-index=0.67, 95%CI=0.62-0.72) and the immunotherapy-based cohort (c-index= 0.65, 95%CI=0.59-0.71). However, all scores performed similarly with a significant overlap in the confidence intervals. CONCLUSION: Our retrospective audit confirms the utility of prognostic scores to predict survival in an Australian EPCT cohort, with similar predictive discrimination across various scoring systems. Integration of these prognostic tools into EPCT screening processes may optimise benefits and reduce risks associated with EPCTs.

Real world efficacy and toxicity of consolidation durvalumab following chemoradiotherapy in older Australian patients with unresectable stage III non-small cell lung cancer.

INTRODUCTION: Consolidation durvalumab following platinum-based chemoradiotherapy (CRT) significantly improved overall survival for patients with unresectable stage III non-small cell lung cancer (NSCLC) in the PACIFIC trial. However, older patients were underrepresented in PACIFIC, and subsequent analyses suggested trends toward poorer survival and increased toxicity in patients aged ≥70 years old. We assessed the effectiveness and safety of consolidation durvalumab following CRT in older Australian patients with unresectable stage III NSCLC. MATERIALS AND METHODS: This retrospective observational study was conducted across seven sites in Sydney, Australia between January 2018 and September 2021. All adult patients with unresectable stage III NSCLC who received platinum-based chemoradiotherapy followed by at least one cycle of consolidation durvalumab were included. Older patients were defined as being ≥70 years old. RESULTS: Of 152 patients included in the analysis, 42.8% (n = 67) patients were 70 years or older. Median follow-up was 26.1 months. The two-year overall survival and median PFS was similar between older and younger patients. At two years, 74.8% (95% confidence interval [CI]: 65.4-84.2%) of patients <70 years old and 65.2% (95% CI: 53.4-77.0%) of older patients were alive (p = 0.07; hazard ratio [HR] 1.64, 95% CI: 0.95-2.81). Median progression-free survival (PFS) in patients <70 years was 30.3 months (95% CI: 22.2-38.4 months) compared with 26.7 months (95% CI: 12.8-40.6 months) in older patients (p = 0.22; HR 1.46, 95% CI: 0.80-2.65). Toxicity was also similar, with 11.5% of patients <70 years old and 18.5% of older patients experiencing grade 3-4 adverse events (AEs; p = 0.23); 16.1% and 24.6% of the patients, respectively, discontinued treatment due to toxicity (p = 0.19). Grade 3-4 AEs and treatment discontinuation were associated with Charlson Comorbidity Index >5 (p = 0.011) and chronic obstructive pulmonary disease diagnosis at presentation (p = 0.002), respectively. DISCUSSION: Older Australian patients receiving consolidation durvalumab following CRT experienced comparable outcomes to their younger peers. Comorbidity burden may be more important determinants of treatment tolerance than chronological age.

Variations in patterns of prescribing durvalumab in stage III lung cancer: a survey of Australian Medical Oncologists.

BACKGROUND: Local Australian guidelines for the optimal management of stage III unresectable NSCLC are lacking. The American Society of Clinical Oncology (ASCO) guidelines recommend consolidation durvalumab for all patients with unresectable stage III NSCLC irrespective of their PD-L1 expression or driver mutation status. The European Society of Medical Oncology (ESMO) differs, with consolidation durvalumab only recommended in those patients whose tumours express PD-L1. METHODS: Due to differing global guidelines we conducted an Australia and New Zealand wide survey of medical oncologists specialising in thoracic cancer to determine the variations in patterns of prescribing durvalumab in stage III unresectable NSCLC. This survey was done electronically and sponsored by the Thoracic Oncology Group of Australia (TOGA). RESULTS: Thirty-two medical oncologists completed the survey. In patients with EGFR¬-mutated stage III unresectable NSCLC, 6% of respondents stated that they prescribed durvalumab for all patients, whilst an additional 6% strongly recommended treatment. Fourty-four percent suggested little benefit of consolidation durvalumab in this cohort, with an additional 19% advocating for observation only. In patients with PD-L1 negative (0%) stage III unresectable NSCLC, 13% of respondents prescribed durvalumab for all patients, whilst an additional 56% strongly recommended treatment. Interestingly, 18%, 10% and 10% of prescribers discussed self-funded oral tyrosine kinase inhibitor (TKI) therapy in patients with EGFR, ALK or ROS-1 mutated NSCLC respectively as a substitute for consolidation durvalumab. CONCLUSION: Overall, the clinical practice of Australian and New Zealand Medical Oncologists is variable, but remains consistent with either the ASCO or ESMO guidelines. Local practice guidelines are required to ensure consistency in prescribing patterns across Australia, as well as providing evidence for self-funded treatments outside standard of care.

Influence of EGFR mutation status and PD-L1 expression in stage III unresectable non-small cell lung cancer treated with chemoradiation and consolidation durvalumab.

BACKGROUND: Consolidation durvalumab after concurrent chemoradiation is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC) based on the PACIFIC trial. However, there have been reports in the literature suggesting the efficacy of the treatment differs in patients whose tumors harbor epidermal growth factor receptor (EGFR) mutations and in those with low programed death ligand-1 (PD-L1) expression. This study describes the survival outcomes for patients with unresectable stage III NSCLC treated with chemoradiation followed by durvalumab with a specific focus on EGFR mutation status and PD-L1 expression. METHODS: This retrospective observational study was conducted across six sites in Greater Sydney, Australia. It included all patients diagnosed with unresectable stage III NSCLC treated with chemoradiation and who received at least one cycle of durvalumab between January 2018 and September 2021. Patients were stratified according to EGFR mutation status and PD-L1 tumor proportion score (TPS) of 1%. RESULTS: Of the 145 patients included in the analysis, 15/145 (10%) patients harbored an EGFR mutation and 61/145 (42%) patients had PD-L1 TPS of <1%. At a median follow-up of 15.1 months from the start of durvalumab, median progression-free survival (PFS) in EGFR mutant versus wild-type patients was 7.5 and 33.9 months, respectively (hazard ratio [HR]: 2.7; 95% confidence intervals [95% CI] 1.2-5.7; p = .01). Overall survival (OS) was not different between EGFR mutant and wild-type patients. There was no statistically significant difference in PFS (HR .7, 95% CI .4-1.7, p = .43) or OS (HR .5, 95% CI .4-4.7, p = .16) between patients with PD-L1 TPS of <1% versus PD-L1 TPS of ≥1%. CONCLUSIONS: Our data adds to the growing evidence that suggests consolidation durvalumab after definitive chemoradiation may not be as efficacious in patients with EGFR-mutant tumors compared with EGFR wild-type NSCLC.

Utility of multigene panel next-generation sequencing in routine clinical practice for identifying genomic alterations in newly diagnosed metastatic nonsmall cell lung cancer.

BACKGROUND: The standard of care in newly diagnosed metastatic non-small cell lung cancer (NSCLC) is to test for aberrations in three genes for driver mutations - ALK, ROS1 and epidermal growth factor receptor (EGFR) - and also for immunohistochemistry to be performed for programmed death-ligand 1 expression level. Next-generation sequencing (NGS), with or without RNA fusion testing, is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) Tiers I-V and X. AIM: Our aim was to analyse NSCLC tumour samples for the prevalence of Tiers I-V mutations to establish guidance for current and novel treatments in patients with metastatic disease. METHODS: NGS was performed employing the Oncomine Precision Assay (without RNA fusion testing) that interrogates DNA hotspot variants across 45 genes to screen 210 NSCLC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. RESULTS: In our cohort, 161 of 210 (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations (EIA) and five of 210 (3%) MET exon 14 skipping mutations (EIB). Non-Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations (EIIB), with a further 47 of 210 (22%) having non-G12C KRAS (EX) mutations. NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. Forty-six percent of patients also demonstrated potential Tier III and IV mutations that are currently under investigation in early-phase clinical trials. CONCLUSIONS: In addition to identifying patients with genomic alterations suitable for clinically proven standard-of-care therapeutic options, the 45-gene NGS panel has significant potential in identifying potentially actionable non-Tier 1 mutations that may become future standard clinical practice in NSCLC.

Brief Report: Real-World Toxicity and Survival of Combination Immunotherapy in Pleural Mesothelioma-RIOMeso.

BACKGROUND: Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-year overall survival of 10%. First-line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate 743 trial, with supportive data from the later line single-arm MAPS2 trial. RIOMeso evaluates survival and toxicity of this regimen in real-world practice. METHODS: Demographic and clinicopathologic data of Australian patients treated with ipilimumab and nivolumab in first- and subsequent-line settings for pleural mesothelioma were collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log-rank test. Toxicity was investigator assessed using Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 119 patients were identified from 11 centers. The median age was 72 years, 83% were male, 92% had Eastern Cooperative Oncology Group less than or equal to 1, 50% were past or current smokers, and 78% had known asbestos exposure. In addition, 50% were epithelioid, 19% sarcomatoid, 14% biphasic, and 17% unavailable. Ipilimumab and nivolumab were used first line in 75% of patients. Median overall survival (mOS) was 14.5 months (95% confidence interval [CI]: 13.0-not reached [NR]) for the entire cohort. For patients treated first line, mOS was 14.5 months (95% CI: 12.5-NR) and in second- or later-line patients was 15.4 months (95% CI: 11.2-NR). There was no statistically significant difference in mOS for epithelioid patients compared with nonepithelioid (19.1 mo [95% CI: 15.4-NR] versus 13.0 mo [95% CI: 9.7-NR], respectively, p = 0.064). Furthermore, 24% of the patients had a Common Terminology Criteria for Adverse Events grade greater than or equal to 3 adverse events, including three treatment-related deaths. Colitis was the most frequent adverse event. CONCLUSIONS: Combination immunotherapy in real-world practice has poorer survival outcomes and seems more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma.

Pembrolizumab with Chemoradiation as Treatment for Muscle-invasive Bladder Cancer: Analysis of Safety and Efficacy of the PCR-MIB Phase 2 Clinical Trial (ANZUP 1502).

BACKGROUND: Radiation may improve the efficacy of immune checkpoint inhibition. This study investigates the combination of pembrolizumab and chemoradiation (CRT) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To assess the feasibility and safety of pembrolizumab combined with CRT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: A single-arm phase 2 trial was performed with 28 participants having cT2-T4aN0M0 MIBC (Eastern Cooperative Oncology Group performance status 0-1; estimated glomerular filtration rate ≥40 ml/min; no contraindications to pembrolizumab) suitable for CRT. INTERVENTION: Whole bladder radiation therapy (RT; 64 Gy in 32 daily fractions, over 6.5 wk, combined with cisplatin (35 mg/m2 intravenously [IV] weekly, six doses) and pembrolizumab (200 mg IV q3 weeks, seven doses), both starting with RT. Surveillance cystoscopy/biopsy and computerised tomography scans performed 12 and 24 wk after CRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was feasibility, determined by a prespecified satisfactory low rate of grade 3 or worse nonurinary toxicity or completion of planned CRT according to defined parameters. Secondary endpoints were complete cystoscopic response, locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS AND LIMITATIONS: Twenty-eight patients were enrolled with a 31-mo median follow-up. Six had Grade >3 nonurinary adverse events during/within 12 wk after treatment; three had more than one cisplatin dose reduction. The 24-wk post-CRT complete response (CR) rate was 88%. Eight patients developed metastatic disease, and three had nonmetastatic progression. The DMFS at 2 yr is 78% (95% confidence interval [CI] 54-90%), with LRPFS at 2 yr of 87% (95% CI 64-96%) and median OS of 39 mo (95% CI 17.1-not evaluable). Limitations are the single-arm design and sample size. CONCLUSIONS: Combining pembrolizumab with CRT for MIBC was feasible, with manageable toxicity and promising CR rates. PATIENT SUMMARY: Immunotherapy treats nonmetastatic/metastatic bladder cancer effectively. We combined pembrolizumab with chemotherapy and radiation to assess its safety and impact on treatment delivery. The combination was feasible with encouraging early activity. Further larger trials are warranted.

Multigene panel next generation sequencing in metastatic colorectal cancer in an Australian population.

BACKGROUND: Next generation sequencing (NGS) is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT[E]) Tier I-V & X. Allele frequency is also increasingly recognised as an important prognostic tool in advanced cancer. The aim of this study was to determine the genomic mutations in metastatic colorectal cancer (CRC) in an Australian multicultural population and their influence on survival outcomes. METHODS: Next generation sequencing with the 50-gene panel Oncomine Precision Assay™ was used on 180 CRC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. RESULTS: From 180 samples, 147 (82%) had at least one gene mutation identified with 68 (38%) having two or more concurrent mutations. Tier I variants included RAS wild-type [EI] in 73 (41%) and BRAF V600E [EIA] in 27 (15%). Non-tier I variants include 2 (1%) ERBB2 amplification [EIIB], 26 (15%) PIK3CA hotspot mutations [EIIIA] and 9 (5%) MET focal amplifications [EIIIA]. NGS testing revealed an additional 22% of cases with Tier II & III mutations. 43% of patients also presented with potentially actionable Tier III & IV mutations. Patients with concurrent TP53 and RAS mutations had significantly reduced overall survival (6.1 months versus 21.1 months, p <0.01). High KRAS allele frequency, as defined by those with over 20% variant allele frequency (VAF), also demonstrated reduced overall survival (12.1 months versus 42.9 months, p = 0.04). CONCLUSIONS: In addition to identifying patients with genomic alterations suitable for clinically proven standard of care therapeutic options, the 50 gene NGS panel has significant potential in identifying potentially actionable non-tier 1 mutations and therefore may become future standard clinical practice.

Improving Access to Cancer Clinical Trials for Patients From Culturally and Linguistically Diverse Backgrounds in Australia: A Survey of Clinical and Research Professionals.

PURPOSE: Patients with cancer from racial and ethnic minorities, referred to as culturally and linguistically diverse (CALD) in Australia, are significantly under-represented in cancer clinical trials. We performed a national survey of the Australian cancer clinical trials workforce to determine barriers and preferred solutions to address this inequity. METHODS: A 15-item online survey containing both closed- and open-ended purpose-designed questions was created using REDCap. The survey was emailed to members of the Clinical Oncology Society of Australia, Medical Oncology Group of Australia, and Australian cancer cooperative trial groups, and promoted via Twitter. Descriptive analyses summarized quantitative data, and free-text entries underwent thematic analysis with NVivo Version 12. RESULTS: Ninety one respondents completed the survey-with representation across Australia. Eighty-seven percent were directly involved in clinical trial recruitment. Sixty-eight percent were clinicians. Seventy-four percent of respondents did not collect routine data on CALD patient enrollment to cancer clinical trials. Communication (eg, lack of translated materials) and opportunity-related barriers (eg, exclusionary trial protocols) were the most frequently perceived barriers to recruitment. Additionally, qualitative analysis indicated that insufficient consultation time and difficulties accessing interpreters for patients with non-English language preference were significant barriers. Trial navigators and a generic cancer trial pamphlet available in multiple languages were judged the most likely solutions to improve recruitment. CONCLUSION: This study articulates the Australian clinical trials workforce's perspective on current barriers and potential solutions to the under-representation of patients from CALD backgrounds on cancer clinical trials. The insights and solutions from this survey provide steps toward achieving equity in Australian cancer clinical trials.

Review of Toxicities of PARP Inhibitors in Metastatic Castrate Resistant Prostate Cancer.

There is emerging evidence for the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with mCRPC with patients harboring germline or somatic mutations deriving clinical benefit. However, the toxicity profile of PARPi in mCRPC is not well established. In March 2022 a literature search was conducted across 4 databases - Medline, PubMed, Cochrane Library and Embase. In total, 14 relevant studies were identified cumulating in 2066 patients that were treated with PARPi. The overall ORR to PARPi alone or in combination with other therapy was 37% (246/666). In 5trials that investigated PARPi alone, the ORR was 39% (141/361). Treatment emergent adverse events (TEAEs) of any grade were reported in 96% (1034/1080) in PARPi treatment arms. TEAEs of grade >= 3 were reported in 57% (611/1080). 45% (457/1006) experienced treatment interruption whilst 31% (310/989) required dose reductions. 11% (114/1006) of patients had their treatment discontinued directly as the result of toxicity associated with the trial medications. The most common hematological toxicity was anemia, reported in 490/1160 (42%) patients. and lowered white blood cell count were the next 2most common toxicities, reported in 186/655 (28%) and 133/729 (18%) respectively. The 3most common non-hematological toxicities reported were nausea, fatigue and anorexia reported in 440/1013 (43%), 340/1013 (34%) and 274/1013 (27%) patients respectively. Overall, TRAEs associated with individual PARPi are still emerging with hematological toxicities being most apparent. Further toxicities will be informed from future clinical trials to allow improved treatment selection, education and management of toxicities in prostate cancer.

Elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poorer progression-free survival in unresectable stage III NSCLC treated with consolidation durvalumab.

Sustained elevation in neutrophil-to-lymphocyte ratio (NLR) after initial chemoradiotherapy (CRT) has been shown to correlate with worse prognosis in a number of solid organ malignancies. Here, we conducted a retrospective observational cohort study involving six sites across Sydney, Australia, including all patients with unresectable stage III NSCLC treated with CRT and consolidation durvalumab between January 2018 and September 2021. Patients had NLR collected prior to CRT and prior to cycle one of durvalumab. We used an NLR value of 3 to stratify patients into high and low groups. Patients with sustained NLR were defined as those with values ≥3 at both timepoints. A total of 145 patients were included in the study. The median age of patients was 66 years with median follow-up of 15.1 months. The median PFS was 17.6 months in the pre-CRT NLR high cohort and not reached (NR) in the pre-CRT NLR low cohort (HR 1.99; p = 0.01). The median OS was 35.5 months in the high pre-CRT NLR cohort compared with 42.0 months in the low pre-CRT NLR cohort (HR 2.62; 95% CI: 1.23-5.56, p < 0.01). Median PFS for sustained NLR elevation was 17.1 months versus NR (HR 1.5; p < 0.01). Pre-CRT NLR and sustained NLR remained independently prognostic for PFS on multivariate analysis (p = 0.04, p = 0.01) respectively. Pre-CRT NLR and sustained NLR is associated with worse PFS outcomes in unresectable stage III NSCLC treated with CRT and durvalumab. Pre-CRT NLR is also associated with worse OS.

Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors.

BACKGROUND: Data suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial (NCT02998567) of guadecitabine and pembrolizumab in patients with advanced solid tumors. We hypothesized that guadecitabine will overcome pembrolizumab resistance. METHODS: Patients received guadecitabine (45 mg/m2 or 30 mg/m2, administered subcutaneously on days 1-4), with pembrolizumab (200 mg administered intravenously starting from cycle 2 onwards) every 3 weeks. Primary endpoints were safety, tolerability and maximum tolerated dose; secondary and exploratory endpoints included objective response rate (ORR), changes in methylome, transcriptome, immune contextures in pre-treatment and on-treatment tumor biopsies. RESULTS: Between January 2017 and January 2020, 34 patients were enrolled. The recommended phase II dose was guadecitabine 30 mg/m2, days 1-4, and pembrolizumab 200 mg on day 1 every 3 weeks. Two dose-limiting toxicities (neutropenia, febrile neutropenia) were reported at guadecitabine 45 mg/m2 with none reported at guadecitabine 30 mg/m2. The most common treatment-related adverse events (TRAEs) were neutropenia (58.8%), fatigue (17.6%), febrile neutropenia (11.8%) and nausea (11.8%). Common, grade 3+ TRAEs were neutropaenia (38.2%) and febrile neutropaenia (11.8%). There were no treatment-related deaths. Overall, 30 patients were evaluable for antitumor activity; ORR was 7% with 37% achieving disease control (progression-free survival) for ≥24 weeks. Of 12 evaluable patients with non-small cell lung cancer, 10 had been previously treated with immune checkpoint inhibitors with 5 (42%) having disease control ≥24 weeks (clinical benefit). Reduction in LINE-1 DNA methylation following treatment in blood (peripheral blood mononuclear cells) and tissue samples was demonstrated and methylation at transcriptional start site and 5' untranslated region gene regions showed enriched negative correlation with gene expression. Increases in intra-tumoural effector T-cells were seen in some responding patients. Patients having clinical benefit had high baseline inflammatory signature on RNAseq analyses. CONCLUSIONS: Guadecitabine in combination with pembrolizumab is tolerable with biological and anticancer activity. Reversal of previous resistance to immune checkpoint inhibitors is demonstrated.

Assessing cognitive toxicity in early phase trials - What are we missing?

OBJECTIVES: Novel therapies, such as, small protein molecule inhibitors and immunotherapies are first tested clinically in Phase I trials. Moving on to later phase trials and ultimately standard practice. A key aim of these early clinical trials is to define a toxicity profile; however, the emphasis is often on safety. The concern is cognitive toxicity is poorly studied in this context and may be under-reported. The aim of this review is to map evidence of cognitive assessment, toxicity, and confounding factors within reports from Phase I trials and consider putative mechanisms of impairment aligned with mechanisms of novel therapies. METHODS: A scoping review methodology was applied to the search of databases, including Embase, MEDLINE, Clinicaltrials.gov. A [keyword search was conducted, results screened for duplication then inclusion/exclusion criteria applied. Articles were further screened for relevance; data organised into categories and charted in a tabular format]. Evidence was collated and summarised into a narrative synthesis. RESULTS: Despite the availability of robust ways to assess cognitive function, these are not routinely included in the conduct of early clinical trials. Reports of cognitive toxicity in early Phase I trials are limited and available evidence on this shows that a proportion of patients experience impaired cognitive function over the course of participating in a Phase I trial. Links are identified between the targeted action of some novel therapies and putative mechanisms of cognitive impairment. CONCLUSION: The review provides rationale for research investigating cognitive function in this context. A study exploring the cognitive function of patients on Phase I trials and the feasibility of formally assessing this within early clinical trials is currently underway at the Royal Marsden.

Study protocol for a randomised controlled trial of enhanced informed consent compared to standard informed consent to improve patient understanding of early phase oncology clinical trials (CONSENT).

INTRODUCTION: Early phase cancer clinical trials have become increasingly complicated in terms of patient selection and trial procedures-this is reflected in the increasing length of participant information sheets (PIS). Informed consent for early phase clinical trials has been contentious due to the potential ethical issues associated with performing experimental research on a terminally ill population which has exhausted standard treatment options. Empirical studies have demonstrated significant gaps in patient understanding regarding the nature and intent of these trials. This study aims to test whether enhanced informed consent for patient education can improve patient scores on a validated questionnaire testing clinical trial comprehension. METHODS AND ANALYSIS: This is a randomised controlled trial that will allocate patients who are eligible to participate in one of four investigator-initiated clinical trials at the Royal Marsden Drug Development Unit to either a standard arm or an experimental arm, stratified by age and educational level. The standard arm will involve the full length trial PIS, followed by electronic or paper administration of the Quality of Informed Consent Questionnaire Parts A and B (QuIC-A and QuIC-B). The experimental arm will involve the full length trial PIS, exposure to a two-page study aid and 10 online educational videos, followed by administration of the QuIC-A and QuIC-B. The primary endpoint will be the difference (using a one-sided two-sample t-test) in the QuIC-A score, which measures objective understanding, between the standard and experimental arm. Accrual target is at least 17 patients per arm to detect an 8 point difference (80% power, alpha 0.05). ETHICS AND DISSEMINATION: Ethics approval was granted by the National Health Service Health Research Authority on 15 June 2020-IRAS Project ID 277065, Protocol Number CCR5165, REC Reference 20/EE/0155. Results will be disseminated via publication in a relevant journal. TRIAL REGISTRATION NUMBER: NCT04407676; Pre-results.

Applications of liquid biopsy in the Pharmacological Audit Trail for anticancer drug development.

Anticancer drug development is a costly and protracted activity, and failure at late phases of clinical testing is common. We have previously proposed the Pharmacological Audit Trail (PhAT) intended to improve the efficiency of drug development, with a focus on the use of tumour tissue-based biomarkers. Blood-based 'liquid biopsy' approaches, such as targeted or whole-genome sequencing studies of plasma circulating cell-free tumour DNA (ctDNA) and circulating tumour cells (CTCs), are of increasing relevance to this drug development paradigm. Liquid biopsy assays can provide quantitative and qualitative data on prognostic, predictive, pharmacodynamic and clinical response biomarkers, and can also enable the characterization of disease evolution and resistance mechanisms. In this Perspective, we examine the promise of integrating liquid biopsy analyses into the PhAT, focusing on the current evidence, advances, limitations and challenges. We emphasize the continued importance of analytical validation and clinical qualification of circulating tumour biomarkers through prospective clinical trials.