Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient’s gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB ( n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies ( n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain–response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type.

Aims Using pharmacokinetics (PK)‐guided 5‐fluorouracil (5‐FU) for metastatic colorectal cancer (mCRC) improves overall survival (OS) and decreases toxicity, yet its value for money in the Australian setting is unknown. Our study assesses the cost‐effectiveness of PK vs . body surface area (BSA) dosing of 5‐FU for patients with mCRC. Methods We developed a semi‐Markov model with four health states to compare PK‐guided dosing within a FOLFOX regimen vs . BSA‐guided dosing for mCRC patients from an Australian healthcare system perspective. Transition probabilities were derived from fitted survival models, with utility values obtained directly from published studies. We calculated direct healthcare costs, quality‐adjusted life years (QALYs) and incremental cost‐effectiveness ratios (ICERs), and included both one‐way and probabilistic sensitivity analyses. Results BSA‐guided FOLFOX provided 1.291 QALYs at a cost of $36 379, compared with PK‐guided FOLFOX which delivered 1.751 QALYs at a cost of $32 564. Therefore, PK‐guided dosing emerges as the dominant strategy offering both better health outcomes and lower costs. The variables that had the greatest impact on the overall ICER were the adverse event rates in the BSA and PK groups, model time horizon, utility of progression‐free survival and PREDICT assay cost. Our univariate and multivariate sensitivity analysis confirmed that the ICER for PK FOLFOX consistently remained below $50 000 per QALY across all tested variables. Conclusions PK dose management of 5‐FU‐based chemotherapy in mCRC patients appears to be a cost‐saving strategy in Australia. However, our model estimates are drawn from limited, low‐quality evidence. Further evidence from randomized controlled trials (RCTs), directly comparing PK‐based to BSA‐based dosing across a variety of current regimens, is needed to address our model's uncertainties.

Background Despite robust evidence and international guidelines, to support routine pharmacogenetic (PGx) testing, integration in practice has been limited. This study explored clinicians’ views and experiences of pre-treatment DPYD and UGT1A1 gene testing and barriers to and enablers of routine clinical implementation. Methods A study-specific 17-question survey was emailed (01 February–12 April 2022) to clinicians from the Medical Oncology Group of Australia (MOGA), the Clinical Oncology Society of Australia (COSA) and International Society of Oncology Pharmacy Practitioners (ISOPP). Data were analysed and reported using descriptive statistics. Results Responses were collected from 156 clinicians (78% medical oncologists, 22% pharmacists). Median response rate of 8% (ranged from 6% to 24%) across all organisations. Only 21% routinely test for DPYD and 1% for UGT1A1. For patients undergoing curative/palliative intent treatments, clinicians reported intent to implement genotype-guided dosing by reducing FP dose for DPYD intermediate metabolisers (79%/94%), avoiding FP for DPYD poor metabolisers (68%/90%), and reducing irinotecan dose for UGT1A1 poor metabolisers (84%, palliative setting only). Barriers to implementation included: lack of financial reimbursements (82%) and perceived lengthy test turnaround time (76%). Most Clinicians identified a dedicated program coordinator, i.e., PGx pharmacist (74%) and availability of resources for education/training (74%) as enablers to implementation. Conclusion PGx testing is not routinely practised despite robust evidence for its impact on clinical decision making in curative and palliative settings. Research data, education and implementation studies may overcome clinicians’ hesitancy to follow guidelines, especially for curative intent treatments, and may overcome other identified barriers to routine clinical implementation.

BACKGROUND:In the development of anticancer agents for solid tumours, body surface area continues to be used to personalise dosing despite minimal evidence for its use over other dosing strategies. With the development of tyrosine kinase inhibitors and other oral targeted anticancer agents, dosing using therapeutic drug monitoring (TDM) is now utilised in many health systems but has had limited uptake in Australia. AIM:To determine attitudes and barriers to the implementation of TDM among Australian oncologists. METHODS:A comprehensive questionnaire was developed by the Dutch Pharmacology Oncology Group from semistructured interviews of stakeholders. Seventy-nine questions across seven domains were developed with three free-text responses. This was rationalised to 17 questions with three free-text responses for Australian medical oncologists who identified limited experience with TDM. RESULTS:Fifty-seven responses were received, with 49 clinicians (86%) identifying limited experience of performing TDM in daily practice. Clinicians were positive (62-91% agree/strongly agree across seven questions) about the advantages of TDM. There was a mixed response for cost-effectiveness and scientific evidence being a barrier to implementation, but strong agreement that prospective studies were needed (75% agreed or strongly agreed); that national treatment guidelines would enable practice (80%) and that a 'pharmacology of oncolytics' education programme would be useful (96%) to provide knowledge for dose individualisation. CONCLUSION:Despite the limited experience of TDM in oncology in Australia, medical oncologists appear positive about the potential benefit to their patients. We have identified three barriers to implementation that could be targeted for increased adoption of TDM in oncology in Australia.

Neuroendocrine tumours (NETs) are rare cancers which often carry significant morbidity and mortality, frequently related to burden of liver metastases. Hyperammonaemia and subsequent hepatic encephalopathy carries a poor prognosis and has been described in these patients. We discuss a case of a woman in her 50s with hyperammonaemic encephalopathy and a new diagnosis of pancreatic NET with hepatic metastases. She presented with a reduced conscious state a few days post commencing chemotherapy. This was considered to have a multifactorial pathophysiology: the primary driver being large volume hepatic metastases and contributed by portosystemic microshunting, sepsis, severe weight loss and malnutrition. We describe how each of these exacerbating factors was addressed and highlight the effective multimodal treatment approach consisting of sequential transarterial chemoembolisation followed by peptide receptor radio nucleotide therapy, resulting in the resolution of hyperammonaemic encephalopathy and radiological partial metabolic response.

589 Background: Neuroendocrine carcinomas (NEC) are rare and aggressive cancers. There are no randomised trials to date to establish standard therapy for advanced G3 gastrointestinal (GI) NENs. Extrapolating from small cell lung cancer data, standard practice is to treat G3 GI-NENs with etoposide and carboplatin. Paclitaxel is also active in NECs however there is no data on the role of nab -paclitaxel. NABNEC (ANZCTR # 12616000958482) aimed to determine the activity, safety and tolerability of carboplatin and nab -paclitaxel in advanced G3 GI-NENs and to enhance our understanding of the biology and imaging characteristics of such NENs. Methods: NABNEC was designed as a randomised non-comparative phase II study, evaluating the activity of nab- paclitaxel in patients with advanced and/or metastatic non-resectable G3 GI-NENs. The statistical plan was that 46 evaluable patients in the experimental arm would give 80% power and 95% confidence to rule out a 30% RR in favour of a more interesting RR of 50% at 6 months. Protocol version 3.0 was amended and randomisation to the control arm was suspended after 12 patients. Primary endpoint was objective response rate (RR) by RECIST 1.1. Secondary endpoints were progression free survival, overall survival, adverse events by NCI-CTCAE V4.03 and quality of life (EORTC QLQC30, QLQ-GINET21 questionnaires). Translational research endpoints include blood and tissue biomarkers including circulating tumour cells profiling, mutation profile (whole exome sequencing) and DNA methylation profile correlated with clinical endpoints. Correlation of 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) to early response has also been evaluated. Results: 60 patients were accrued between Sep 2016 and Dec 2021 from 16 centres, resulting in 58 evaluable patients, 12 (control arm), 46 (experimental arm). 43 patients (75%) had tumours with Ki-67>55%; the remainder had Ki-67 between 20 and 55%. About 20% had pancreatic primaries; more than half had liver metastases. The NABNEC trial met its primary endpoint. RR was 53% (38-69%) in the experimental treatment arm compared to 42% (16-71%) in the control group. Progression free survival was not different between the 2 treatments. 24m overall survival was 25% in the experimental group compared to 17% in the control. Grade 3 toxicity was worse in the nab-paclitaxel arms (52% v 42%). Quality of life and tertiary outcomes are being analysed. Conclusions: The combination of carboplatin and nab-paclitaxel is an active regimen for G3 GI-NENs. Further evaluation in a Phase III study is warranted. Clinical trial information: ACTRN12616000958482.

Central Nervous System Multiple Myeloma (CNS-MM) is a rare but aggressive complication of MM, and its treatment remains an unmet clinical need. Herein we present a real-world national analysis of incidence, characteristics, prognostic factors and outcome of a large cohort of patients with CNS-MM. We evaluated 53 patients with CNS-MM (M/F: 23/30; median age: 59, range: 20-96 years; IgG: 27, IgA: 10, light-chain: 11, non-secretory: 4, IgD: 1; ISS1: 22, ISS2: 13, ISS3: 18; RISS1: 15, RISS2: 22, RISS3: 16) out of 4352 MM patients (1.2%), who were treated within the Greek Myeloma Study Group centers from 2000 to 2022 (23% of patients were diagnosed after 2016). A control group of MM patients matched for age, gender, and stage (ISS/RISS) who were treated during the same period was used for comparisons. Presence of soft tissue plasmacytomas (STP) and/or plasma cell leukemia (PCL; circulating plasma cells, cPCs: ≥5%) was determined and analyzed as extramedullary involvement (EMI). Median time to CNS-MM from MM diagnosis was 28 months (range 0-149 months); 6/53 (11.3%) patients experienced CNS-MM at initial MM diagnosis. Clinical manifestations of CNS-MM included visual disturbances/diplopia: 32%, paresis/paraplegia: 22%, lethargy/confusion: 37%, headache: 22%, cranial nerve palsy: 13% and dysarthria: 11%. PCL was present in 16/53 (30%) CNS-MM patients, while 29/53 (54.7%) CNS-MM patients had bone and/or STP vs. 13/53 matched controls (p=0.001); EMI was found in 24/53 (45%) patients with CNS-MM vs. 4/53 (7%) in controls (p<0.001). 35/53 (66%) CNS-MM patients had leptomeningeal infiltration (LMI) and 34% had intraparenchymal lesions. Median number of cells in the cerebrospinal fluid (CSF) was 60/μL (range 10-2550) and almost all of them (80%, range: 20-100%) were clonal plasma cells. Out of 53 CNS-MM patients, 14 (26.4%) had only CNS involvement without marrow infiltration by PCs; 51% had ≥1 high-risk molecular features (i.e., del17p, t4:14, t14:16, 1q+), and this was marginally higher vs. controls (36%; p=0.15). CD56 negative marrow PCs did not differ between groups (33% vs. 37%). A binary logistic regression analysis demonstrated that EMI was the strongest prognostic factor for the development of CNS-MM (p=0.01; HzR: 5.7). Median number of lines of treatment before the development of CNS-MM was 2 (range 0-9). First line anti-myeloma treatment in patients who developed CNS-MM included conventional chemotherapy (CT) or thalidomide-based regimens in 19 patients, bortezomib-based triplets in 27 and daratumumab-based regimens (DBR) in 7; this did not differ from controls. Overall response rate (ORR) in first-line therapy was similar between CNS-MM and controls (85% for both groups; CR 41% vs. 36%, respectively). After a median follow-up of 150 months post-MM diagnosis (95% CI: 107-192), 46 CNS-MM patients (87%) deceased (MM progression: 34, infection/sepsis: 10, cerebral hemorrhage: 2). Median overall survival (OS) of CNS-MM patients vs. matched controls from initial MM diagnosis was 43 months (95% CI: 31-54) vs 60 months (95% CI: 34-86) (p=0.002; Figure). Regarding CNS-MM therapy, 17 patients received IMiD-based regimens and 26 received PI-based regimens, 6 received CT and 4 received DBR. Patients with CNS-MM and marrow infiltration by PCs displayed an ORR of 31% only; CNS symptoms improved in 74% of all patients. Median OS of CNS-MM patients from the time of CNS involvement was 4 months (95% CI: 2.6-5.3), and it was longer in 12 patients treated after 2016 [18 months (95% CI: 7-29) vs. 2 months (95% CI: 1-3)]. Cerebrospinal fluid (CSF) infusions were performed in 28 patients (53%); 9 patients (19%) underwent radiotherapy. A multivariate analysis showed that EMI, either at diagnosis or during MM course, was the strongest negative predictor for post CNS-MM OS (p=0.008; HR: 3.4 95% CI: 1.4-8.0). Moreover, LMI was a negative predictor (p=0.02; HR: 2.7, 95% CI: 1.2-6.3) for OS, whereas treatment after 2016 had a positive impact (p=0.02; HR: 0.28, 95% CI: 0.12-0.8); CSF infusions did not affect OS. In conclusion, our analysis representing one of the largest real-world series of CNS MM patients after 2016, showed that, OS of CNS-MM remains poor however, there is a positive impact of treatment after 2016, reflecting the efficacy of modern anti-myeloma therapy; EMI strongly predicts for CNS-MM and induces a 3-fold increase in the probability of post CNS-MM death indicating a potential need for CNS prophylaxis in these patients.

11150 Background: With around 90% KRASmutation (mt) frequency, pancreatic ductal adenocarcinoma (PDAC) is considered the most RAS-addicted cancer. Despite guideline recommendations, genomic testing is not routine in all PDAC patients (pts) in Australia, due to unproven clinical impact. As more novel KRAS-direct therapeutics enter clinical trials, understanding the real-world frequency of individual mutations and prognostic significance, and facilitating trial recruitment are important goals, all of which can be supported by registry data. Methods: Data extracted from the PURPLE pancreatic cancer registry from 9 participating Australian cancer centres, between 2016-2022, was analysed to compare clinicopathological features, survival based on KRASmt status, and assess feasibility of the platform to identify and molecularly stratify patients for future clinical trials. Survival estimates were calculated using Kaplan-Meier curves and log-rank testing on SPSS (Macintosh v.29). Results: Of 721 PDAC routine care pts identified, next generation sequencing (NGS) was undertaken in 378/721 (52%). Median patient age was 68 years (range 52-83); 152 (40%) had resectable, 111 (29%) locally advanced and 115 (30%) metastatic disease. 57/378 (15%) were KRAS wildtype. Of 321 pts with a KRAS mt, codons 12,13, and 61 were the most common sites of mt, including G12D (45%), and G12V (30%), with lower frequencies of G12R (13%), Q61H (6%), G12A (3%), G12C (1%), and G13D (1%). Comparing KRAS wildtype to KRASmt pts, there was no difference in median age (68 vs 67, p=0.63), gender (male: 49% vs 60%, p=0.23), Charlson comorbidity index (p=0.30), or stage at first presentation (p=0.99). Overall KRAS wildtype pts were more likely to be ECOG PS 0 at diagnosis (p=0.01) and to receive at least 1 modality of treatment (p=0.004). For all pts, median overall survival (OS) in KRASwildtype versus KRAS mt pts was 29.0 months versus 19.7 months (p=0.007), and for the 115 metastatic pts 15.1 versus 10.4 months (p=0.28). Further analysis of the impact by disease stage and by individual RAS mt is underway. Conclusions: Registry based analysis informs understanding of KRAS mt status of PDAC in a community setting. Here, KRAS mt status was associated with worse OS outcomes, likely in part due to the association with ECOG PS and receiving less active treatment. With newer promising KRAS-targeted therapies becoming available in clinical trials, known RAS status will aid identification of trial candidates. The clinical utility of NGS and rationale for reflex testing in PDAC is increasing. Clinical Registry information (ACTRN12617001474347).

Background Pancreatic cancer incidence is increasing in younger populations. Differences between early onset pancreatic cancer (EOPC) and later onset pancreatic cancer (LOPC), and how these should inform management warrant exploration in the contemporary setting. Methods A prospectively collected multi-site dataset on consecutive pancreatic adenocarcinoma patients was interrogated. Patient, tumour, treatment, and outcome data were extracted for EOPC (≤50 years old) vs LOPC (>50 years old). Results Of 1683 patients diagnosed between 2016 and 2022, 112 (6.7%) were EOPC. EOPC more frequently had the tail of pancreas tumours, earlier stage disease, surgical resection, and trended towards increased receipt of chemotherapy in the curative setting compared to LOPC. EOPC more frequently received 1st line chemotherapy, 2nd line chemotherapy, and chemoradiotherapy than LOPC in the palliative setting. Recurrence-free survival was improved for the tail of pancreas EOPC vs LOPC in the resected setting; overall survival was superior for EOPC compared to LOPC across the resected, locally advanced unresectable and metastatic settings. Conclusions EOPC remains a small proportion of pancreatic cancer diagnoses. The more favourable outcomes in EOPC suggest these younger patients are overall deriving benefits from increased treatment in the curative setting and increased therapy in the palliative setting.

AbstractThe clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta‐analysis aim to evaluate the safety outcomes of reported PGx‐guided strategies (Analysis 1) and identify well‐studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta‐analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx‐guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57–0.91, p = 0.006, I2 = 34%). Meta‐analyses 2 identified nine medicine(class)‐variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA‐DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine‐variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti‐cancer and supportive care medicine safety and efficacy.

Best response according to histological grade

This study explored the acceptability of a novel pharmacist-led pharmacogenetics (PGx) screening program among patients with cancer and healthcare professionals (HCPs) taking part in a multicenter clinical trial of PGx testing (PACIFIC-PGx ANZCTR:12621000251820). Medical oncologists, oncology pharmacists, and patients with cancer from across four sites (metropolitan/regional), took part in an observational, cross-sectional survey. Participants were recruited from the multicenter trial. Two study-specific surveys were developed to inform implementation strategies for scaled and sustainable translation into routine clinical care: one consisting of 21 questions targeting HCPs and one consisting of 17 questions targeting patients. Responses were collected from 24 HCPs and 288 patients. The 5-to-7-day PGx results turnaround time was acceptable to HCP (100%) and patients (69%). Most HCPs (92%) indicated that it was appropriate for the PGx clinical pharmacist to provide results to patients. Patients reported equal preference for receiving PGx results from a doctor/pharmacist. Patients and HCPs highly rated the pharmacist-led PGx service. HCPs were overall accepting of the program, with the majority (96%) willing to offer PGx testing to their patients beyond the trial. HCPs identified that lack of financial reimbursements (62%) and lack of infrastructure (38%) were the main reasons likely to prevent/slow the implementation of PGx screening program into routine clinical care. Survey data have shown overall acceptability from patients and HCPs participating in the PGx Program. Barriers to implementation of PGx testing in routine care have been identified, providing opportunity to develop targeted implementation strategies for scaled translation into routine practice.

Objectives To identify changes in the healthcare preferences, patient experiences, and quality of life of patients with NETs at 6-month follow-up, informing the design of supportive care services. Methods This study presents 6-month follow-up data of a mixed-methods multi-site study. Demographic, clinical, and patient-reported outcome questionnaire data was collected. Results High percentages of suboptimal experiences of care were reported. Patients reported less positive experiences with being involved in decisions about their care and treatment; their family or someone close to them having the opportunity to talk to their cancer doctor, or having their family or someone close to them receive all the information they need to help care for them at home. Patients also reported negative experiences for on the information about their cancer accessible online and the usefulness of the information they accessed. Differences between baseline and follow-up scores were mostly not significant apart from anxiety and sleep disturbance scales, Conclusions Patients with NETs report difficulties in accessing and understanding written information that is persistent over time. Practice implications Outcomes will inform the design and development of an informational resource aimed at facilitating improved understanding for patients with NETs.

Purpose Whilst the treatment paradigm for colorectal cancer has evolved significantly over time, there is still a lack of reliable biomarkers of treatment response. Treatment decisions are based on high-risk features such as advanced TNM stage and histology. The role of the tumour microenvironment, which can influence tumour progression and treatment response, has generated considerable interest. Patient-derived explant cultures allow preservation of native tissue architecture and tumour microenvironment. The aim of the scoping review is to evaluate the utility of patient-derived explant cultures as a preclinical model in colorectal cancer. Methods A search was conducted using Ovid MEDLINE, EMBASE, Web of Science, and Cochrane databases from start of database records to September 1, 2022. We included all peer-reviewed human studies in English language which used patient-derived explants as a preclinical model in primary colorectal cancer. Eligible studies were grouped into the following categories: assessing model feasibility; exploring tumour microenvironment; assessing ex vivo drug responses; discovering and validating biomarkers. Results A total of 60 studies were eligible. Fourteen studies demonstrated feasibility of using patient-derived explants as a preclinical model. Ten studies explored the tumour microenvironment. Thirty-eight studies assessed ex vivo drug responses of chemotherapy agents and targeted therapies. Twenty-four studies identified potential biomarkers of treatment response. Conclusions Given the preservation of tumour microenvironment and tumour heterogeneity, patient-derived explants has the potential to identify reliable biomarkers, treatment resistance mechanisms, and novel therapeutic agents. Further validation studies are required to characterise, refine and standardise this preclinical model before it can become a part of precision medicine in colorectal cancer.

Purpose of Review Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges. Recent Findings In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Summary Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient’s disease biology for precision diagnosis, prognostication and optimal treatment allocation.

Importance:Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers. Objective:To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers. Design, Setting, and Participants:This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts. Interventions:High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control). Main Outcomes and Measures:The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation. Results:Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001). Conclusions and Relevance:In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population. Trial Registration:ANZCTR Identifier: ACTRN12618000811202.

AbstractPurpose:BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies.Patients and Methods:We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.Results:Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification.Conclusions:The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.

e24129 Background: While a leading cause of morbidity and mortality in cancer, prior studies report low awareness of cancer-associated thrombosis (CAT) among adults with cancer. Despite multiple guideline endorsed thromboprophylaxis (TP) agents and evolving data for personalised TP strategies, objective willingness to engage and preferences for care within ambulatory settings, have yet been elucidated. Methods: Individuals commencing systemic anticancer therapies lung and gastrointestinal cancers enrolled in the TARGET-TP trial of risk-directed ambulatory TP (ANZCTRN12618000811202) reported awareness, preferences, and engagement (related to CAT and TP) at enrolment, using a 6-item study specific survey. Participants were informed regarding the impact of CAT and the rationale for the study as part of the consent process however surveys were completed prior to clot risk-assessment, before being allocated and informed of trial arm (observation or intervention), and with instruction to answer based on knowledge and beliefs before participating in the consent process. Experiences with TP were assessed longitudinally in trial participants randomised to enoxaparin, using the validated 15-item Anti-Clot Treatment Scale (ACTS). Results were reported descriptively, compared over time and among subgroups of interest - including cancer type, new vs previously treated, age, sex, stage and treatment centre (specialist/general). Results: Data from 273/328 (83%) trial participants who completed surveys were evaluated. One third (34%) reported being unaware of CAT, but, given information, nearly all (99%) were willing to be proactive to prevent clots, including use of anticoagulants (97%): oral (92%) vs injectable (82%). Individuals reported willingness to use injectable (vs oral) in hypothetical situations where the injectable agent offered greater efficacy (91%), reduced bleeding risk (86%), or was less likely to interact with cancer medicines (87%). Results were similar among subgroups except individuals with lung cancer who reported higher CAT awareness if receiving care at specialist vs general hospital (79% vs 56%, P = 0.02). Among 83/100 (83%) trial participants randomised to enoxaparin TP who completed at least one ACTS survey, burdens of TP were infrequently reported: high burden (4%), any burden (19%). The most burdensome aspect was inconvenience of daily treatment, and least burdensome aspect related to perceived bleeding risks. More than 86% of individuals reported benefits of TP. Perceived burdens/benefits were consistent over the 6-month reporting period and within subgroups. Conclusions: Findings demonstrate gaps in supportive cancer care education across health services that if overcome present an opportunity to harness an overwhelming willingness of individuals with cancer to proactively engage in clot prevention strategies. Clinical trial information: ANZCTRN12618000811202 .

AIM:Peritoneal dissemination of infiltrative appendiceal tumors is a rare and poorly understood phenomenon. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognized treatment option for selected patients. Neoadjuvant systemic chemotherapy (NAC) has been shown to be associated with improved overall survival (OS) in colorectal peritoneal metastases but little is known of the impact of this from an appendiceal adenocarcinoma perspective.METHOD:A prospective database of 294 patients with advanced appendiceal primary tumors undergoing CRS ± HIPEC between June 2009 and December 2020 was reviewed. Baseline characteristics and long-term outcomes were compared between patients with adenocarcinoma who received neoadjuvant chemotherapy or upfront surgery.RESULTS:Eighty-six (29%) patients were histologically diagnosed with an appendiceal cancer. These included intestinal-type adenocarcinoma (11.6%), mucinous adenocarcinoma (43%), and goblet cell adenocarcinoma (GCA) or signet ring cell adenocarcinoma (SRCA) (45.4%). Twenty-five (29%) of these underwent NAC, of which eight (32%) exhibited some degree of radiological response. There was no statistical difference in OS at 3 years between the NAC and upfront surgery groups (47.3% vs. 75.8%, p = 0.372). Appendiceal histology subtypes, particularly GCA and SRCA (p = 0.039) and peritoneal carcinomatosis index >10 (p = 0.009), were factors independently associated with worse OS.CONCLUSION:Administration of NAC did not appear to prolong OS in the operative management of disseminated appendiceal adenocarcinomas. GCA and SRCA subtypes display a more aggressive biological phenotype.

The standard treatment of colorectal cancer (CRC) typically involves a combination of surgery, chemotherapy and radiotherapy. One of the most exciting paradigm shifts in recent times is the use of immunotherapy as part of standard treatment for several tumour types such as melanoma,1 non-small cell lung cancer2 and renal cell carcinoma.3 However, it has not been shown to be very effective in CRC until the past few years when immune checkpoint inhibitors (ICI) produced remarkable results in a subset of patients with CRC characterized by high microsatellite instability (MSI-H) due to deficient DNA mismatch repair (dMMR). In order to understand the mechanisms of action of ICIs, it is important to appreciate the genetic and immunological differences between dMMR and pMMR patients. MMR is a system involved in identifying and repairing mismatched bases during DNA replication and is regulated by 4 key genes, mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6), and postmeiotic segregation increased 2 (PMS2). Mutational or epigenetic inactivation of these genes leads to dMMR, which in turn causes accumulation of mutations that often occur at areas of short tandem repetitive DNA sequences called microsatellites, hence also termed MSI-H. Genetic instability due to dMMR/MSI-H is thought to occur in about 15% of CRC,4 and may be sporadic or hereditary in the form of Lynch syndrome. From an immunological standpoint, there are distinct histopathological features associated with a dMMR/MSI-H phenotype, such as a Crohn's-like lymphoid reaction and the presence of tumour-infiltrating lymphocytes. This T-cell-infiltrated tumour microenvironment may be explained by the high tumour mutational burden, leading to generation of high levels of non-self-immunogenic antigens (neoantigens) which stimulates host anti-tumour immune response. However, these tumours can evade immune surveillance by overexpressing programmed death-ligand 1 (PD-L1) which acts on programmed cell death protein 1 (PD-1) receptor on T cells. The latter is a key immune checkpoint that suppresses T cell-mediated immune response under physiological conditions. Therefore, by using ICIs to block the interaction between PD-1 and PD-L1, the anti-tumour activity of T cells can be restored or even enhanced to improve immune response. Initial results of immunotherapy use in non-selective CRC were disappointing, with most studies demonstrating limited efficacy.5, 6 Subsequently, Le et al. hypothesised that dMMR patients were more responsive to anti-PD-1 therapy, due to their higher tumour mutational burden and prominent immune infiltrate, and initiated a phase II trial of pembrolizumab (anti-PD-1) in solid tumours which grouped patients by their MMR status.7 Preliminary results showed that the objective response rate and progression-free survival rate at 20 weeks were 40% and 78% for dMMR metastatic CRC, respectively, compared to 0% and 11% for pMMR metastatic CRC. These encouraging results have prompted further trials to focus on the effect of ICIs broadly across MSI-H solid tumours. In a study that pooled the results of 149 patients with different tumour types, enrolled across 5 single-arm clinical trials (including KEYNOTE-016 and KEYNOTE-164), treatment with pembrolizumab resulted in a 36% objective response rate in metastatic CRC patients and 46% in patients with other tumour types.8 Such was the efficacy of pembrolizumab that the US FDA granted accelerated approval in 2017 for its tissue-agnostic use in patients with dMMR/MSI-H unresectable or metastatic solid tumours, regardless of primary site. Since then, pembrolizumab has been shown to significantly improve progression-free survival, compared to chemotherapy, when received as first-line therapy in patients with dMMR/MSI-H metastatic CRC (KEYNOTE-177).9 Other ICIs have also shown equally promising results, such as nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) in the CheckMate 142 trial.10 Whilst previous studies were mostly in patients with metastatic CRC, more recent studies have shown excellent response to ICIs in patients with earlier stage CRC. In a phase II clinical trial by Cercek et al.,11 patients with dMMR stage II or III rectal adenocarcinoma would receive 3-weekly dostarlimab (anti-PD-1) for 6 months, followed by chemoradiotherapy and surgery, unless a complete clinical response (cCR) was achieved. Remarkably, despite the small sample size and short follow-up, all 12 patients (100%) had cCR after anti-PD-1 therapy and did not undergo further treatment including surgery. Similarly, in the latest NICHE-2 trial where patients with non-metastatic dMMR colon cancer received neoadjuvant nivolumab plus ipilimumab, 95% of patients had major pathological response, with 67% achieving pathological complete response.12 The authors suggested that neoadjuvant immunotherapy could become the standard of care in early colon cancer and potentially allow some patients to consider organ-sparing approaches. It is still unclear why patients with earlier stage CRC have such a significant response compared to those with metastatic CRC but it may be related to variations in the gut microbiome or alternatively, a more intact host immune system unaffected by chemoradiotherapy and where tumour mutational burden is low. At present, the recommendation for use of ICIs is largely limited to patients with metastatic disease, with pembrolizumab being listed on the Pharmaceutical Benefits Scheme in Australia as a first-line treatment option for unresectable or metastatic dMMR CRC since August 2021. Although recent studies have shown excellent efficacy of ICIs in earlier stage dMMR/MSI-H CRC, long-term response durability and survival data is not available so surgery remains the standard of care. However, it begs the question whether ICIs may be considered earlier in the treatment algorithm such as in the neoadjuvant setting. For this reason, universal MMR screening, either through MMR immunohistochemistry or MSI testing (not all MSI originates from dMMR), of all newly diagnosed CRC cases must be performed. This will identify suitable dMMR/MSI-H patients to access immunotherapy via clinical trials to evaluate the use of ICIs in a wider context. Future research should also focus on understanding the mechanisms of immunoresistance in the majority of CRCs (85%) which are associated with chromosomal instability. Developing strategies to convert these immunologically ‘cold’ tumours into ‘hot’ ones, such as combining ICIs with conventional therapies, is the focus of many ongoing studies. One such example is the Ave-Rec trial which is evaluating the addition of avelumab (anti-PD-L1) following long-course chemoradiotherapy in patients with resectable, locally advanced rectal cancer.13 Through broadening the susceptibility of other subsets of CRC to immunotherapy, its full potential may be unleashed, shining a beacon of hope for the treatment of CRC. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.