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As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57+ CD4+ T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil samples. Circulating CD57+ CD4+ T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8+ effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset had a pre-exhaustion transcriptomic signature marked by TCF7, TOX, and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition. Thus, CD57+ CD4+ T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers. CTLA4 is a key modifier of CD4+ T-cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated by infection.

PURPOSE We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL). METHODS HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible). RESULTS HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, −0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics. CONCLUSION Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.

As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T cell differentiation, and explain how environmental exposures modify clinical phenotypes conferred by single gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while CD57+ CD4+ T cells are normally rare in the circulation, we found that they are increased in patients with PAD, and markedly by CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil. Circulating CD57+ CD4+ T cells (CD4cyt) exhibit a cytotoxic transcriptome similar to CD8+ effectors, can kill B cells, and inhibit B cell responses. CTLA4 restrains the formation of CD4cyt. While CD57 also marks an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset has a precursor of exhaustion transcriptomic signature marked by TCF7, TOX, ID3, and constitutive expression of CTLA4, and are robust to becoming cytotoxic even after CTLA4 inhibition. Thus, CD57+ CD4+ T cell phenotypes of cytotoxicity and exhaustion are compartmentalized between blood and germinal centres. CTLA4 is a key modifier of CD4+ T cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated in CTLA4 deficiency by the environmental stimulus of infection.

IntroductionGlioblastoma (GBM) is the most common malignant primary central nervous system cancer in adults. The objective of the Multi-Arm GlioblastoMa Australasia (MAGMA) trial is to test hypotheses in real world setting to improve survival of people with GBM. Initial experimental arms are evaluating the effectiveness of interventions in newly diagnosed GBM (ndGBM). This study will compare maximal surgical resection followed by chemoradiotherapy plus adjuvant chemotherapy for 6 months with the addition of (1) ‘neoadjuvant’ chemotherapy beginning as soon as possible after surgery and/or (2) adjuvant chemotherapy continued until progression within the same study platform.Methods and analysisMAGMA will establish a platform for open-label, multiarm, multicentre randomised controlled testing of treatments for GBM. The study began recruiting in September 2020 and recruitment to the initial two interventions in MAGMA is expected to continue until September 2023.Adults aged ≥18 years with ndGBM will be given the option of undergoing randomisation to each study intervention separately, thereby giving rise to a partial factorial design, with two separate randomisation time points, one for neoadjuvant therapy and one for extended therapy. Patients will have the option of being randomised at each time point or continuing on with standard treatment.The primary outcome for the study is overall survival from the date of initial surgery until death from any cause. Secondary outcomes include progression-free survival, time to first non-temozolomide treatment, overall survival from each treatment randomisation, clinically significant toxicity as measured by grade 3 or 4 adverse events and health-related quality-of-life measures. Tertiary outcomes are predictive/prognostic biomarkers and health utilities and incremental cost-effectiveness ratio.The primary analysis of overall survival will be performed separately for each study intervention according to the intention to treat principle on all patients randomised to each study intervention.Ethics and disseminationThe study (Protocol version 2.0 dated 23 November 2020) was approved by a lead Human Research Ethics Committee (Sydney Local Health District: 2019/ETH13297). The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.Trial registration numberACTRN12620000048987.

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as "M0" at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29-1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16-0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. PATIENT SUMMARY: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting.

BackgroundTemozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.MethodsVERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.ResultsA total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.ConclusionThe veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.

Summary Background Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. Methods We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. Findings Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p Interpretation [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. Funding Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

LBA294 Background: AGOC has limited options after second-line therapy. Regorafenib (Rego), an oral multi-targeted tyrosine kinase inhibitor (TKI) targeting angiogenic, stromal and oncogenic receptor TKs, prolonged progression free survival (PFS) versus placebo (PBO) across all regions/subgroups in the INTEGRATE phase 2 randomised trial (JCO 2016 43(23):2728-2735). INTEGRATE IIa was designed to examine if Rego improves overall survival (OS). Methods: Double-blind placebo-controlled phase 3 trial comparing Rego + best supportive care (BSC) vs PBO + BSC using 2:1 randomisation, stratified by tumour location (GO junction vs gastric), geographic region (Asia vs rest of world), prior VEGF inhibitors (Y/N). Eligibility criteria: histologically/cytologically confirmed AGOC, evaluable metastatic/locally advanced disease, failure/intolerance of ≥ 2 prior lines of therapy with a platinum agent + fluoropyrimidine. Primary objective: OS in the whole study population. OS among Asian sub-population is a key secondary objective. Target of at least 221 events from 250 patients provides 80% power to detect an OS hazard ratio (HR) of 0.67. Pooled OS analysis incorporating INTEGRATE phase 2 data is also planned. Secondary endpoints include PFS, objective response rate, safety and quality of life. Results: 251 patients enrolled (Oct16 - Sep21) from 5 countries:157 from Asia (Korea, Taiwan, Japan);169 Rego and 82 PBO. After 238 events, median OS (in months) for Rego vs PBO was 4.5 vs 4.0 (HR 0.70 [95%CI: 0.53 to 0.92]; p = 0.011) in the whole study population, with a 12 mo survival of 19% vs 6%. Median PFS was 1.8 v 1.6 (HR = 0.52; [95%CI: 0.40-0.69]; p = < .0001). After pre-planned adjustment for multiplicity, there were no statistically significant differences across regions (Asia versus non-Asia) or other pre-specified subgroups. Pooled analysis median OS was 5.0 v 4.1 (HR 0.69 [95% CI:0.56 to 0.87]; p = 0.001). Rego toxicity was similar to previously reported. Conclusions: Rego improves survival compared with PBO in advanced refractory AGOC, offering a new treatment option. This result creates a therapeutic platform for combination studies. INTEGRATE IIb is an ongoing international randomised Phase 3 trial in pre-treated patients with AGOC comparing Rego + nivolumab to standard chemotherapy (NCT0487936). Clinical trial information: NCT02773524 .

Summary Background There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. Methods DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. Findings Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5–30·2). 31 (57%; 95% CI 44–70) of 54 patients were alive and progression-free at 6 months. The most common grade 3–4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. Interpretation The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. Funding AstraZeneca.

IntroductionThere is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial.Methods and analysisThis multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m2) 4–6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4–6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18–70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma.Ethics and disseminationThe protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.Drug SupplyAstraZeneca.Protocol versionCTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021.Trial registration numberClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.

IntroductionGrades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsiesMethods and analysisThis study will be a multicentre pilot study enrolling patients with recurrent grade 2/3 gliomas that have previously been treated with radiotherapy and chemotherapy at diagnosis or at first relapse. Contemporaneous tumour tissue at the time of first relapse, defined as tissue obtained within 6 months of relapse and without subsequent intervening therapy, will be obtained from patients. Molecular screening will be performed by targeted next-generation sequencing at the reference laboratory (PathWest, Perth, Australia). RNA and DNA will be extracted from representative formalin-fixed paraffin embedded tissue scrolls or microdissected from sections on glass slides tissue sections following a review of the histology by pathologists. Extracted nucleic acid will be quantified by Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Library preparation and targeted capture will be performed using the TruSight Tumor 170 (TST170) kit and samples sequenced on NextSeq 550 (Illumina) using NextSeq V.2.5 hi output reagents, according to the manufacturer’s instructions. Data analysis will be performed using the Illumina BaseSpace TST170 app v1.02 and a custom tertiary pipeline, implemented within the Clinical Genomics Workspace software platform from PierianDx (also refer to section 3.2). Primary outcomes for the study will be the number of patients enrolled and the number of patients who complete molecular screening. Secondary outcomes will include the proportion of screened patients enrolled; proportion of patients who complete molecular screening; the turn-around time of molecular screening; and the value of a brain tumour specific multi-disciplinary tumour board, called the molecular tumour advisory panel as measured by the proportion of patients in whom the treatment recommendation was refined compared with the recommendations from the automated bioinformatics platform of the reference laboratory testing.Ethics and disseminationThe study was approved by the lead Human Research Ethics Committee of the Sydney Local Health District: Protocol No. X19-0383. The study will be conducted in accordance with the principles of the Declaration of Helsinki 2013, guidelines for Good Clinical Practice and the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007, updated 2018 and as amended periodically). Results will be disseminated using a range of media channels including newsletters, social media, scientific conferences and peer-reviewed publications.Trial registration numberACTRN12620000087954; Pre-results.

BACKGROUND VERTU was a randomized phase II trial evaluating veliparib, a brain-penetrant PARP inhibitor, combined with radiotherapy and temozolomide, for patients with newly diagnosed MGMT-unmethylated glioblastoma. As part of planned correlative work after study completion, we assessed genome-wide DNA methylation patterns to predict methylation class, glioblastoma subtype and MGMT status. METHODS Patients were randomized 2:1 to experimental (60Gy/30 fractions with veliparib 200mg bid, then temozolomide 150-200mg/m2 D1-5 + veliparib 40mg bid D1-7 Q28D for 6 cycles) versus standard arm (60Gy/30 fractions with temozolomide 75mg/m2 daily, then temozolomide 150-200mg/m2 D1-5 Q28D for 6 cycles). The primary objective to improve 6-month progression-free survival (PFS-6m) was not met (doi: 10.1093/neuonc/noab111). Methylation data were generated using the Illumina Infinium Methylation EPIC bead chip array. Tumor tissues were categorized using the Heidelberg methylation-based classifier. RESULTS Methylation data were successfully generated for 98/125 patients (poor quality DNA [n = 12], no consent [n = 11], insufficient tissue [n = 4]). Those with classifier scores below 0.5 (n = 25), tumor microenvironment only (n = 6) and rediagnosis as pleomorphic xanthoastrocytoma (n = 1) were excluded, leaving n = 66. Methylation classes were GBM RTK II (n = 23, PFS-6m 43% [95%CI 23-62]), RTK I (n = 20, PFS-6m 50% [95%CI 27-69]), MES (n = 20, PFS-6m 40% [95%CI 19-60]), MID (n = 2) and G34 (n = 1). Glioblastoma subtypes were mesenchymal (n = 28, PFS-6m 50% [95%CI 30-66]), proneural (n = 24, PFS-6m 50% [95%CI 29-68]) and classical (n = 14, PFS-6m 36% [95%CI 13-59]). MGMT status were unmethylated (n = 58, PFS-6m 48% [95%CI 35-60]) and methylated (n = 8, PFS-6m 38% [95%CI 9-67]). There was no evidence of interaction between treatment arm and methylation class (excluding GBM MID and G34, P = 0.45), glioblastoma subtype (P = 0.68) or MGMT status (P = 0.52). CONCLUSIONS Genome-wide DNA methylation patterns in VERTU identified a spectrum of methylation-defined subgroups, reflecting tumoral heterogeneity. This may have utility for future clinical trials and practice. The effect of veliparib in VERTU appeared to be consistent across subgroups. ACTRN12615000407594.

BACKGROUND Nivolumab is a PD-1 inhibitor with known safety profile. An increase in mutations as we age is well documented in glioblastoma and other cancers. Higher mutational load is associated with increased response to nivolumab in extracranial malignancies. NUTMEG examined the activity of nivolumab added to temozolomide in glioblastoma patients aged ≥ 65 years. METHODS NUTMEG was an international multicenter phase II trial for newly diagnosed glioblastoma patients aged ≥ 65 years, randomized 2:1 to experimental (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide 150-200mg/m2 D1-5 Q28D + nivolumab 240mg D1,15 Q28D C1-4 and 480mg D1 Q28D C5-6) versus standard arm (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide alone 150-200mg/m2 D1-5 Q28D), stratified by age, ECOG status, MGMT status and resection extent. RESULTS 103 patients were enrolled (69 in experimental arm, 34 in standard arm). Median age was 73 years, 36% ECOG 0, 57% MGMT-unmethylated and 51% gross macroscopic resection. Median follow-up is 31 months to date, with 77 deaths (surviving patients to continue follow-up and final results will be presented). Median overall survival was 11.8 months in the experimental arm versus 12.0 months in the standard arm (HR 0.95 95%CI 0.59-1.53 for experimental relative to control). Six-month progression-free survival rate using mRANO was 64% in the experimental arm versus 49% in the standard arm (HR 0.81 95%CI 0.51-1.26). Grade 3/4 adverse events were reported in 46% of experimental arm (7% lung infection, 7% thromboembolic events, 6% fatigue, 6% muscle weakness) and in 29% of control arm (9% fatigue, 6% seizure, 6% thromboembolic events). CONCLUSIONS There was insufficient evidence of clinical benefit with nivolumab in this population. No new safety signals were identified. Central imaging review is underway and correlative studies will characterize the immune landscape, including mutational load, neoantigen and other immune markers. NCT04195139.

Background Among patients with non-metastatic pancreatic cancer, 80% have high-risk, borderline resectable or locally advanced cancer, with a 5-year overall survival of 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in these patients. Methods and design MASTERPLAN is a multi-centre randomised phase II trial of 120 patients with histologically confirmed potentially operable pancreatic cancer (POPC) or inoperable pancreatic cancer (IPC). POPC includes patients with borderline resectable or high-risk tumours; IPC is defined as locally advanced or medically inoperable pancreatic cancer. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy alone (control arm) by minimisation and stratified by patient cohort (POPC v IPC), planned induction chemotherapy and institution. Chemotherapy can have been commenced ≤28 days prior to randomisation. Both arms receive 6 × 2 weekly cycles of modified FOLFIRINOX (oxaliplatin (85 mg/m2 IV), irinotecan (150 mg/m2), 5-fluorouracil (2400 mg/m2 CIV), leucovorin (50 mg IV bolus)) plus SBRT in the investigational arm. Gemcitabine+nab-paclitaxel is permitted for patients unsuitable for mFOLFIRINOX. SBRT is 40Gy in five fractions with planning quality assurance to occur in real time. Following initial chemotherapy ± SBRT, resectability will be evaluated. For resected patients, adjuvant chemotherapy is six cycles of mFOLFIRINOX. Where gemcitabine+nab-paclitaxel was used initially, the adjuvant treatment is 12 weeks of gemcitabine and capecitabine or mFOLFIRINOX. Unresectable or medically inoperable patients with stable/responding disease will continue with a further six cycles of mFOLFIRINOX or three cycles of gemcitabine+nab-paclitaxel, whatever was used initially. The primary endpoint is 12-month locoregional control. Secondary endpoints are safety, surgical morbidity and mortality, radiological response rates, progression-free survival, pathological response rates, surgical resection rates, R0 resection rate, quality of life, deterioration-free survival and overall survival. Tertiary/correlative objectives are radiological measures of nutrition and sarcopenia, and serial tissue, blood and microbiome samples to be assessed for associations between clinical endpoints and potential predictive/prognostic biomarkers. Interim analysis will review rates of locoregional recurrence, distant failure and death after 40 patients complete 12 months follow-up. Fifteen Australian and New Zealand sites will recruit over a 4-year period, with minimum follow-up period of 12 months. Discussion MASTERPLAN evaluates SBRT in both resectable and unresectable patients with pancreatic ductal adenocarcinoma. Trial registration Australia New Zealand Clinical Trials Registry ACTRN12619000409178, 13/03/2019. Protocol version: 2.0, 19 May 2019

BackgroundIn this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)—mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR).MethodsA multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics.ResultsSeventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1–2.ConclusionDurvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR.Trial registration numbersANZGOG1601, ACTRN12617000106336, and NCT03015129.

Objectives To determine the activity and safety of lutetium-177 (177 Lu)-prostate-specific membrane antigen (PSMA)-617 in men with metastatic castration-resistant prostate cancer (mCRPC) commencing enzalutamide, who are at high risk of early progression, and to identify potential prognostic and predictive biomarkers from imaging, blood and tissue. Participants and methods ENZA-p (ANZUP 1901) is an open-label, randomized, two-arm, multicentre, phase 2 trial. Participants are randomly assigned (1:1) to treatment with enzalutamide 160 mg daily alone or enzalutamide plus 177 Lu-PSMA-617 7.5 GBq on Days 15 and 57. Two additional 177 Lu-PSMA-617 doses are allowed, informed by Day-92 Gallium-68 (68 Ga)-PSMA positron emission tomography (PET; up to four doses in total). The primary endpoint is prostate-specific antigen (PSA) progression-free survival (PFS). Other major endpoints include radiological PFS, PSA response rate, overall survival, health-related quality of life, adverse events and cost-effectiveness. Key eligibility criteria include: biochemical and/or clinical progression; 68 Ga-PSMA PET-avid disease; no prior androgen signalling inhibitor, excepting abiraterone; no prior chemotherapy for mCRPC; and ≥2 high-risk features for early enzalutamide failure. Assessments are 4 weekly during study treatment, then 6 weekly until radiographic progression. Response Evaluation Criteria in Solid Tumours (RECIST) are used to assess imaging conducted every 12 weeks, 68 Ga-PSMA PET at baseline, Days 15 and 92, and at progression, and 18 F-fluorine deoxyglucose (18 F-FDG) PET at baseline and progression. Translational samples include blood (and optional biopsies) at baseline, Day 92, and first progression. Correlative studies include identification of prognostic and predictive biomarkers from 68 Ga-PSMA and 18 F-FDG PET/CT, circulating tumour cells and circulating tumour DNA. The trial will enrol 160 participants, providing 80% power with a two-sided type-1 error rate of 5% to detect a hazard ratio of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. Results and conclusion The combination of 177 Lu-PSMA-617 and enzalutamide may be synergistic. ENZA-p will determine the safety and efficacy of the combination in addition to developing predictive and prognostic biomarkers to better guide treatment decisions.

International collaboration in oncology trials has the potential to enhance clinical trial activity by expediting the recruitment of large patient populations, testing treatments in diverse populations and facilitating the study of rare tumours or specific molecular subtypes. However, a number of challenges continue to hinder the efficient and productive conduct of both commercial and non-commercial international clinical trials. These challenges include complex and burdensome regulatory requirements, the high cost of conducting trials, and logistical challenges associated with ethics review, drug supply and biospecimen collection and management. We propose solutions to promote oncology trial collaboration, such as regulatory reform, harmonisation of trial initiation and management processes and greater recognition and funding of academic (non-commercial) clinical trials. It is only through coordinated effort and leadership from researchers, regulators and those responsible for health systems that the full potential of international trial collaboration can be realised.

BACKGROUND Grade 2 and 3 (G2/3) gliomas are the second largest group of brain tumors in adults. Although the prognosis for G2/3 gliomas at the time of relapse mirror those of glioblastoma, there are few trials in this space. METHODS LUMOS was a national multi-center pilot study for patients with relapsed G2/3 gliomas designed to match contemporaneous tissue obtained at the time of disease progression with subsequent targeted therapies. The objective was to establish the feasibility of a precision oncology, umbrella approach to obtain and type tissue within a useful timeframe. As a key feature of LUMOS, a multidisciplinary Molecular Tumor Advisory Panel (MTAP) with subspecialty neuro-oncology expertise was formed to interpret the complex genomic information and provide a simplified recommendation to the treating physician. RESULTS Ten patients (median age 42: range 32-62; four G2 astrocytoma, one G3 astrocytoma, three G2 oligoendroglioma, one G3 oligodendroglioma, one mixed tumor) were enrolled in the study. Eight patients had biopsies within 6 months of study entry whilst two underwent a biopsy during the study. All patients had potentially targetable alterations (10 IDH, 3 FGFR, 2 PIK3K, CCND3, NRAS, CDK4, PRPRZ1-MET fusion and MET amplification). Matched therapies were delivered for two patients via compassionate access outside the study. The median turnaround time (TAT) of MTAP reports was 6.2 weeks (range 4.2-9.7 weeks) but 4.6 weeks when lag time for shipping was removed. CONCLUSION LUMOS confirmed that this design was feasible with good turnaround times. The MTAP facilitated education and support for treating physicians. Thes findings support moving to a larger study using contemporaneous and longitudinal tissue samples matched with targeted therapies as part of a comprehensive umbrella study design. Delivery and interpretation of molecular data is a challenge shared across oncology which may be mitigated with a neuro-oncology specific molecular tumor board.

BACKGROUND Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide. METHODS Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities. PROGRESS Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.

Purpose/Objective(s) Synergy and abscopal phenomena have been observed with radiation and immunotherapy in pre-clinical and early clinical studies. Nivolumab, a PD-1 receptor antibody, improved overall survival in advanced NSCLC progressing after chemotherapy. We hypothesized that the addition of SABR might increase the activity of nivolumab. The aim of NIVORAD was to determine the activity and safety of treating a site of disease with a single fraction of SABR during therapy with nivolumab in advanced NSCLC progressing after 1 or 2 lines of chemotherapy. Materials/Methods Adults with metastatic NSCLC progressing after 1 or 2 lines of chemotherapy and a disease site suitable for SABR were randomly assigned (2:1) to either nivolumab 240mg 2-weekly until disease progression or prohibitive toxicity given together with a single fraction of SABR (18-20 Gy on day 8-14 of cycle 1); or, the same regimen of nivolumab without SABR. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints included objective tumor response rate (OTRR), overall survival (OS), PFS at 1 year and 2 years, and adverse events (AEs). The planned sample size of 120 provided 80% power with a 1-sided type 1 error rate of 5% to distinguish the observed proportions alive and progression free at 6 months from benchmarks of 50% (worthy of pursuit) versus 35%. The study was closed early because of slow accrual. Results Fifty of the planned 120 participants were recruited from MAR2017 to JUN2019 (median age 66 years; male 58%; ECOG PS 0 32%, PS 1 68%; current smoker 30%) and randomly assigned to either nivolumab plus SABR (n = 34) or nivolumab alone (n = 16). Median follow-up was 25 months. PFS was similar among those assigned nivolumab plus SABR versus nivolumab alone (HR = 0.82, 95% CI 0.44 to 1.54, P = 0.6; PFS at 6mo 44% vs 43%, at 1y 27% vs 19%, and at 2y 16% vs 6%, respectively). OTRR (8/34 [24%] vs 4/16 [25%]) and OS (HR 0.94, P = 0.9) were also similar in the two treatment groups, as were the numbers of participants with grade 3-4 AEs: 24/30 (80%) vs 12/16 (75%) respectively. There were no treatment-related deaths in either arm. Conclusion Nivolumab plus SABR demonstrated similar activity and safety to nivolumab alone in NSCLC progressing after 1 or 2 lines of chemotherapy, with a potential signal of long-term efficacy, although the study was underpowered to detect this. Research should focus on identifying more active regimens of SABR and immunotherapy worthy of further evaluation.

TPS8599 Background: Combination PD1/CTLA4 immune checkpoint blockade and platinum-pemetrexed (CP) chemotherapy are standard first-line options for the treatment of unresectable malignant pleural mesothelioma (MPM). Two recent, single-arm, phase 2 trials (DREAM and PrE0505) combining the PD-L1 inhibitor durvalumab and standard first line CP both exceeded pre-specified efficacy criteria. The Phase 3 DREAM3R trial aims to determine the effectiveness of including durvalumab with first line CP chemotherapy in advanced MPM. Methods: Treatment-naïve patients with advanced MPM will be randomized (2:1) to either durvalumab 1500 mg every 3 weeks plus chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 5 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles (Arm A), followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, versus doublet chemotherapy alone for 4-6 cycles with all patients monitored for progression. The target sample size is 480 patients recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival (OS) is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Key eligibility criteria include: MPM of any histological subtype; measurable disease per RECIST 1.1 modified for mesothelioma (mRECIST 1.1); ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for MPM, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Patients will be further stratified at randomization by: Age (18-70 years vs. > 70), sex, histology (epithelioid vs. non-epithelioid), planned platinum (cisplatin vs. carboplatin) and geographic region (USA vs. ANZ). The primary endpoint is OS. Secondary endpoints include progression-free survival; objective tumor response; adverse events; health-related quality of life; and healthcare resource use in ANZ. Tertiary correlative objectives aim to further explore and validate potential prognostic and/or predictive biomarkers (including those identified in the DREAM and PrE0505 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes) via tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The study is active and enrolling in both ANZ and in the US. Clinical trial information: NCT04334759 and ACTRN 12620001199909.

Introduction Consent to biobanking remains controversial, with little empirical data to guide policy and practice. This study aimed to explore the attitudes, motivations, and concerns of both oncology patients and health care professionals (HCPs) regarding biobanking. Materials and methods Qualitative interviews were conducted with oncology patients and HCPs purposively selected from five Australian hospitals. Patients were invited to give biobanking consent as part of a clinical trial and/or for future research were eligible. HCPs were eligible if involved in consenting patients to biobanking or to donate specimens to clinical trials. Results Twenty-two patients participated, with head and neck (36%) and prostate (18%) the most common cancer diagnoses; all had consented to biobanking. Twenty-two HCPs participated, from across eight cancer streams and five disciplines. Themes identified were (a) biobanking is a "no brainer"; (b) altruism or scientific enquiry; (c) trust in clinicians, science, and institutions; (d) no consent-just do it; (e) respecting patient choice ("opt-out"); (f) respectful timing of the request; (g) need for emotional/family support; (h) context of the biobanking request matters; and (i) factors for biobanking success. Discussion These findings reinforced previous findings regarding high public trust in, and support for, biobanking. An initial opt-in consent approach with the option of later opt-out was favored by patients to respect and recognize donor generosity, whereas HCPs preferred an upfront opt-out model. Factors impacting biobanking success included the context of the request for use in a trial or specific research question, pre-existing patient and HCP rapport, a local institution champion, and infrastructure. Implications for practice Patients and health care professionals (HCPs) who experienced cancer biobanking consent were overwhelmingly supportive of biobanking. The motivations and approaches to seeking consent were largely mirrored between the groups. The findings of this study support the opt-in model of biobanking favored by patients; however, HCPs preferred an opt-out model. Both groups recognize the importance of making the request for biobanking at an appropriate time, preferably with emotional or family support, and respecting the timing of the request and privacy of the patient. Biobanking success can be promoted by hospital departments with a research focus by identifying an institutional biobanking champion and ensuring local infrastructure is available.

Background The primary aim of this study was to evaluate the activity of intraperitoneal bevacizumab (IP-bev) in delaying re-accumulation of malignant ascites in women with chemotherapy-resistant epithelial ovarian cancer (CR-EOC) who have ceased chemotherapy. Secondary outcomes were safety and quality of life. Methods Women with CR-EOC and malignant ascites that reaccumulated within 28 days of their last paracentesis (P-1) were administered IP-bev 5 mg/kg following their first therapeutic paracentesis on study (P0). Additional doses of IP-bev were allowed at each subsequent paracentesis (P1, P2, etc) provided the interval from the last dose was 42 days or greater (median time from first to second therapeutic ascitic drainage). Results 24 participants (median age 67 years [range 38–86]; median 4.5 lines prior systemic treatment [range 1–12]; ECOG performance status of 0 in 1, 1 in 8, and 2–3 in 15) were recruited. The doses of IP-bev administered were 1 in 13 participants, 2 in 5, 3 in 2, 4 in 1, and 5 in 1. The proportion with a TTP of >42 days using competing risk analysis was 77% (95% CI 58–92). Median time from P0 to P1 or death was 48 days (range 8–248). Median paracentesis-free interval (P0–P1 or death) was 4.29-fold (95% CI 2.4–5.8) higher following a first dose of IP-bev compared with the time between paracenteses prior to study entry (P-1–P0). Conclusion IP-bev was safe, active, and warrants further study as a palliative intervention for recurrent ascites in CR-EOC patients receiving best supportive care.

TPS366 Background: Advanced Gastro-oesophageal Carcinoma (AGOC) has a poor prognosis, and there is no established standard treatment following failure of first- and second-line chemotherapy. Regorafenib (BAY 73-4506) is an investigational oral multi-targeted tyrosine kinase inhibitor (TKI) which targets angiogenic (VEGF, TIE-2), stromal (PDGF-β), and oncogenic (RAF, RET and KIT) receptor tyrosine kinases, and has shown activity in this setting. Single agent regorafenib prolonged progression free survival (PFS) versus placebo across all regions/subgroups in the INTEGRATE randomised phase 2 trial. Current options in refractory AOGC involves sequencing through chemotherapy with the latest active agent approved being trifluridine/tipiracil, TAS-102. Promising activity in refractory AOGC has been seen with the combination of regorafenib & nivolumab. INTEGRATE IIb–will compare the effectiveness of the combination of regorafenib & nivolumab in pre-treated patients with AGOC to current standard chemotherapy. Methods: Randomised phase III, open label study with 2:1 randomisation (RegoNivo : standard chemotherapy) and stratification by: Geographic region (Asia vs. Rest of World); Prior VEGF inhibitors (Yes vs No); Prior immunotherapy (Yes vs No). RegoNivo arm will receive 90mg (3x30mg) of regorafenib days 1-21 of each 28-day treatment cycle with intravenous nivolumab 240 mg day 1 of each 14 day cycle until disease progression or prohibitive adverse events as per protocol. The control arm will receive the investigator’s choice of the following chemotherapy; a taxane (paclitaxel or docetaxel), irinotecan or oral trifluridine/tipiracil (TAS102). Primary endpoint: OS. Secondary endpoints: PFS, response rate, quality of life, toxicity, exploratory correlative biomarkers. Clinical trial information: NCT04879368.

Background: Cisplatin and pemetrexed chemotherapy provides modest survival benefits for malignant pleural mesothelioma (MPM). This study evaluated cisplatin and pemetrexed with, and followed by, the anti-PD-L1 (programmed death ligand-1) antibody durvalumab in advanced MPM. Methods: DREAM was a single-arm, multicentre open label phase 2 study in patients with treatment-naive advanced MPM. Eligible patients had Eastern Cooperative Oncology Group performance status 0 or 1 and measurable disease. The first six patients were treated on a two-cycle safety lead-in. All patients received cisplatin 75mg/m2, pemetrexed 500mg/m2, and durvalumab 1125mg fixed dose on day 1 of a three-weekly schedule to maximum six cycles chemotherapy. Change from cisplatin to carboplatin AUC5 was permitted. Durvalumab was continued to complete up to 12 months total treatment. The primary endpoint was progression-free survival at six months (PFS6); secondary outcomes included objective tumour response rate (RR), overall survival (OS), and adverse event (AE) rates. Findings: Fifty-four patients were registered and treated. Most were male (83%), with epithelioid subtype (83%), and a median age of 68 years. The proportion alive and progression-free at six months was 54%; median PFS was 6.9 months (95% CI 5.5–9.0). Median OS was 18.4 months (95% CI 13.1–24.8). RR according to modified RECIST for MPM was 48% (95% CI 36–61%), with partial responses in 26 (48%) and stable disease in 21 (37%) patients, respectively. AEs reflected the expected toxicities of combining chemotherapy and durvalumab. None of the five deaths during study treatment were attributed to durvalumab. There was no association between tumour expression of PD-L1 and PFS. Interpretation: This single-arm phase 2 trial demonstrated that the combination of durvalumab, cisplatin, and pemetrexed has promising activity and safety to warrant the conduct of a randomised phase 3 trial. Funding: AstraZeneca provided study drug and funding. Declaration of Interest: The other authors declared no conflicts of interest. Ethical Approval: DREAM conformed to ethical principles of the Declaration of Helsinki and the International Council on Harmonization guidelines on Good Clinical Practice. The protocol was approved by a central Human Research Ethics Committee (HREC), and all site HRECs. All patients provided written informed consent before any screening procedures. Patients confirmed eligible after screening were registered to the study.

Bleomycin, etoposide, and cisplatin (BEP) chemotherapy administered every 3 weeks for 4 cycles remains the standard first line treatment for patients with intermediate- and poor-risk metastatic germ cell tumours (GCTs). Administering standard chemotherapy 2-weekly rather than 3-weekly, so-called ‘accelerating chemotherapy’, has improved cure rates in other cancers. An Australian multicentre phase 2 trial demonstrated this regimen is feasible and tolerable with efficacy data that appears promising. The aim of this trial is to determine if accelerated BEP is superior to standard BEP as first line chemotherapy for adult and paediatric male and female participants with intermediate and poor risk metastatic GCTs. This is an open label, randomised, stratified, 2-arm, international multicentre, 2 stage, phase 3 clinical trial. Participants are randomised 1:1 to receive accelerated BEP or standard BEP chemotherapy. Eligible male or female participants, aged between 11 and 45 years with intermediate or poor-risk metastatic GCTs for first line chemotherapy will be enrolled from Australia, the United Kingdom and the United States. Participants will have regular follow up for at least 5 years. The primary endpoint for stage 1 of the trial (n = 150) is complete response rate and for the entire trial (n = 500) is progression free survival. Secondary endpoints include response following treatment completion (by a protocol-specific response criteria), adverse events, health-related quality of life, treatment preference, delivered dose-intensity of chemotherapy (relative to standard BEP), overall survival and associations between biomarkers (to be specified) and their correlations with clinical outcomes. This is the first international randomised clinical trial for intermediate and poor-risk metastatic extra-cranial GCTs involving both adult and pediatric age groups open to both males and females. It is also the largest, current randomised trial for germ cell tumours in the world. Positive results for this affordable intervention could change the global standard of care for intermediate and poor risk germ cell tumours, improve cure rates, avoid the need for toxic and costly salvage treatment, and return young adults to long, healthy and productive lives. ACTRN 12613000496718 on 3rd May 2013 and Clinicaltrials.gov NCT02582697 on 21st October 2015.

5584 Background: Activity of durvalumab in patients with deficient mismatch repair (dMMR) advanced endometrial carcinoma (EC) was confirmed in the PHAEDRA trial (ANZGOG 1601). This study investigated the association between immune biomarkers and clinical outcomes in PHAEDRA. Methods: Formalin-fixed paraffin embedded sections immunohistochemically stained for PD-L1 using the Ventana platform, were with matched H&E slides scored independently by two pathologists according to the Ventana PD-L1 (SP263) algorithm for urothelial carcinoma (UC). Immune biomarkers assessed were PD-L1 staining of tumor cells (TCP) and immune cells (IC), and presence of tumor-associated immune cells (ICP). Results: Sixty-seven of the 71 patients had sufficient tumor for PD-L1 testing. AUC were 0.667, 0.726 and 0.644 for TCP, ICP and IC, respectively for predicting tumor response. Optimal cutpoints were TCP≥1%, ICP≥10% and IC≥35%. ICP≥10% achieved the highest sensitivity (53%) and specificity (82%) of the individual cutpoints. The optimal cutpoint algorithm was able to identify patients who would not respond, (sensitivity 88%, negative predictive value 92%), but had low specificity (48%) and positive predictive value (37%). Differences in PFS were found using ICP≥10% (logrank p = 0.01), compared to TCP (p = 0.25), IC (p = 0.48) and the UC algorithm (p = 0.08) (Figure 1). PFS was shorter in patients with pMMR than dMMR after adjusting for ICP (HR 2.99, 95%CI: 1.61-5.57, p < 0.001). Adjustment for MMR reduced the prognostic significance of ICP≥10% for PFS (HR 0.59, 95% CI: 0.28-1.23, p = 0.16). For OS, differences were seen for the UC algorithm (p = 0.02), but not ICP (p = 0.07), TCP (p = 0.18) or IC (p = 0.23). Similarly to PFS, adjustment for MMR reduced the prognostic significance of the UC algorithm for OS (HR: 0.53, 95% CI: 0.25-1.12, p = 0.10). Conclusions: In this exploratory analysis, ICP was more closely associated with tumor response and PFS than TCP or IC. ICP alone was better than the UC algorithm for predicting PFS. The optimum cutpoint algorithm was promising for identifying non-responders, but requires external validation. Clinical trial information: ACTRN12617000106336.

TPS4172 Background: Eighty per cent of patients with non-metastatic pancreatic cancer have high-risk, borderline resectable (BRPC) or locally advanced pancreas cancer (LAPC), conferring a 5-year overall survival of only 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) added to neoadjuvant chemotherapy in these patient cohorts. Methods: MASTERPLAN is an investigator-initiated prospective multi-centre randomized phase II trial. Inclusion criteria include histologically confirmed high-risk, BRPC or LAPC. High risk is defined as tumour > 4cm, extrapancreatic extension or node positive. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy (control arm) by minimisation with stratification by operability (potentially operable - high risk; BRPC versus inoperable – LAPC; medically inoperable), planned chemotherapy and institution. Both treatment arms receive 6 x 2 weekly cycles of modified FOLFIRINOX (mFOLFIRINOX). Gemcitabine and nab-paclitaxel is permitted if mFOLFIRINOX is unsuitable. The investigational arm receives SBRT (40Gy in 5 fractions) with real time quality assurance. Resectability will be evaluated following initial chemotherapy +/- SBRT. Adjuvant chemotherapy is 6 cycles (12 weeks) of mFOLFIRINOX, or the same duration of gemcitabine and capecitabine (GEMCAP) if neoadjuvant gemcitabine/ nab-paclitaxel given. SBRT adverse events (AEs) will be recorded until study cessation. The primary endpoint is 12-month locoregional control. Secondary endpoints: safety, surgical morbidity and mortality, radiological response rate, progression free survival, pathological response rate, surgical resection rate, R0 resection rate, quality of life, deterioration free survival and overall survival. Biospecimens are collected for translational research for potential prognostic/predictive biomarkers of clinical endpoints and include serial tumour tissue collection from patients undergoing fiducial marker insertion and/or surgery, biopsy at disease progression, serial blood collection and serial buccal and faecal sample collection. An interim analysis will review locoregional failure, distant metastasis and rate of death on the first 40 patients after completion of 12 months follow up. The sample size is 120 patients (80 intervention:40 control), balanced for BRPC/LAPC (60 in each cohort). The minimum follow up is 12 months. The first site opened in October 2019 and 10 patients have been recruited from five sites at 17 Feb 2021. Overall 15 sites in Australia and New Zealand are planned to open to recruitment. Australian Clinical Trials Registry Number: ACTRN12619000409178. Clinical trial information: ACTRN12619000409178.

The CABARET trial (ACTRN12610000915055) reported no difference in overall survival (OS) between patients with recurrent glioblastoma (GBM) randomized to either bevacizumab monotherapy or bevacizumab plus carboplatin. However, a subset of patients showed durable responses and prolonged survival, with recorded survival times of over 30 months in five of 122 patients (4%). Patient selection for bevacizumab therapy would be enhanced if a predictive biomarker of response or survival could be identified; this biomarker sub-study attempted to identify novel biomarkers. Patients who opted to participate in this sub-study and who had adequate biospecimens for analysis (n = 54) were retrospectively evaluated for the expression of a series of tumor proteins. Immunohistochemistry (IHC) was used to measure the expression of 19 proteins previously implicated in cancer treatment response to bevacizumab. MGMT promoter methylation was also assessed. Tumor DNA from five patients with outlying survival duration (‘poor’ and ‘exceptional’ survivors) was subjected to whole genome sequencing (WGS). No single protein expression level, including VEGF-A, predicted OS in the cohort. WGS of poor and exceptional survivors identified a gain in Chromosome 19 that was exclusive to the exceptional survivors. Validation of this finding requires examination of a larger independent cohort.

Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

TPS177 Background: 177Lu‐PSMA‐617 (LuPSMA) is a novel radionuclide with promising activity and tolerability in metastatic, castration-resistant prostate cancer (mCRPC). Pre-clinical studies have shown that androgen receptor blockade with enzalutamide upregulates PSMA-receptor expression, and that PSMA-receptor blockade increases treatment response to enzalutamide. We hypothesise that concurrent administration of LuPSMA and enzalutamide will be synergistic in mCRPC. The aims of ENZA-p are to determine the activity and safety of LuPSMA and enzalutamide in men with mCRPC at high-risk of early progression on enzalutamide alone; and to identify potential prognostic and predictive biomarkers from imaging, blood, and tissue. Methods: This open-label, randomised, multicentre, phase 2 trial will recruit 160 men with mCRPC. Key eligibility criteria include progression on androgen deprivation therapy, 2 or more high-risk features for early (LDH ≥ULN; ALP ≥ULN; albumin 5 bone metastases; visceral metastases; PSA doubling time 14 days; prior abiraterone), no prior treatment with a novel androgen signalling inhibitor (except abiraterone), no prior chemotherapy for mCRPC, and PSMA-avid disease on positron emission tomography (PET) with 68Ga-PSMA. Participants are randomly assigned (1:1) enzalutamide 160 mg daily or enzalutamide 160 mg daily plus LuPSMA 7.5 GBq on days 15 and 57. Two subsequent doses of Lu-PSMA will be administered if the 68Ga-PSMA PET on day 92 shows persistent PSMA expression in the tumour. Imaging assessments include CT and technetium bone scan at baseline, day 99, then every 12 weeks; 68Ga-PSMA-11 PET at baseline, days 15, 92, and first progression; and 18F FDG PET at baseline and first progression. Translational samples including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA) and biopsies (optional) will be collected at baseline, day 92, and first progression. The primary endpoint is PSA progression-free survival (PSA-PFS). Secondary endpoints include radiological-PFS, PSA-response rate, pain response and PFS, clinical-PFS, overall survival, health related quality of life, adverse events, and cost-effectiveness. Correlative studies include identification of prognostic and predictive biomarkers from 68Ga-PSMA, 18F FDG PET/CT, CTCs, and ctDNA. A sample size of 160 provides 80% power with a 2-sided type 1-error rate of 5% to detect a HR of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. Accrual was 5 on 13 October 2020. ENZA-p is an investigator-initiated, academic trial led by ANZUP in collaboration with the NHMRC Clinical Trials Centre, University of Sydney. Clinical trial information: NCT04419402.

Purpose We evaluated the activity of regorafenib, an oral multikinase inhibitor, in advanced gastric adenocarcinoma. Patients and Methods We conducted an international (Australia and New Zealand, South Korea, and Canada) randomized phase II trial in which patients were randomly assigned at a two-to-one ratio and stratified by lines of prior chemotherapy for advanced disease (one v two) and region. Eligible patients received best supportive care plus regorafenib 160 mg or matching placebo orally on days 1 to 21 of each 28-day cycle until disease progression or prohibitive adverse events occurred. The primary end point was progression-free survival (PFS). Final analysis included data to December 31, 2014. Results A total of 152 patients were randomly assigned from November 7, 2012, to February 25, 2014, yielding 147 evaluable patients (regorafenib, n = 97; placebo, n = 50). Baseline characteristics were balanced. Median PFS significantly differed between groups (regorafenib, 2.6 months; 95% CI, 1.8 to 3.1 and placebo, 0.9 months; 95% CI, 0.9 to 0.9; hazard ratio [HR], 0.40; 95% CI, 0.28 to 0.59; P < .001). The effect was greater in South Korea than in Australia, New Zealand, and Canada combined (HR, 0.12 v 0.61; interaction P < .001) but consistent across age, neutrophil-to-lymphocyte ratio, primary site, lines of chemotherapy, peritoneal metastasis presence, number of metastatic sites, and plasma vascular endothelial growth factor A. A survival trend in favor of regorafenib was seen (median, 5.8 months; 95% CI, 4.4 to 6.8 v 4.5 months; 95% CI, 3.4 to 5.2; HR, 0.74; P = .147). Twenty-nine patients assigned to placebo received open-label regorafenib after disease progression. Regorafenib toxicity was similar to that previously reported. Conclusion In this phase II trial, regorafenib was effective in prolonging PFS in refractory advanced gastric adenocarcinoma. Regional differences were found, but regorafenib was effective in both regional groups. A phase III trial is planned.

TPS385 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinising hormone releasing hormone analogue (LHRHA) for at least one year, is standard of care for men with very high-risk localised prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high risk features. Darolutamide is an androgen receptor antagonist with favourable tolerability. Our aim is to determine the efficacy of adding darolutamide to ADT and RT given in the setting of either primary definitive therapy (RP or RT), or adjuvant therapy for very high-risk PC. Methods: This study is a randomised (1:1) phase III placebo-controlled, double-blind trial for men planned for RT who have very high-risk localised PC, or very high-risk features with PSA persistence or rise within one year following RP. The trial will be stratified by: use of adjuvant docetaxel; pelvic nodal involvement; RP. 1100 participants will be randomised to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomisation. Participants are allowed nonsteroidal antiandrogen (up to 90 days) in addition to LHRHA up until randomisation. Early treatment with 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety and resistance to study treatment. Clinical trial information: NCT04136353.

TPS271 Background: Pan added to combination chemotherapy is established first-line therapy for RAS and BRAF wild type mCRC. Elderly patients are not well represented in clinical trials and may be more suited to treatment protocols with lower toxicity risks; FU plus bevacizumab (bev) is commonly used. Treatment related efficacy, toxicity, impact on quality of life and other outcomes of pan based regimens in an elderly population have not been well studied. Methods: A prospective non-comparative randomized phase 2 study. Australian Clinical Trials Registry Number: ACTRN 12618000233224. Main inclusion criteria include: Untreated patients aged 70 years or older; RAS and BRAF wild type; ECOG performance 0-2. Randomisation 1:1, stratified by primary tumour side, performance status, number of metastatic sites; to pan 6mg/kg 2 weekly or panitumumab plus FU 400 mg/m² bolus; leucovorin 200mg/m²; FU 2400mg/m² 48 hour infusion 2 weekly. Primary endpoint is 6-month progression-free survival (PFS). Sample size is 80 patients based on expected 6-month PFS rate of 73% with FU and bev. Using the method of Metha-Cain, if 24 or more patients are progression free at 6 months, the one sided 95% confidence interval includes 73% and we declare similar activity. Secondary endpoints include overall survival; toxicity and overall treatment utility, a composite measure of treatment benefit based on radiology, clinical progress, toxicity and patient reflection of the impact of treatment on their daily lives. Patients undergo a comprehensive health assessment at baseline and limited health assessment at 4 months. Physical activity trackers are worn for 2 weeks at treatment commencement and again at week 16. Tumour tissue and blood samples (at baseline, cycle 3 day 1 and at 24 weeks) will be collected for translational research. First site opened in June 2018. Twelve patients have been recruited to date from 9 sites in Australasia. Eighteen sites were open as at September 2019. Clinical trial information: 12618000233224.

BACKGROUND TMZ offers minimal benefit in pts with de novo uMGMT GBM. V is synergistic with RT and TMZ in uMGMT preclinical GBM models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. VERTU tested V in pts with uMGMT GBM. METHODS VERTU is a randomized Phase 2 trial comparing Standard Arm (Arm A), RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Experimental Arm (Arm B), RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with de novo uMGMT GBM according to centralised testing. RESULTS 125 pts were randomized 1:2 (41:84). The 2 groups were matched for age, sex, performance status and extent of resection. Median follow-up was 25.8 months and 91 pts had died. The 6-month Progression-Free Survival (6mPFS) for Arms A and B were 34% (95% CI 20–48) and 46% (95% CI 36–57) respectively. The median PFS for Arms A and B were 4.2m (95% CI 2.5–6.0) and 5.7m (95% CI 4.1–6.6) respectively (HR = 0.80, 95%CI 0.55–1.18). 55% of pts in both arms experienced Grade 3/4 adverse events (AEs) with no significant differences in frequency or severity between the arms. Most common Grade 3/4 AEs were thrombocytopenia, seizures, hyperglycaemia and diarrhoea. CONCLUSION VERTU demonstrated that a novel treatment strategy for patients with de novo uMGMT GBM was feasible and tolerable. The observed 6mPFS and PFS were similar in both arms. Overall survival and other endpoints will be presented. Central MRI review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing. (ANZCTR#ACTRN12615000407594).

Background AGOC has a poor prognosis with limited benefits from treatments following failure of chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT). INTEGRATE (phase 2) demonstrated REG effectiveness in prolonging PFS in AGOC pts, with a positive OS trend and less toxicity than other REG trials at the same doses. REG was effective across all regions/subgroups, with regional differences noted in magnitude of effect. INTEGRATE II (phase 3) will explore whether REG is effective in prolonging survival in all patients, and in the Asian sub-population Methods International randomised phase III, double-blind, placebo-controlled trial with 2:1 (REG:placebo)(PBO) randomisation and stratification by tumour location, geographic region, and prior VEGF inhibitors. Histologically confirmed AGOC patients, with evaluable metastatic or locally advanced disease refractory to/relapsed following at least 2 lines of CT, will receive best supportive care plus 160mg REG or matched placebo orally on days 1-21 of each 28 day cycle until disease progression or prohibitive adverse events. Primary endpoint is OS. Secondary endpoints: PFS, response rate, quality of life, safety, identification of prognostic/predictive biomarkers for study endpoints, and REG PK across geographical regions. 350 patients (50% from Asia, with at least 50 patients to be recruited from Japan) randomized in a 2:1 ratio will provide 90% power to detect a hazard ratio (HR) for OS of 0.67 with a 2-sided α of 0.05 assuming PBO median survival is 4.5 mos. The sample size accommodates an interim analysis undertaken once 2/3 of required events have occurred. Results 27 ANZ, 8 Canadian, 15 Korean, 5 Taiwanese, and 2 Japanese sites have been activated with 106 patients enrolled. Remaining Japanese/US sites expected to activate through Q1/Q2 2019.