Australasian Gastrointestinal Trials Group Research Articles

Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy

BackgroundOesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance.MethodsWhole-genome sequencing data from 59 treatment-naïve and 18 post-treatment samples from 29 OAC patients was analysed. Twenty-seven of these were enrolled in the DOCTOR trial, sponsored by the Australasian Gastro-Intestinal Trials Group. Two biopsies from each treatment-naïve tumour were assessed to define ‘shared’ (between both samples) and ‘private’ (present in one sample) mutations.ResultsMutational signatures SBS2/13 (APOBEC) and SBS3 (BRCA) were almost exclusively detected in private mutation populations of treatment-naïve tumours. Patients presenting these signatures had significantly worse disease specific survival. Furthermore, mutational signatures associated with platinum-based chemotherapy treatment as well as high platinum enrichment scores were only detected in post-treatment samples. Additionally, clones with high putative neoantigen binding scores were detected in some treatment-naïve samples suggesting immunoediting of clones.ConclusionsThis study demonstrates the high intra-tumour heterogeneity in OAC, as well as indicators for treatment-induced changes during tumour evolution. Intra-tumour heterogeneity remains a problem for successful treatment strategies in OAC.

AGITG MONARCC: A randomized phase 2 study of panitumumab monotherapy and panitumumab (pan) plus 5 fluorouracil (FU) as first-line therapy for RAS and BRAF wild type metastatic colorectal cancer—A trial by the Australasian Gastro-Intestinal Trials Group (AGITG).

AGITG MONARCC: A randomized phase 2 study of panitumumab monotherapy and panitumumab (pan) plus 5 fluorouracil (FU) as first-line therapy for RAS and BRAF wild type metastatic colorectal cancer—A trial by the Australasian Gastro-Intestinal Trials Group (AGITG).

Management of rectal cancer in the era of total neoadjuvant therapy and watch and wait: A multidisciplinary team discussion at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting 2022.

Rectal cancer is a common malignancy. The management of rectal cancer has recently evolved and has undergone a paradigm shift with the advent of treatment approaches such as total neoadjuvant therapy and the watch-and-wait approach. However, despite the recently available evidence, there is no consensus on the optimal management approach in the setting of locally advanced rectal cancer. To address some of the controversies, a joint multidisciplinary panel discussion was conducted at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting in November 2022. Members from different subspecialties formed two panels and discussed three clinical cases in a debate format. Each case represented some of the complex issues faced by clinicians in this setting. The discussion is now presented in this manuscript, which depicts the different available management approaches and reiterates the importance of a multidisciplinary approach.

Operational Challenges of an Asia-Pacific Academic Oncology Clinical Trial.

The Asia-Pacific (APAC) region is a major focus for multinational clinical trials, although its cultural, linguistic, economic, and regulatory diversity pose significant challenges for trial conduct, particularly for academic clinical trials. We describe our experience running the investigator-initiated phase III randomized, fully accrued, Aspirin for Dukes C and high-risk Dukes B Colorectal cancer trial (ASCOLT, ClinicalTrials.gov identifier: NCT00565708, N = 1,587), studying the benefit of aspirin in resected high-risk colorectal cancer. ASCOLT opened in 2008 and is the first large academic adjuvant trial fully conducted in the APAC region. Centrally coordinated by the Trial Management Team at the National Cancer Centre Singapore, it has involved 74 sites across 12 APAC countries/regions, including five middle-income countries. Challenges encountered included regulatory complexity, communication and logistical barriers, limited funding and resources, disparate experience and infrastructure across sites, recruitment holds because of changes in local laws, patient attrition, and disruptions caused by the COVID-19 pandemic. Over 100 contracts and 49 ethics board reviews were required, contributing to a lengthy prestudy preparation time of 2 years and start-up times of approximately 6 months per site. Some of the mitigating actions included engaging local cooperative groups (eg, the Australasian Gastro-Intestinal Trials Group in Australia and New Zealand) and seven contract research organizations to manage sites, regular communication with the central team, transition to electronic data management, and a centralized drug-dispensing system. To ensure an efficient and patient-centered clinical trials environment in the APAC region and sustained growth, we suggest coordinated approaches to harmonize regulatory processes, APAC academic oncology trials consortia to streamline processes and provide governance, and ongoing commitment from governments, funding agents, and industry.

Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic esophageal and gastroesophageal carcinoma with dysphagia: A single arm phase 2 clinical trial, PALEO.

TPS4172 Background: Many patients diagnosed with esophageal cancer have dysphagia from their primary tumor and de novo metastatic disease. While multiple therapies are available, there is no accepted standard or sequence of therapies to both relieve dysphagia and control distant disease. Our preceding Phase I clinical trial showed that a 2 week hypofractionated chemoradiotherapy (CRT) protocol (30Gy/10# with concurrent weekly carboplatin and paclitaxel) is well tolerated and provides rapid dysphagia relief. Immune checkpoint inhibition has activity in esophageal and gastroesophageal (GEJ) cancer and concurrent radiotherapy may improve T cell priming through tumor antigen release. In PALEO, patients begin durvalumab concurrent with primary tumor CRT, and receive stereotactic body radiotherapy (SBRT) (24Gy/3#) to a single metastasis to maximize the breadth of tumor antigen exposure. Tissue and blood-based studies are planned to identify biomarkers for response, including immunosequencing to test for post-radiotherapy expansion in T cell receptor diversity. Methods: Eligible patients have biopsy-proven esophageal or GEJ cancer, either squamous cell or adenocarcinoma histology, with oligometastatic (1-5 metastases on FDG-PET scan outside the primary tumor radiotherapy field) or locoregionally advanced disease unsuitable for surgery, dysphagia (Mellow score >0), and ECOG PS 0-2. Key exclusion criteria are prior treatment, tumor HER2 positivity, prior thoracic radiotherapy, tracheo-esophageal fistula, esophageal stent in situ and contraindications to immunotherapy. Patients begin durvalumab 1500mg q4w with CRT to the primary tumour (30Gy/10# with weekly carboplatin AUC2 and paclitaxel 50mg/m2), and continuing to disease progression, unacceptable toxicity or 2 years. SBRT to one metastasis (24Gy/3#) is delivered in week 7. Trial primary endpoint is progression free survival rate at 6 months (PFS6) with the aim to rule out a PFS6 rate of 50% in favor of 67.5%, with 80% power and a one-sided 0.05 significance level. Secondary endpoints include dysphagia relief, nutritional status change (patient weight, removal of enteral feeding tubes, PG-SGA score), quality of life, response rate, toxicity, overall survival and exploratory translational endpoints. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG) for conduct at 8 sites in Australia and New Zealand. 6 of planned 54 patients have been enrolled. ACTRN12619001371189. Clinical trial information: Clinical trial information: ACTRN12619001371189 .

INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)

BackgroundAdvanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO).Methods/designINTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator’s choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation.DiscussionINTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC.Trial registrationINTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

Predictive and prognostic features of metastatic colorectal cancer arising from the transverse colon: A pooled analysis of the CCTG/AGITG CO.17 and CO.20 randomized trials.

124 Background: Primary tumour location is predictive of anti-EGFR benefit and prognostic in metastatic colorectal cancer (mCRC). Transverse colon cancers are often categorized as right sided, but the optimal cut point is unclear. Canadian Cancer Trials Group (CCTG)/Australasian Gastro-Intestinal Trials Group ( AGITG) CO.17 compared Cetuximab (Cet) vs. best supportive care (BSC) in mCRC. CCTG/AGITG CO.20 studied the addition of Brivanib Alaninate to Cet in pre-treated KRAS wildtype (WT) mCRC. We investigated the predictive and prognostic features of transverse colon primary location in a pooled cohort from these trials. Methods: Data from patients with RAS WT mCRC from CO.17 and KRAS WT mCRC from CO.20 randomized to cetux were analyzed for treatment outcomes according to location - right, transverse and left. The cecum to transverse colon was considered right sided, while the splenic flexure to rectum was considered left sided. Results: 553 patients were included, 201 (36.3%) from CO.17 and 352 (63.7%) from CO.20. Primary site distribution was: 32 (5.8%) transverse, 101 (18.3%) right and 420 (75.9%) left. On multivariate analysis from 457 (82.6%) patients treated with Cet, left side was associated with superior OS (HR, 0.40; 95% CI, 0.24-0.68, p=0.0006) and PFS (HR, 0.48; 95% CI,0.29-0.79, p=0.004) compared to transverse colon. No significant difference was noted in OS (HR, 0.74; 95% CI, 0.41-1.31, p=0.30) and PFS (HR, 0.79; 95% CI, 0.46-1.36, p=0.40) between right side versus transverse colon. Sidedness was not associated with prognostic difference in OS or PFS in the 96 (17.4%) patients receiving BSC alone. Outcomes according to primary site and treatment are shown. Conclusions: Transverse mCRC has comparable prognostic and predictive features to right sided mCRC. In keeping with previous studies, left side was predictive of greater Cet benefit and presented better overall prognosis when single agent Cet was used after 5-FU, oxaliplatin and irinotecan. [Table: see text]

INTEGRATE IIa: A randomised, double-blind, phase III study of regorafenib versus placebo in refractory advanced gastro-oesophageal cancer (AGOC)—A study led by the Australasian Gastro-intestinal Trials Group (AGITG).

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 .

Disparities in tyrosine kinase inhibitor use in older patients with gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma [ [1] Mastrangelo G. Coindre J.M. Ducimetiere F. et al. Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions. Cancer. 2012; 118: 5339-5348 Crossref PubMed Scopus (175) Google Scholar ]. The median age of GIST diagnosis is in the seventh decade, with a trend towards increasing incidence with increasing age [ [2] Søreide K. Sandvik O.M. Søreide J.A. Giljaca V. Jureckova A. Bulusu V.R. Global epidemiology of gastrointestinal stromal tumours (GIST): a systematic review of population-based cohort studies. Cancer Epidemiol. 2016; 40: 39-46 Crossref PubMed Scopus (361) Google Scholar ]. Tyrosine kinase inhibitor (TKI) use in both the localized and advanced setting has significantly prolonged overall survival [ [3] Joensuu H. Eriksson M. Sundby Hall K. et al. Survival outcomes associated with 3 years vs 1 year of adjuvant Imatinib for patients with high-risk gastrointestinal stromal tumors: an analysis of a randomized clinical trial after 10-year follow-up. JAMA Oncol. 2020; 6: 1241-1246 Crossref PubMed Scopus (65) Google Scholar , [4] Casali P.G. Zalcberg J. Le Cesne A. et al. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian sarcoma group, and Australasian gastrointestinal trials group intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol. 2017; 35: 1713-1720 PubMed Google Scholar ]. In patients with high-risk disease, following resection of their GIST, adjuvant treatment with at least three years of imatinib is the standard of care [ [3] Joensuu H. Eriksson M. Sundby Hall K. et al. Survival outcomes associated with 3 years vs 1 year of adjuvant Imatinib for patients with high-risk gastrointestinal stromal tumors: an analysis of a randomized clinical trial after 10-year follow-up. JAMA Oncol. 2020; 6: 1241-1246 Crossref PubMed Scopus (65) Google Scholar ]. Patients with metastatic disease receive TKI therapy until disease progression or patient stops tolerating therapy well. Imatinib was the first TKI approved in the metastatic setting; sunitinib and regorafenib are second- and third-line options, respectively. This study explores real world TKI practice patterns in the United States (US) for treatment of GIST in individuals with private insurance coverage, evaluating potential differences in TKI use between younger and older patients (aged 65 and above).

Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic oesophageal and gastrooesophageal carcinoma with dysphagia: a single arm phase II clinical trial (PALEO, sponsored by the Australasian Gastro-Intestinal Trials Group)

BackgroundOesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations.MethodsPALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy.DiscussionThis unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response.Trial registrationAustralian and New Zealand Clinical Trials Registry: ACTRN12619001371189, registered 8 October 2019.

Gender profile of principal investigators in a large academic clinical trials group.

IntroductionGender equity in medicine has become a significant topic of discussion due to consistently low female representation in academia and leadership roles. Gender imbalance directly affects patient care. This study examined the gender and craft group of the Principal Investigators (PI) of clinical trials run by the Australasian Gastro-Intestinal Trials Group (AGITG)MethodsPublicly available data was obtained from the AGITG website. Trials were divided into upper, lower gastrointestinal cancer, miscellaneous (neuroendocrine and gastrointestinal stromal tumours). Where multiple PIs were listed, all were counted. Craft group was assigned as surgical, medical, radiation oncology or other.ResultsThere were 69 trials with 89 PI, where 52 trials were represented exclusively by male PIs. Of all PIs, 18 were women (20.2%); all were medical oncologists. Prior to 2005, all PIs were male. The craft group distribution of PIs was: 79% medical oncologists, 12% surgical oncologists, 8% radiation oncologist, 1% nuclear medicine physicians. Regarding trials with multiple PI's, there were 19 in total. Of these, 11 had only male PIs, which included 5 surgeons. Females were more likely to be a co-PI (42%) as opposed to sole PI (18%). There was no gender policy publicly available on the AGITG website.ConclusionsThere is a low percentage of female PIs in academic oncology trials in the portfolio of this large international trials group. No trial was led by a female surgical or radiation oncologist. There is a need to understand the reasons driving the disparity so that specific strategies can be put in place.

APJS-1 International trial activity of AGITG

The Australasian Gastrointestinal Trials Group (AGITG) is the main cooperative trials group performing multidisciplinary gastrointestinal clinical trials in Australia and New Zealand. The group has a strong history of international collaboration and has undertaken trials with US and European trial groups. More recently AGITG has had more of a focus in the Asian region and has developed strong relationships with several key Asian partners including within Japan. This relationship has developed primarily in the gastric cancer space through the INTEGRATE gastric cancer trials program.

Overview of Radiation Treatment Volume Variations in Anal Cancer Contouring Guidelines

Recently, an Eastern Cooperative Oncology Group - American College of Radiology Imaging Network guideline was published to describe recommended treatment volumes in patients with a diagnosis of early-stage anal cancer. There are notable differences in descriptions for both the primary target and elective nodal volumes when comparing this guideline with established guidelines from the United Kingdom National Cancer Research Institute, Australasian Gastrointestinal Trials Group, and Radiation Therapy Oncology Group. Support for these volume differences is based on retrospective data, but ultimately, prospective data from ongoing clinical trials are needed to validate these approaches.

The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours.

Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.

Update on optimal management for pancreatic cancer: expert perspectives from members of the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty

ABSTRACT Introduction Pancreatic cancer remains a challenging malignancy due to the high proportion of patients diagnosed at advanced stages and the limited treatment options. This article discusses recent evidence in the management of both localized and advanced pancreatic cancer and offers an expert opinion on current best practice. Areas covered For patients with localized disease, the evidence for adjuvant chemotherapy is discussed as well as emerging neoadjuvant approaches for resectable, borderline resectable, and locally advanced disease. Advances in metastatic disease are discussed including cytotoxic chemotherapy, targeted therapies, and the role of genomic testing to identify patients with molecular alterations. Reviewed literature included journal publications, abstracts presented at major international oncology meetings, and ongoing clinical trials databases. Expert opinion Pancreatic cancer is a devastating diagnosis and despite recent advances has a very poor prognosis. Only a minority of patients, 20%, are diagnosed with potentially curable disease. The shifting paradigm toward neoadjuvant therapy may improve resectability and survival rates; however, robust evidence is required. Thus far, there has only been limited progress in advanced stage disease. Genomic testing may potentially identify more treatment targets although limited to small subgroups.

Healthcare Costs of Laparoscopic versus Open Surgery for Rectal Cancer Patients in the First 12 Months: A Secondary Endpoint Analysis of the Australasian Laparoscopic Cancer of the Rectum Trial (ALaCaRT).

Laparoscopic-assisted surgery for rectal cancer is widely used, however the healthcare costs are thought to be higher than for open resection. This secondary endpoint analysis of a randomized controlled trial aimed to evaluate total healthcare costs of laparoscopic-assisted surgery compared with open resection for rectal cancer over a 12-month period. Patients in the Australasian Laparoscopic Cancer of the Rectum Trial (ALaCaRT) were included in a prospective costing analysis. All healthcare use for the index surgery and hospital admission, readmissions, and follow-up care over 12months were included. Unit costs were valued in Australian dollars (AUD$) using scheduled Medicare fees and hospital cost weights. The primary outcome was mean per patient cost. Non-parametric bootstrapping with 10,000 replications was undertaken for robustness checks. Data from 468 patients indicated that the laparoscopic-assisted surgical procedure incurred a mean cost of AUD$4542 (standard deviation [SD] AUD$1050)-AUD$521 higher than the open procedure mean cost of AUD$4021 (SD AUD$804) due to longer operative time and involvement of more costly equipment (95% confidence interval [CI] AUD$354-AUD$692). At 12 months, the average cost for the laparoscopic-assisted and open groups was AUD$43,288 (SD AUD$40,883) and AUD$45,384 (SD AUD$38,659), respectively, due to the shorter subsequent hospital stays. No overall significant cost difference between groups was found (95% CI -AUD$9358 to AUD$5003). One-way sensitivity analyses confirmed the robustness of the results. While initially higher, the costs of laparoscopic-assisted surgery for rectal cancer were similar to open resection at 12 months. Clinicians may choose a surgical approach based on clinical need. The Australasian Gastro-Intestinal Trials Group (AGITG) was the legal sponsor and trial coordination was performed by the NHMRC Clinical Trials Centre. The trial was registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12609000663257).

1438TiP INTEGRATE IIb: A randomised phase III open label study of regorafenib + nivolumab vs standard chemotherapy in refractory advanced gastro-oesophageal cancer (AGOC)

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 II 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. Randomised phase III, open label study with 2:1 randomisation (RegoNivo: standard chemotherapy) and stratification by: 1. Geographic region (Asia vs. Rest of World) 2. Prior VEGF inhibitors (Yes vs No) 3. 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. NCT04879368. Australasian Gastro-Intestinal Trials Group.

MONARCC: a randomised phase II study of panitumumab monotherapy and panitumumab plus 5-fluorouracil as first-line therapy for RAS and BRAF wildtype metastatic colorectal cancer: a study by the Australasian Gastrointestinal Trials Group (AGITG)

BackgroundDoublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a “lighter” treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population.Methods/designMONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies.DiscussionMONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer.Trial registrationAustralia New Zealand Clinical Trials Registry: ACTRN12618000233224, prospectively registered 14 February 2018.

Australasian Gastro-Intestinal Trials Group (AGITG) MASTERPLAN: Randomized phase II study of modified neoadjuvant FOLFIRINOX alone or in combination with stereotactic radiotherapy (SBRT) for patients with high-risk and locally advanced pancreatic cancer.

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.

Personalizing First-Line Systemic Therapy in Metastatic Colorectal Cancer: Is There a Role for Initial Low-Intensity Therapy in 2021 and Beyond? A Perspective From Members of the Australasian Gastrointestinal Trials Group

Palliative chemotherapy is the cornerstone of treatment for the majority of patients with metastatic colorectal cancer, with the aim of increasing length and quality of life. Although guidelines outline the available treatment options in the first line, they provide limited guidance on choice and intensity of the chemotherapy backbone. Data from the TRIBE and TRIBE2 studies confirm a survival benefit with triplet FOLFOXIRI and bevacizumab, and this is a preferred option for younger patients with good performance status able to tolerate it. However, the relative benefit of a fluoropyrimidine doublet with oxaliplatin or irinotecan over single-agent fluoropyrimidine with or without a biologic is less certain; the available data demonstrate that single-agent fluoropyrimidine plus a biologic with planned sequencing of subsequent agents can produce similar overall survival outcomes with reduced toxicity. Our analysis of local real-world registry data suggests that this is an underutilized approach, particularly in younger and fitter patients. Established prognostic factors, including patient age, performance status, tumor sidedness, and biomarkers such as RAS/BRAF, are key in treatment selection; patients with left-sided RAS/BRAF wild-type disease or patients with low tumor bulk may be ideal for a less intensive regimen. Further studies are required to confirm the value of less-intensive regimens in the modern era, where the incorporation of biologic therapies has become routine and where non-chemotherapy options are emerging as viable options for molecularly defined patient subsets.