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Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Background: Metastatic TNBC (mTNBC) has a poor prognosis. Preclinical data suggests benefit for combination therapy of immune checkpoint inhibitor and anti-angiogenesis. Olinvacimab (O) is a fully humanised monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and antiangiogenic and antitumor effects have been demonstrated. Pembrolizumab (P) is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O and P to establish a phase 2 recommended dose of O. Methods: From December 2018 to September 2020, we conducted a two-site, single arm, open-label study of O and P in pts with mTNBC. Eligible patients (pts) were >18 years, had ER, PR & HER2-negative MBC with at least one measurable lesion and adequate organ function. Pts with history of serious thromboembolism, gastrointestinal haemorrhage and prior anti-VEGF therapy were excluded. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg q7d (dose level 1) or 16mg/kg day q7d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Treatment continued until dose limiting toxicity (DLT), disease progression (PD) or treatment intolerance. Results: 11 pts, median age 62 (range 39-67) were recruited and received at least one dose of treatment. 8 (73%) had ECOG PS 1 and 3 (27%) had ECOG PS 2. 5 pts had previous chemotherapy for mTNBC (with 3 pts also having received immunotherapy), 6 pts were treated in the first-line metastatic setting (with all pts having received anthracycline and taxane in the adjuvant setting). 5 pts received O at 12mg/kg with P, completing a median of 6 cycles (range 1-18). As no DLTs were seen, 6 pts were treated with O at 16mg/kg with median of 8 cycles (range 2-21), with no DLTs being observed. Treatment was ceased due to PD in 6 pts, 3 pts are receiving treatment at data cut-off. Haemangiomas were seen in 8 pts accounting for 47 events of CTCAE grade 1 and 21 events of grade 2. Treatment emergent adverse events (TEAEs) of ≥grade 3 was seen in 6 pts (27 events), with 8 events being related to treatment. 4 pts (36%) had partial response (PR) as best overall response 5 pts (45%) had clinical benefit (PR+SD≥24weeks). Conclusions: Combination therapy of O and P was well tolerated with evidence of efficacy in mTNBC pts who had all previously received anthracycline and taxanes, with 3 pts having previously received immunotherapy. These results support the combination entering into a phase 2 study. Citation Format: Arlene Chan, Eugene Moylan, Sally Jackson, Jeannette Devoto, Nicola Jones, Silvie Radmil, Kate Wilkinson, Aflah Roohullah, Tamiem Adam, Seon Young Lee, Weon Sup Lee, Jin-San Yoo. Phase Ib trial of olinvacimab and pembrolizumab in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-18.

Background: Tigilanol tiglate, a short-chain diterpene ester, is being developed as intratumoral treatment of a broad range of cancers. We conducted the first-in-human study of intratumoral tigilanol tiglate in patients with solid tumors. Methods: Tigilanol tiglate was administered in a multicentre, non randomized, single-arm study, with escalating doses beginning with 0·06 mg/m2 in tumors estimated to be at least twice the volume of injection (dose-escalation cohorts). Patients with smaller tumors were assigned to the local effects cohort and received the appropriate dose for tumor size. Findings: Twenty-two patients were enrolled. The maximum dose was 3·6 mg/m2 and the maximum tolerated dose was not reached. There was one report of dose-limiting toxicity (upper airway obstruction), two serious adverse events (upper airway obstruction and septicemia), 160 treatment-emergent adverse events, and no deaths. Injection site reactions in all tumors and tumor types occurred even at the lowest dose. Six of the 22 patients experienced a treatment response, with four of the six patients achieving complete response. Interpretation: Intratumoral tigilanol tiglate was generally well tolerated, the maximum tolerated dose was not reached, and clinical activity was observed in 9 tumor types including complete response in four patients. These results support the continued development of tigilanol tiglate for intratumoral administration. Funding: QBiotics Group Limited Brisbane, Queensland, Australia was the sponsor of the study. Keywords: Diterpene ester, EBC-46, Intratumoral, Protein kinase C, Tigilanol tiglate

Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.

Background: SCB-313 is a recombinant human TRAIL-Trimer™ fusion protein engineered using a stabilized trimeric form of the TRAIL-protein. Binding of SCB-313 to the death receptors 4 and 5 leads to the activation of the extrinsic apoptosis pathway. Method: We performed a pooled analysis of two phase 1 studies conducted in Australia and China (NCT03443674 and NCT04051112, respectively). SCB-313 was given by intraperitoneal infusion 4 times at day D1, D4, D8, D11 in Australia study and D1, D8, D9, D10 in China study. Five dose cohorts: 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg were evaluated using a sequential dose escalation design (accelerated titration dosing combined with 3+3 design) in pts with MA. The primary objective for both studies was safety and tolerability. Secondary objectives included PK/PD and efficacy. Results: 7 pts were enrolled in Australia (by data cutoff Mar 5th, 2021) and 12 pts in China (by data cutoff May 21st, 2021). 16 pts completed DLT observation period. Median age 57.6y, ECOG 1-2, 36.8% male. Colon cancer, n=5; ovarian cancer, n=4; breast cancer, n=3; gastric cancer, n=2; other cancers, n=5. Treatment-emergent adverse events (TEAE) were reported in 19 pts (100.0%). Most AEs were mild to moderate in severity (Grade 1 or 2). There were 9 (47.4%) pts who experienced Grade 3 AEs and no Grade 4 or 5 AEs were reported. No SCB-313 related SAEs or AEs leading to study discontinuations or death were reported. No DLT occurred. The most common TEAE included abdominal pain, pyrexia, abdominal distension. In Australia study, median (min, max) ascites flow rate of pts with MA (n=7) was 800 (400, 1091) ml/24h at baseline and 163.8 (-767, 412), 137.7 (-796.6, 392.6), -91.5 (-844.8, 517.5) and 120 (-47.92, 1105) ml/24h post first, second, third and the fourth SCB-313 administration respectively. In China study, the median flow rate at baseline (n=11) and post each subsequent SCB-313 dosing were respectively 723.1 (108.2, 1175), 12.1 (-335.1, 965.9), 84.2 (-442.5, 882), -13.9 (-404.4, 431.8) and -57.85 (-446.4, 2028) ml/24h. Estimated half-life of SCB-313 in peritoneal fluid after 1st injection is 3-4 hours (min, max: 1.85, 5.05). Cmax and AUC showed a nonlinear dose-dependent increase and near complete elimination from the peritoneal fluid by 24 hrs. In Australia study, apoptosis specific serum CK-18 concentrations increased following the first dose and remained above baseline for 5/7 pts. Conclusion: Although the MTD was not defined by these studies, SCB-313 therapy presents an acceptable safety profile at all tested dose levels. Measurable ascites flow rate decrease were observed at all dose- levels. These data support further development of SCB-313 for pts with MA. Citation Format: Ye Guo, Aflah Roohullah, Junli Xue, Wei Zhao, Morteza Aghmesheh, David Martin, Yu Zhou, Chao Gao, Yixuan Yang, Derek-Zhen Xu, Jin Li. First-in-human (FIH) phase I studies of SCB-313, a novel TNF-related apoptosis-inducing ligand TRAIL-Trimer™ fusion protein, for treatment of patients (pts) with malignant ascites (MA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6180.

3105 Background: MET is a proto-oncogene encoding a receptor tyrosine kinase c-MET for hepatocyte growth factor (HGF). Dysregulated MET signaling by MET exon14 skipping, MET gene amplification and c-MET overexpression in cancer plays a critical role in the development of primary oncogenesis, acquired drug resistance and metastasis. This is a first-in-human trial, phase 1 dose-escalation study of the highly selective MET kinase inhibitor, ABN401. ABN401was evaluated in subjects with advanced solid tumors in South Korea and Australia. Methods: Patients with advanced solid tumors were enrolled in escalating dose cohorts using an accelerated titration design. ABN401 was orally administered daily with 21-day cycle. The primary objective was to evaluate safety and tolerability to define dose-limiting toxicity (DLT), maximum tolerated dose (MTD) according to CTCAE v5. Secondary objectives included pharmacokinetic, recommended phase II dose (RP2D), and preliminary efficacy assessments. Tumor assessment was determined using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Results: Out of 28 screened patients, 16 patients with 6 different tumor types were treated with ABN401 at daily dose levels of 50, 100, 200, 400, 800 and 1200 mg, 15 patients were evaluated for DLT and one unevaluable. No DLT was observed in all 6 dose levels and the MTD has not been reached. No drug related grade ≥ 3 AEs were observed: only one drug-related SAE (transient peripheral edema) was reported. For treatment response, 5 patients with stable disease, and 2 with partial response were observed. These two patients with partial response had non-small cell lung cancer (NSCLC) with c-MET overexpression and had been treated with ABN401 for 10 and 18 months, respectively. Conclusions: ABN401 dosed up to 1200 mg QD was well tolerated with an acceptable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors. The extension (pilot expansion) for additional efficacy assessment is under way at 800 mg daily dose with c-MET altered NSCLC patients in South Korea and Australia. In addition, a phase 2 expansion study is to start in the United States and South Korea. Clinical trial information: NCT04052971.

Background Colorectal cancer is the third most common cancer and second leading cause of cancer mortality in Australia, thus carrying a significant disease burden. Aims This analysis aims to explore real-world treatment landscape of metastatic colorectal cancer in the third-line setting. Methods We retrospectively analysed treatment of recurrent and advanced colorectal cancer (TRACC) registry database from 2009 onwards. Patients treated with palliative intent who progressed after two lines of therapies were included. One treatment line was defined as any combination of systemic therapy given until progression. Results Out of 1820 patients treated palliatively, 32% (590 patients) met study criteria. Of these, 43% (254 patients) proceeded to third-line therapy, equating to 14% of all metastatic patients. In KRAS mutant or unknown tumours (97 patients), fluoropyrimidine (FP)-oxaliplatin combination was the most common choice (51%), followed by FP-irinotecan (15%), trifluridine/tipiracil (11%), mono-chemotherapy (10%), regorafenib (5%) and others (7%). Majority of FP-doublet (83%) was given as rechallenge. In 157 patients with KRAS wildtype disease, monotherapy with EGFR inhibitor was most commonly used (41%), followed by EGFR inhibitor with chemotherapy (20%), FP-doublet (18%), mono-chemotherapy (6%), trifluridine/tipiracil (6%), regorafenib (1%) and others (8%). Median overall survival was 7.1 months (range 0.4-41.2), and median time on third-line treatment was 3 months (range 0.1-40). Conclusions In real-world Australian population, treatment choices differed based on KRAS status and will likely change with the availability of newer drugs on the pharmaceutical benefits scheme. Survival outcomes are comparable to newer agents in clinical trials for select patients.

47 Background: BRAFmt is a negative prognostic factor in mCRC but also identifies a patient population that may benefit from BRAF targeted therapy. Results from recent trials (BEACON and SWOG1406) demonstrate improved survival outcomes in second- and third-line settings when combining a BRAF inhibitor, an EGFR inhibitor (EGFRi) +/- a MEK inhibitor. In both trials, irinotecan and cetuximab was the control arm with a dismal response rate of 2-4% and progression free survival (PFS) of only 2 months. This suggests chemotherapy plus an EGFRi may not be the optimal approach where BRAF-targeted therapies are not available or have failed. Methods: Data from July 2009 to September 2021 was analysed from TRACC, a multi-site Australian mCRC comprehensive prospective registry enrolling consecutive patients. Patient characteristics, treatment and survival outcomes were examined for patients treated with chemotherapy (CT) alone, with bevacizumab (BEV) or with an EGFRi. Results: Of 2046 registry patients, 256 (13%) harboured a BRAFmt. 72 BRAFmt patients had received second-line (28%) treatment, including CT alone (n = 28), CT plus BEV (n = 26), and CT plus EGFRi (n = 18). Baseline characteristics are shown in the table. Median second-line PFS was 3.3, 4.7 and 1.8 months, for CT alone, CT plus BEV and CT plus EGFRi respectively. Median overall survival (OS) was 8.7, 7.9 and 2.5 months respectively. In multivariate analysis, PFS when treated with CT plus EGFRi trended inferior to CT alone (p = 0.054) and CT plus BEV (p = 0.061), whereas for OS, treatment with CT plus EGFRi was inferior to CT alone (p = 0.038) and CT plus BEV (p = 0.015). Poor PFS was associated with age ≥ 65 years (HR 3.03, p < 0.001) and ECOG ≥ 2 (HR 2.62, p = 0.004), but not associated with a right side primary (p = 0.17), mismatch repair (MMR) status (p = 0.86), or ≥ 3 organs with metastases (p = 0.32). Poor OS was associated with age ≥ 65 years (HR 3.11, p < 0.001), ECOG ≥ 2 (HR 7.32, p < 0.001), right side primary (HR 3.03, p = 0.002) and proficient MMR status (HR 3.57, p = 0.018), but not associated with ≥ 3 organs with metastases (p = 0.17). Conclusions: Less than one-third of BRAFmt mCRC patients received second-line therapy in a real-world setting, indicating an urgency to explore activity of BRAF targeted therapy in the first line setting. Treated patients received limited benefit, with CT plus EGFRi PFS outcomes comparable to BEACON control arm (1.8 vs 2.0 months) and trending inferior to other options. The best OS outcomes were achieved with CT alone or CT plus BEV.[Table: see text]

Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer. Methods Patients with advanced or metastatic solid tumours, who had progressed on standard therapy or for whom standard therapy was not known, were administered ASLAN-002 orally. The starting dose was 100 mg once daily (QD) with subsequent cohorts to receive doses of 200 mg QD, 300 mg QD, 450 mg QD, 600 mg QD, 300 mg twice daily (BID), 450 mg BID, and 600 mg BID. Results Forty patients were included across 7 dose cohorts. Cohort 8 (600 mg BID) was not opened due to the lack of appreciable pharmacokinetic (PK) differences between 300 mg BID and 450 mg BID and higher incidences of grade 3 or 4 adverse events (AE) in Cohort 7 (450 mg BID). Fifteen patients (37.5%) experienced a grade 3 or 4 AE. The most commonly reported AEs were nausea (55%), fatigue (47.5%) and constipation (30%). One dose limiting toxicity (DLT) of atrial fibrillation was observed with 450 mg BID. Conclusions ASLAN-002 is well tolerated at 300 mg BID and is the recommended dose for future phase II studies (RP2D). Clinical Trials Registry Number: NCT01721148 .

Aims: There is limited data on health-related quality of life (HRQoL) in locally advanced rectal cancer. We assessed HRQoL before, during and after neoadjuvant chemoradiation, correlated this to corresponding clinician-reported adverse events (CR-AEs) and explored disparities between patients of Asian ethnicity versus Caucasians. Correlation between HRQoL and treatment response was also assessed. Methods: A consecutive sample of patients was recruited. HRQoL was assessed with the EORTC QLQ-C30 before chemoradiation, week three of chemoradiation and one-week pre-surgery. Clinical variables including CR-AEs were recorded at these time-points. Patients self-reported socio-demographic variables. Treatment response was assessed by the tumour regression grade. HRQoL data were analysed with multilevel models. Results: Fifty-one patients were recruited. HRQoL completion rates were &ge, 86%. Cognitive and role functioning worsened significantly during treatment. Emotional, role and social functioning improved significantly at pre-surgery. Fatigue and nausea/vomiting worsened during treatment while fatigue, appetite loss, diarrhoea and financial difficulties improved from treatment to pre-surgery. Almost 30% of the cohort were Asian ethnicity. Differences were found in multiple HRQoL domains between Asians and Caucasians, with Asians faring worse. Significant differences were evident in physical, role and cognitive functioning, and in seven out of the 8 symptom scales. The correlation between patient-reported outcomes and clinician-reported outcomes was weak, with diarrhoea having the strongest correlation (r = 0.58). Vomiting during treatment correlated with poor response, whilst baseline constipation correlated with good response. Conclusion: Chemoradiation for locally advanced rectal cancer affects multiple HRQoL domains. Our findings highlight the importance of psychological aspects of treatment. Significant differences were identified between the Asian and Caucasian populations, with Asians consistently performing worse. Poor correlations between patient and clinician reporting strongly support the inclusion of patient-reported outcomes in clinical studies. HRQoL domains of vomiting and constipation are potential biomarkers of treatment response.

TPS3157 Background: c-MET (hepatocyte growth factor (HGF) receptor) overexpression, either by gene amplification, or mutation is associated with oncogenic transformation in numerous malignancies including lung, gastric, skin, renal, colorectal, and pancreatic cancers. ABN401 inhibits the activation of c-MET by reversibly interfering with the binding of c-Met tyrosine kinase to adenosine triphosphate (ATP) and blocking the receptor's downstream signaling that has demonstrated efficacy in NSCLC and gastric cancer in mouse xenograft and PDx models. This clinical trial is in progress in patients with advanced cancers. Methods: ABN401 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study in patients with advanced solid tumors, and dose-expansion (phase 2) in patients with targeted indications and c-MET biomarker expression (NCT04052971). The phase 1 explores ascending daily doses of oral ABN401 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). A preplanned extension (pilot expansion) study has been initiated based on predefined positive efficacy signals at intermediate doses up to 10 NSCLC patients who have c-MET alteration. Once RP2D is determined, the phase 2 expansion of up to 10-29 patients in four specific tumor-type cohorts is planned, utilizing a Simon's optimal two-stage design to evaluate the clinical activity of ABN401. ABN401-001 study began enrolling patients in August 2019 and is ongoing in Korean and Australia. Dose escalation up to cohort 4 has been completed, enrollment to cohort 5 began in November 2020. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria and safety findings reviewed by the DRC, which will determine the RP2D and MTD. Key Phase 1 eligibility criteria include 1) histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma and 2) refractory metastatic disease, or refractory locally advanced disease not amenable to local therapy. For the extension (pilot expansion) study, patients must have NSCLC with MET exon 14 skipping, MET amplification and/or c-MET overexpression. An exploratory study is being conducted for co-development of a companion diagnostic (CDx) system including a CTC device and ddPCR kit through liquid biopsy. Clinical trial information: NCT04052971.

2517 Background: HX009 is a novel humanized antibody fusion protein which binds to CD47 and PD-1 concurrently. HX009 significantly inhibited tumor growth in mouse xenograft models. In Cynomolgus monkeys, the highest non-severely toxic dose in repeat dose testing was 15mg/kg. HX009-I-01 (ClinicalTrials.gov：NCT04097769) is a first-in-human study evaluating the safety and efficacy of HX009 in subjects with advanced malignancies. Here we report the preliminary results from this study. Methods: The study is being conducted in Australia at 3 sites. The study design follows a 3+3 dose-escalation scheme, enrolling cohorts of at least 3 subjects (except the first dose level) sequentially until MTD or the maximum dose is reached. HX009 is administered as single agent every 2 weeks via intravenous infusion. The 7 dose levels planned are: 0.1mg/kg (1 subject), 0.3mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 5mg/kg, 7.5mg/kg. All AEs are graded using NCI CTCAE v5.0. Efficacy assessments are per RECIST 1.1. Blood samples are obtained for pharmacokinetics (PK) and for immunogenicity assessments by the development of Antidrug Antibodies. Results: As of the January 22 2021 cutoff date, 21 patients (12M/9F) with a median age of 69.0 years (range 38-86) have received dose levels of 0.1-7.5 mg/kg. Patients with the following tumor types have been enrolled: colorectal cancer (7), squamous cell carcinoma (3), endometrial cancer (2), breast cancer (3), malignant epithelioid mesothelioma (1), gallbladder cancer (1), pancreatic cancer (1), glioblastoma(1), ovarian cancer (1), gastroesophageal junction adenocarcinoma (1). Patients had received a median of 3 (range 1-9) prior anti-cancer regimens. Treatment-related AEs have been reported in 10 (47.6%) patients to date. Most AEs are grade 1 or 2. The most frequent treatment-related AEs include nausea (n = 2, G1), rash (n = 2, G1), vomiting (n = 2, G1), and decreased appetite (n = 2, G1). Only 1 treatment-related SAE of pneumonitis. One treatment-related anemia (G2), and no thrombocytopenia. No DLT was observed in all 7 dose levels. Among 18 patients who have had at least one post-baseline tumor assessments, partial responses (PR) have been achieved in 3 patients with the following tumor types (dose level): gallbladder adenocarcinoma (1mg/kg), triple negative breast cancer (5mg/kg), metastatic squamous cell carcinoma of head and neck (5mg/kg). In addition, there are 6 patients with best overall response of stable disease. As of the data cutoff date, 6 patients are still receiving treatment. Updated clinical and PK results will be presented at the meeting. Conclusions: HX009, on an every 2 weeks dosing schedule, up to 7.5 mg/kg, is well-tolerated, without any DLT to date. Antitumor activity was seen at 1 mg/kg and 5 mg/kg cohorts with objective responses in multiple tumor types; Further investigation in phase Ib/II studies is warranted. Clinical trial information: NCT04097769.

Background Colorectal cancer is the third most common cancer and second leading cause of cancer mortality in Australia. In patients with metastatic disease who have progressed after two lines of therapies, survival is 4-6 months with best supportive care, and 6-8 months with newer agents. This retrospective analysis aims to explore real-world treatment landscape of metastatic colorectal cancer in the third-line setting. Methods We analysed the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry database from 2009 onwards. Patients treated with palliative intent who have progressed after two lines of therapies were included. One treatment line is defined as any combination of systemic therapy given until progression. Patient demographics, third line choices and survival outcomes were examined. Results A total of 2831 patients had metastatic colorectal cancer, and of these, 23% (642 patients) met study criteria. 48% (306 patients) of study population proceeded to receive third line therapy. A large proportion of patients had received doublet chemotherapy in both first and second lines. Median age was 62 years and ECOG at the start of third line was 1-2 (75%). A fluoropyrimidine-based doublet with oxaliplatin or irinotecan was the most common treatment choice in 42%. Other treatments included mono-chemotherapy +/- biological agent (23%), EGFR inhibitor alone (22%), EGFR inhibitor with doublet chemotherapy (6%), trifluridine/tipiracil (4%), regorafenib (2%), immunotherapy ( Conclusions In a real-world Australian population, 11% of all patients diagnosed with metastatic disease received third line treatment, with commonest regimens being doublet chemotherapy. This treatment landscape may change with the approval of new drugs. Overall survival in these patients is comparable to third line trials on these agents. Analyses are underway to further characterise the breakdown of treatment regimens in all three lines in these patients, and assess survival with rechallenge regimens. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

AIM: To compare outcomes for patients presenting with stage IV colorectal cancer and an asymptomatic primary tumour, undergoing primary tumour resection (PTR) plus palliative chemotherapy vs primary chemotherapy up-front. METHODS: A literature search was conducted using MEDLINE and EMBASE. The primary outcome was overall survival. Secondary outcomes included perioperative mortality, morbidity and delayed surgical intervention rates in patients undergoing PTR and subsequent complication rates in patients with an un-resected primary tumour. Tertiary outcomes included impact on systemic treatment and identification of prognostic factors relevant for survival in this cohort. RESULTS: Twenty non-randomised studies met the inclusion criteria. Eleven studies included comparative overall survival data. Three studies showed an overall survival advantage for PTR, 7 studies showed no statistically significant advantage, and 1 study showed a significant worsening in survival in the surgical group. The perioperative mortality rate ranged from 0% to 8.5%, and post-operative morbidity rate from 10% to 35%, mainly minor complications that did not preclude subsequent chemotherapy. The rate of delayed primary-tumour related symptoms, most commonly obstruction, in patients with an un-resected primary tumour ranged from 3% to 46%. The strongest independent poor prognostic factor was extensive hepatic metastases, in addition to poor performance status, M1b stage and non-use of modern chemotherapy agents. CONCLUSION: Based on the current literature, both PTR and up front chemotherapy appear appropriate initial management strategies, with a trend towards an overall survival advantage with PTR. The procedure has a low post-operative mortality, and most complications are transient and minor. The results of recruiting randomised trials are eagerly anticipated.

Epithelial cell adhesion molecule (EpCAM)-targeted capture remains the most common isolation strategy for circulating tumor cells (CTCs). However, epithelial-to-mesenchymal transition (EMT) leads to decreased epithelial EpCAM expression affecting the optimal CTC capture. In this study, we tested a cohort of ovarian cancer cell lines using flow cytometry to identify N-cadherin as the additional immunomagnetic cell surface target for ovarian cancer cell isolation. Combined immunomagnetic targeting of mesenchymal N-cadherin and epithelial EpCAM enriched CTCs from advanced ovarian cancer patient blood approximately three times more efficiently than targeting of EpCAM alone. We also show that more EMT-phenotype CTCs are captured by including N-cadherin targeting into CTC isolation protocols. However, after N-cadherin-based CTC isolation, in some blood samples of healthy individuals, we also observed the presence of cells expressing markers common to CTCs. Our data show that these “false positives” can be largely distinguished from CTCs as circulating endothelial cells (CECs) by vascular endothelial–cadherin co-staining. CEC counts are highly variable in patients and healthy controls. Our data demonstrate that a combination of EpCAM with N-cadherin-targeted isolation can improve CTC detection and widen the EMT-phenotype spectrum of captured CTCs.

To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease.We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts: (1) the AGITG MAX trial (Phase III randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine, bevacizumab and mitomycinC); (2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (any first-line regimen ± bevacizumab); and (3) two cancer centres in New South Wales, Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre (NSWCC) from January 2005 to Decenber 2012, (any first-line regimen ± bevacizumab). For the AGITG MAX trial capecitabine was compared to the other two arms (capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycinC). In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases. Secondary endpoints included progression-free survival, chemotherapy duration, and overall survival. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test.Eighty-four MAX, 179 TRACC and 69 NSWCC patients had peritoneal disease. There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts. Of the patients without peritoneal disease in the MAX trial, 4/300 (1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123 (0.8%) in the capecitabine alone arm. In the TRACC registry 3/126 (2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53 (1.9%) in the chemotherapy alone arm. In a further analysis of patients without peritoneal metastases in the TRACC registry, the rate of gastrointestinal perforations was 9/369 (2.4%) in the chemotherapy/bevacizumab group and 5/177 (2.8%) in the chemotherapy alone group. The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts: MAX 6.9 m vs 4.9 m, HR = 0.64 (95%CI: 0.42-1.02); P = 0.063; TRACC 9.1 m vs 5.5 m, HR = 0.61 (95%CI: 0.37-0.86); P = 0.009; NSWCC 8.7 m vs 6.8 m, HR = 0.75 (95%CI: 0.43-1.32); P = 0.32. Chemotherapy duration was similar across the groups.Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone.

2526Background: CRLX301 is an investigational NDC with DOC covalently conjugated to a cyclodextrin-polyethylene glycol co-polymer designed to enhance delivery to tumor tissue. Preclinical studies of CRLX301 showed enhanced drug accumulation in tumor and greater tumor growth suppression in murine models compared to DOC. Methods: Patients (pt) with advanced solid tumors were treated with escalating doses of CRLX301 IV once every 21 days (Q3W). The first two cohorts were single pt cohorts and then adjusted to 3+3 design. Primary objective: MTD and/or RP2D. Secondary objectives: safety, anti-tumor activity and PK. Results: 20 pts were enrolled. All were evaluable for DLT. Prior lines of chemotherapy: median 3 (range 0 to 6); 8 pts had prior taxane therapy. Tumor types: cholangiocarcinoma (5), head and neck (3), lung (2) and others (10). All drug-related AEs were toxicities typically associated with DOC. The most common drug-related AEs (all grades) were fatigue (70%), infusion reaction (40%), nausea (35%), di...

595 Background: Metastatic colorectal cancer with peritoneal disease (PmCRC) represents a phenotype that may derive a greater clinical benefit from bevacizumab (BEV) due to the effect of VEGF on peritoneal spread and ascites production. However, there is concern of greater adverse events, in particular GI perforations. We investigated the clinical benefit and safety of adding BEV to chemotherapy in PmCRC in clinical trial and nontrial populations. Methods: We compared PFS and OS in PmCRC patients receiving first-line chemotherapy with and without BEV in: (1) the AGITG MAX trial (capecitabine [CAP] vs CAP/BEV +/- mitomycin C) and (2) two cancer centers in New South Wales between Jan 2005 and Dec 2012 (any regimen +/- BEV). Secondary endpoints included chemotherapy duration and GI adverse events. Time to event outcomes were estimated using the method of Kaplan-Meier and comparisons made using the logrank test. Proportional hazards models were used to obtain hazard ratios for regression analysis. Results: See Table. 84 MAX and 69 nontrial pts had PmCRC and there was a 37% reduction in the risk of progression in those receiving BEV, which is similar when compared to the nonperitoneal disease pts (HR= 0.63 95% CI 0.52-0.79 p value < 0.001). OS in the PmCRC group was significantly worse than the nonperitoneal group (14.3 months vs 18.8 months p value = 0.02). Chemotherapy duration was similar across the groups. The rate of notable GI adverse events, including GI perforation was not increased in the PmCRC group receiving BEV in either cohort. One pt had a GI perforation after receiving CAP+BEV. Conclusions: Pts with mCRC and peritoneal disease receiving first-line therapy in trial and nontrial populations appear to derive a similar proportional benefit when BEV is added to systemic therapy without an increase in GI adverse events. However, this subgroup of patients continues to have a worse prognosis. [Table: see text]