BackgroundInterest in hereditary lung cancer is increasing, in particular germline mutations in the Epidermal Growth Factor Receptor (EGFR) gene. We review the current literature on this topic, discuss risk of developing lung cancer, treatment and screening options and describe a family of 3 sisters with lung cancer and their unaffected mother all with a rare EGFR germline mutation (EGFR p.R776H).MethodsWe searched PubMed, Medline, Embase, the Cochrane Library, Google Scholar and scanned reference lists of articles. Search terms included “EGFR germline” and “familial lung cancer” or “EGFR familial lung cancer”. We also describe our experience of managing a family with rare germline EGFR mutant lung cancer.ResultsAlthough the numbers are small, the described cases in the literature show several similarities. The patients are younger and usually have no or light smoking history. 50% of the patients were treated with a tyrosine kinase inhibitor (TKIs) with OS over six months.ConclusionAlthough rare, germline p.R776H EGFR lung cancer mutations are over-represented in light or never smoking female patients who often also possess an additional somatic EGFR mutation. Treatment with TKIs appears suitable but further research is needed into the appropriate screening regime for unaffected carriers or light/never smokers.

Lorlatinib is a third generation ALK inhibitor with marked efficacy in NSCLC. CTCAE-defined weight gain and dyslipidaemia has been reported in patients receiving lorlatinib in registrational trials. Lipid-lowering agents may interact with lorlatinib metabolism. We conducted a single centre retrospective analysis of NSCLC patients receiving lorlatinib. The primary objective was to quantify weight gain and lipid profile changes in accordance with CTCAE v5.0. Extraction from electronic medical records was undertaken by authors. Mean relative dose intensity (RDI) was defined as % of full dose lorlatinib for duration of therapy. All analyses were descriptive. Patients without baseline weight recorded were excluded. The project was approved by the hospital service evaluation committee. 43 patients were evaluable. 77% (n=33/43) were ALK+ and 23% (n=10/43) ROS1+. Mean duration of lorlatinib was 14.5 months. Mean RDI was 81%. Weight gain occurred in 81% (n=35/43) of patients, 44% (n=19/43) Grade≥1 and 9% (n=4/43) Grade≥3. Mean weight gain/BMI was 6.4kg/2.4kg/m2 (range 0-30.1kg/11.4kg/m2). Dietitian referral occurred in 5% (n=2/43). Increase in total cholesterol (TChol) occurred in 51% (n=22/43) and triglyceride in 58% (n=25/43) of patients. 84% (n=36/43) were prescribed statins and 2% (n=1/43) ezetimibe/statin. 35% (n=15/43) patients had normal baseline TChol (<5mmol/L), 100% (n=15/15) of whom developed elevated TChol on lorlatinib, 73% (n=11/15) within 30 days of commencement. One patient with elevated TChol (8.3mmol/l) developed acute coronary syndrome 5 weeks after stopping lorlatinib. Table: 40PBaseline characteristicsTotal; n=43 (%)Median age55.5 yearsSexMale18 (42)Female25 (58)OncogeneALK33 (77)ROS110 (23)Treatment line1st0 (0)2nd14 (33)3rd13 (30)4th8 (19)5th7 (16)6th1 (2)Initial dose100mg40 (93)75mg2 (5)50mg1 (2)Dose modificationsYes21 (49)No22 (51)Concomitant steroidsYes: ≥2 weeks14 (33)Yes: <2 weeks3 (7)No26 (60)Mean RDI81%Median duration on lorlatinib14.5 monthsWeight gain, n=43 (%)Yes- maximum grade20%)4 (9)No8 (19)Unknown1 (2)Cholesterol, n=43 (%)TChol increaseYes22 (51)No21 (49)Mean increase1.94mmol/LMaximum grade of hypercholesterolaemia in pts with normal baseline TChol, n=15 (%)G110 (67)G24 (27)G31 (7)G40 Open table in a new tab Real world prevalence of weight gain was similar to that reported in landmark trials. Dyslipidaemia is frequent and requires active treatment which may impact metabolism of lorlatinib. Larger scale evaluation on quality of life impact and medical risk of weight gain/dyslipidaemia is required.

The hereditary nature of non-small cell lung cancer (NSCLC) is poorly understood. Previous studies have found inherited pathogenic germline variants (PGVs) are more common in patients with EGFR mutant (EGFRm) NSCLC. We sought to describe the frequency of PGVs in a cohort of EGFRm patients undergoing treatment at a UK cancer centre. We invited NSCLC patients with activating somatic mutations in exon 18-21 of EGFR who attended the Royal Marsden Hospital Lung Unit between May 2022 to April 2023 to participate in a pilot of mainstream germline genetic testing. Patients consented to germline testing with an 84 gene panel of known hereditary cancer-related genes. Demographic data, clinicopathological information and family history were recorded. To date, 49 patients have undergone germline genetic testing. The median age of diagnosis was 60 years, all had adenocarcinoma histology, 65% were female, 71% were never smokers and 18% had a family history of lung cancer (Table). The most frequent somatic EGFR mutations were exon 19 deletions and L858R present in 63% and 18%, respectively. PGVs were detected in 8% (4/49) of patients. Two patients had PGVs detected in genes associated with a potential predisposition to lung cancer, a 37-year-old female with a TP53 PGV and a 71-year-old male with PGVs in both ATM and CHEK2. The remaining two patients had PGVs in genes not yet known to be associated with an increased risk of lung cancer (MUTYH and MITF).Table: 2207PPatient characteristics and genetic testing resultsn=49 (%)Median age of diagnosis60 (range 35-76)SexMale17 (35)Female32 (65)Smoking StatusNever35 (71)Ex/current12 (25)Unknown2 (4)Stage at diagnosisI5 (10)II2 (4)III1 (2)IV41 (84)Somatic EGFR MutationExon 19 deletion31 (63)L858R9 (18)Exon 20 insertion4 (8)Other5 (10)Family historyFamily history of malignancy30 (61)Family history of lung cancer9 (18)Pathogenic germline variant detected4 (8)TP53 R337H1 (2)ATM E2007Rfs*11 and CHEK2 T367Mfs*151 (2)MUTYH G396D1 (2)MITF E318K1 (2) Open table in a new tab In a United Kingdom cohort of EGFRm NSCLC patients 2/49 (4%) had PGVs in lung cancer predisposing genes; the tumour suppressor gene TP53 and DNA damage repair pathway genes ATM and CHEK2. Our data support the feasibility and importance of germline testing in routine oncological care. Germline results should be considered as a risk criterion for inclusion in lung cancer CT screening programmes.

Lorlatinib is an ALK and ROS1 targeted next-generation tyrosine kinase inhibitor (TKI). Real-world treatment related adverse event (TRAE) data are limited. We reviewed TRAEs and therapeutic efficacy for advanced non-small-cell lung cancer (NSCLC) patients receiving lorlatinib at our centre.

Although commonly excluded from large clinical trials, studies have demonstrated uncommon EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Variant identification is essential to identify these patients who may benefit from targeted therapy. Detection of uncommon EGFR alterations can be challenging due to the limited coverage of frequently used real-time polymerase chain reaction (PCR) assays. We describe the frequency of uncommon EGFR mutations detected at our institution by next generation sequencing (NGS) and the ability of commonly used PCR assays to identify these alterations.

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of multiple cancers. However, they are associated with a spectrum of immune-related adverse events (irAEs). Infliximab is a recommended treatment for corticosteroid refractory irAEs, but real-world data is limited. We conducted a retrospective review of patients in our institution who received infliximab for irAEs between May 2021 to July 2022. Data was correlated against internal guidelines which require upfront testing for TB, HIV, VZV and Hepatitis B and C. Over this period, 31 patients received infliximab (male n=20). Median age 66.7 years (range: 33-86). Seventeen patients (54.8%) had melanoma, 6 (19.4%) non-small-cell lung cancer, 4 (12.9%) renal cancer, 3 (9.7%) gastrointestinal cancer and 1 (3.2%) uterine cancer. Eighteen (58.1%) patients received ipilimumab/nivolumab combination, 7 (22.6%) pembrolizumab containing regimes, 3 (9.7%) nivolumab, 2 (6.5%) durvalumab and 1 (3.2%) patient received ipilimumab single agent. Highest grade irAE was Grade 3 in 71.0% (n=22), G2 in 19.4% (n=6), G4 in 6.5% (n=2) and G5 in 3.2% (n=1). Gastrointestinal irAE accounted for 87.1% (n=27) of the cohort, 9.7% of patients (n=3) had rheumatological irAE, with 1 case of pneumonitis. The median number of ICI cycles prior to infliximab treatment was 3 (range 1 to 29). Median number of infliximab doses was 2 (range 1 to 3). ICI treatment was discontinued after irAE requiring infliximab in 25 patients (80.6%). All patients received corticosteroids before infliximab. Twenty-four patients (77.4%) were tested for TB (T-Spot test) prior to infliximab initiation. All patients tested received negative results. Testing rates for Hepatitis B and C was 100%, while 93.5% of patients (n=29) were tested for HIV. Testing rates for VZV was 58.1% (n=18). Two patients developed shingles post infliximab and were treated with aciclovir. No patients experienced reactivation of TB or hepatitis post infliximab treatment. In our institution, most patients treated with infliximab had received ICI therapy for melanoma. The most frequent indication for infliximab was gastrointestinal toxicity. Aside from shingles, no post-infliximab treatment infections were reported in this cohort.

The addition of atezolizumab to carboplatin/etoposide (A-CE) for patients with extensive stage SCLC (ES-SCLC) has been recently established as standard first-line treatment on the basis of the IMPOWER-133 trial. Unfortunately, efficacy and safety data of this combination in the real-world setting is lacking. We retrospectively evaluated consecutive patients with ES-SCLC treated with A-CE between January 2020 and September 2021 in eight centres in the UK. Clinical and pathological data was collected and analysed. A total of 192 patients were included. Baseline clinical characteristics are summarized in the table. One hundred forty seven (77,8%) patients received four cycles of A-CE; median number of doses of atezolizumab was 7 (range 1-20). Fifty-two (27%) patients also received prophylactic cranial irradiation and sixty-one (31,7%) consolidation thoracic radiotherapy. Seventy-six (39,6%) patients received at least one subsequent treatment. At a median follow-up of 15 months, median progression-free survival (PFS) and overall survival (OS) were 5,31 and 8,85 months, respectively. Overall response rate was 69,7%. The OS rates at 12 months and 18 months were 38,25% and 20,36%, respectively. Treatment-related adverse events led to discontinuation of treatment in 32 patients (16,7%).Table: 1541PMedian age – years (range)66 (35-83)Sex – no. (%)MaleFemale83 (43,2)109 (56,8)Smoking status NeverCurrentFormerUnknown9 (4,7)50 (26,0)116 (60,4)17 (8,8)ECOG performance status score – no. (%)012330 (17)140 (73)21 (11)1 (0,5)Stage (TNM 8th edition) – no. (%)IIIIV14 (7,3)178 (93)Concomitant autoimmune disease – no. (%) Brain metastasis – no. (%)12 (6) 29 (15) Open table in a new tab Data from our series show comparable PFS but inferior OS than those reported in the trial. Known negative prognostic factors were more common in our cohort of patients at baseline and may have determined a shorter OS. Real-world data in this setting could help to optimise clinical management of these patients.

Exon 19 deletions, exon 21 L858R and exon 20 insertions represent the most frequent alterations in EGFR mutated non-small cell lung cancer (NSCLC). These alterations now all have approved targeted therapies. In contrast, there is limited data assessing activity of EGFR-directed therapy for uncommon EGFR alterations. We sought to describe clinical outcomes of patients with rare EGFR mutations that received systemic anticancer therapy (SACT) at our institution.

Background: Reduced diagnostic procedures and late presentation during COVID19 may lead to late diagnosis of NSCLC. De novo BM may thus be more common during COVID19. Baseline incidence of BM in asymptomatic patients (pts) needs to be defined. Methods: Consecutive pts with stage IV NSCLC referred to Royal Marsden Hospital between Jun-Nov 2020 were included. Prospectively collected data were analysed descriptively. Results: Of 172 pts, 95 (55%) underwent brain imaging, 77 (45%) did not. More pts with brain imaging had good ECOG and received systemic therapy compared to those without brain imaging (table). 37/95 (39%) pts had BM on imaging. In pts with BM, 65% had BM symptoms, 35% did not. 12/27 (44%) pts with 1–5 BM were asymptomatic compared to 1/10 (10%) pts with ≥6 BM (p = 0.07). 32/95 (34%) pts with brain imaging had BM symptoms; of which 24 (66%) had BM confirmed on imaging. However, 13/63 (21%) asymptomatic pts also had BM detected on imaging. 10/37 (27%) pts with BM received stereotactic radiosurgery, of which 5 were asymptomatic. Of the remaining 27 pts with BM, 12 received TKI alone, 1 was monitored, 4 received palliative radiotherapy, 8 were unfit for treatment, 2 died. 11/37 (30%) pts with BM did not receive systemic therapy. Table 180PCharacteristicsBrain imaging N = 95 N (%)No brain imaging N = 77 N (%)AgeMedian (range)70 (34–95)74 (47–91)SmokingNever20 (21%)12 (16%)Ex/current74 (78%)51 (66%)NA1 (1%)14 (18%)ECOG016 (17%)5 (6%)1–268 (72%)37 (48%)3–411 (11%)27 (35%)NA0 (0%)8 (10%)SubtypeAdenocarcinoma68 (72%)45 (58%)Squamous cell11 (12%)12 (16%)Other11 (11%)4 (5%)NA5 (5%)16 (21%)MolecularVariant detected52 (55%)25 (32%)No variant28 (29%)31 (40%)NA15 (16%)21 (27%)BM symptomsYes32 (34%)4 (5%)*Not for active treatment.No63 (66%)60 (78%)NA013 (17%)Systemic therapyNA0 (0%)2 (3%)Yes64 (67%)32 (42%)No31 (33%)43 (56%)Poor ECOG Pt wishes Died Surgery/radiotherapy only Monitor17 4 5 3 228 2 12 0 1* Not for active treatment. Open table in a new tab Conclusions: The incidence of de novo BM was high in pts with stage 4 NSCLC during COVID19 (39%), higher than historical rates (25%). Many pts with BM were asymptomatic (35%). Brain imaging should be considered in all pts with a new diagnosis of stage 4 NSCLC. Whether early diagnosis and treatment of BM affects survival will need to be explored. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: W. Cui: Research grant/Funding (self): Breast Cancer Trials group; Research grant/Funding (self): Australian Government Research Training scholarship. C. Milner-Watts: Honoraria (self): AstraZeneca. A.R. Minchom: Honoraria (self), Advisory/Consultancy: Janssen Pharmaceutica; Honoraria (self), Advisory/Consultancy: Merck Pharmaceuticals; Honoraria (self): Novartis Oncology; Honoraria (self): Bayer Pharmaceuticals; Honoraria (self): Faron Pharmaceuticals; Travel/Accommodation/Expenses: LOXO oncology. S. Popat: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: EMD Serono; Honoraria (self), Advisory/Consultancy: Guardant Health; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Blueprint; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy: GSK; Honoraria (self), Advisory/Consultancy: BeiGene; Honoraria (self), Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Amgen. M.E.R. O'Brien: Advisory/Consultancy: MSD; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Roche; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: BMS. All other authors have declared no conflicts of interest.

Gastric cancers are highly prevalent in both the East and the West, although they differ in aetiology and prognostic outcome. Management of gastric cancer from screening to definitive treatment varies substantially between Eastern and Western countries and regions, owing to numerous factors, including government incentives to carry out population-wide screening programmes to detect early disease, differences in clinical and biological tumour behaviours and responsiveness to treatment, patient accessibility to effective treatment, etc. This review highlights and contrasts the differences in tumour aetiology and histology, as well as the management approaches between the East and the West, which gives important insights and inspirations on future international multicentre research collaboration to combat this dreadful malignancy.

Background ICONIC is a single arm phase 2 trial investigating the safety and efficacy of 4 cycles pre-operative and 4 cycles post-operative FLOT-A in resectable OGA. We report results from the safety run-in phase and early translational biomarker data. Methods Eligible pts were enrolled into the 3+3 design dose finding stage. Standard dose FLOT was administered with 10mg/kg iv avelumab q2 weeks (dose level 0). Dose limiting toxicities (DLTs) were assessed for 28d. Biopsies were taken at baseline and post cycle 2. Results At data cut-off (12/4/19) 6 pts were enrolled and completed pre-operative treatment. 1/6 pts experienced a DLT (chest pain during 5FU infusion), and dose level 0 was established as the safe dose for the efficacy stage of the trial. During pre-operative FLOT-A all pts experienced at least one grade 1-2 adverse event (AE), most commonly diarrhoea (5/6 pts), fatigue, nausea, peripheral neuropathy and hypokalaemia (all 4/6 pts); 3/6 pts experienced at least one grade 3-4 AE: neutropenia and elevated liver enzymes (1pt), thrombotic event (1pt) and cardiac chest pain (1pt). 4/6 pts reported any grade chest pain and underwent cardiac work up: 1 episode was due to PE, 1 of likely GI origin and 2 cardiac in nature, which then recurred in one pt who was re-exposed to FLOT without avelumab. 3/6 pts completed 4 cycles pre-operative FLOT-A: 1pt discontinued avelumab due to diarrhoea, 2 pts discontinued FLOT-A due to cardiac chest pain and switched to a regimen without 5FU. 5 pts have undergone surgery at data cut-off, without unexpected complications. Immunofluorescence shows changes of CD8-, memory- and regulatory T cell infiltrates between baseline and on-treatment biopsies, and detailed results will be presented. Conclusions This is the first data showing that FLOT can be combined with a PD-L1-inhibitor with FLOT-A having a manageable safety profile at dose level 0 (standard dose FLOT + 10mg/kg avelumab). As chest pain of variable aetiologies was observed in 4/6 patients this will be closely monitored and assessed during the efficacy phase. No unexpected complications have been observed during surgery following FLOT-A treatment. Clinical trial identification 2016-003306-13. Legal entity responsible for the study Royal Marsden Hospitals NHS Foundation Trust. Funding Royal Marsden Hospital NHS Foundation Trust Institute of Cancer Research, Merck Pharmaceuticals. Disclosure M. Davidson: Travel / Accommodation / Expenses: Celgene. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Honoraria (institution): AstraZeneca. I. Chau: Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (institution): Eli-Lilly. D. Cunningham: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. D. Morganstein: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche. M.D. Forster: Research grant / Funding (institution): Merck; Honoraria (institution): Merck. M. Gerlinger: Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. All other authors have declared no conflicts of interest.

Background: A key aim of neoadjuvant therapy in oes cancer is to increase the chance of complete R0 resection. Microscopic residual disease after surgery is reported in around 30% cases, mainly involving the circumferential resection margin (CRM), with current staging techniques unable to accurately identify pts at risk of residual tumour at the CRM. Previous small single site studies have shown that high res T2-weighted MRI achieves detailed imaging of oes anatomy and has the potential to serve as an additional non-invasive staging modality. Methods: As part of the UK STO3 trial pts from participating centres with operable lower oes and type I/II OGJ adenoca were enrolled in the MRI observational sub-study. All pts underwent standard staging investigations, with additional MRI scans pre and post neoadjuvant chemo, followed by surgery. MRI parameters were consistent across sites and included CRM, T/N staging and apparent diffusion coefficient (ADC) assessment. Scans were reviewed locally and centrally to assess interobserver variability. Chemo response and association with pathological outcome were recorded. Results: Between Aug 2011 and Mar 2015 57 pts were recruited from 11 sites. Of these 32 had matched pre and post chemo scans and 28 had corresponding pathological outcome data available. Negative CRM status was correctly identified on post chemo MRI in 17/19 (89%) cases; positive CRM in 3/9 (33%) cases. When compared to pathological staging there was concordance between MRI T staging in 36% cases, with overstaging in 43% and understaging in 21%. Concordance between MRI and CT for T/N staging was 66% and 77% respectively. Tumour size reductions and ADC increases were observed during chemo. Local sites predicted significantly more CRM involvement than central review (48 vs 19%). Conclusions: This represents the first prospective, multi-centre, national trial of MRI in oes cancer and is the first report of interobserver variability between treatment centres. Although limited by small numbers, MRI showed promising specificity to identify negative surgical margins and reasonable correlation with pathological outcome. Discrepancy between local and central review was observed, suggesting that more standardised methods of MRI assessment in oes cancer are required. Clinical trial identification: EudraCT: 2006-000811-12. Legal entity responsible for the study: Medical Research Council, UK. Funding: Cancer Research UK, Clinical Trials Awards Advisory Committee. Disclosure: D. Cunningham: Research funding: Amgen, AstraZeneca, Bayer, Celgene, Merck-Serono, Medimmune, Merrimack, Novartis, Roche, Sanofi. N. Starling: Research funding: AZ, BMS, Merck; Honoraria: AZ. All other authors have declared no conflicts of interest.

There is increasing evidence that treatment beyond second line provides significant survival benefit for selected advanced oesophageal and gastric adenocarcinoma patients, and important randomised controlled trials of both chemotherapy, targeted therapy and immunotherapy have recently been reported in this space. Despite this growing evidence base there are presently no formal guidelines for third line treatment available to clinicians, and as these agents move into routine clinical practice patient selection and rational sequencing of treatment will become an increasingly relevant clinical challenge. This review critically appraises the current evidence base for third line treatment and discusses patient selection, potential predictive biomarkers and future directions for third line treatment in this challenging condition.

We report on the treatment and survival of 511 patients with advanced esophagogastric adenocarcinoma treated during a 6-year period at a single center. During the period of analysis, the uptake of sequential lines of treatment in the second line and beyond increased, and such an approach was associated with improved survival outcomes. Background: Although progress has been made in the molecular stratification of esophagogastric adenocarcinoma, the outlook for advanced disease remains poor. The present evaluation of over 500 patients treated at a single European high-volume tertiary center during a 6-year period gives important information on current and developing “realworld” treatment patterns and outcomes. Results: The overall survival for the whole cohort was 11.5 months, with a range of treatments used in first-, second-, and third-line settings. Treatment with sequential lines of therapy was associated with better outcomes, although only 39% and 14% of patients subsequently received treatment in the secondand third-line setting, respectively. Treatment within a therapeutic clinical trial was associated with significantly improved survival. Conclusion: At present, a substantial proportion of patients with advanced esophagogastric adenocarcinoma will not proceed beyond first-line therapy, and for this group refinement of initial systemic therapies are required to improve outcomes. Although a number of established firstand second-line treatment options are now available, the therapeutic landscape of the disease continues to change, most notably in the application of immunotherapy and increasing interest in establishing evidence-based interventions in the third-line setting and beyond. A small but growing proportion of patients will benefit from sequential treatment approaches incorporating multiple lines of therapy, and improved selection of such patients will be a key challenge for clinicians moving forwards. Data such as these provide an overview of current treatment patterns and outcomes which can be used to inform planning of future research effectively within existing treatment frameworks. Clinical Colorectal Cancer, Vol. -, No. -, --a 2018 Elsevier Inc. All rights reserved.

Background: The iMYC trial is a biomarker-driven study in advanced OG cancer that prospectively screens patients for MYC amplification to assess the feasibility of ibrutinib therapy. MYC is implicated in OG cancer carcinogesis and as the acquisition of fitness enhancing mutations can drive tumour progression and treatment resistance, we present data from the screening component of the study evaluating the frequency and diversity of MYC amplification using FISH and ddPCR analysis of primary OG tumours and circulating tumour (ct)DNA. Methods: To find potential on-chromosome (chr) 8 references for the MYC gene for the purposes of ddPCR, OG tumour sample copy number data were obtained from cBioportal using the CGDS-R package. A dual probe FISH assay to detect MYC amplification was optimised on archival OG tumour samples where centrometric probes for chr 8 and probes mapping specifically to the coding region of the MYC gene (exons 1-3) were used to distinguish between increased copies of chr 8 and extra copies of MYC. Results: To date 96 archival tumour samples have successfully undergone FISH analysis with MYC amplification seen in 26/96 (27%). The % of cells with MYC amplification ranged widely between samples (median 57.5, range 11-94%). Intra-tumour heterogeneity was seen: 19/26 (73%) amplified samples showed a range of differing amplification ratios within the tumour specimen (bartlett test for equal variance p < 0.001) with evidence of MYC extrachromosomal amplification accounting for genetic heterogeneity. For patients displaying MYC amplification by FISH, detection of amplification by ddPCR in either tumour tissue or ctDNA was restricted to those tumours displaying a homogenous and high-level FISH amplification pattern. Conclusions: This study represents the first attempt to screen for MYC amplification prospectively in advanced OG cancer and illustrates the utility of FISH in assessing clonal diversity and visualisation of extrachromosomal amplifications. Using a novel ddPCR assay we have detected MYC amplifications from both archival tumour and ctDNA in homogeneous and highly amplified cases however the ddPCR assay is not optimal in detecting small clonal subpopulations of amplified cells in OG cancer. Clinical trial indentification: NCT02884453. Legal entity responsible for the study: Royal Marsden NHS Foundation Trust oundation Trust Funding: Janssen Pharmaceuticals Disclosure: D. Cunningham: Research funding from Roche, Amgen, Celgene, Merck, BMS, Novartis, Astra Zeneca, Bayer, Merrimack, Medimmune, Clovis, I. Chau: Advisory Board: Sanofi Oncology, Eli-Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Five Prime Therapeutics; Research funding: Janssen-Cilag, Sanofi Oncology, Merck-Serono, Novartis Honorarium: Taiho, Pfizer, Amgen, Eli-Lilly, Gilead Science. All other authors have declared no conflicts of interest.