In the last 5 years, the introduction of immune checkpoint inhibitors (ICPi) have dramatically improved treatment outcome in patient with non-small cell lung cancer (NSCLC) who do not harbour an actionable mutation. Whilst hyperglycaemia is known to have widespread immune modulating effects, little is known about the frequency of hyperglycaemia following treatment with a checkpoint inhibitor. Meanwhile, there is emerging evidence suggesting poorer outcomes in diabetic patients treated with ICPi. Pharmacy records were used to identify patients from the lung unit who have received treatment with ICPi. The electronic patient's record (EPR) was used to identify those with hyperglycaemia at baseline or following treatment and to identify those with pre-diagnose diabetes. Hyperglycaemia was defined as a fasting glucose > 7 mmol/L or random glucose ≥ 11.1 mmol/L. Clinical and demographic data as well as the date of 1st dose of checkpoint inhibitor, date 1st elevated glucose level and date of radiologically confirmed progression or death or last contact were also obtained from patient's records. Glucose levels were analysed to one year after the cessation of checkpoint inhibitor therapy. A total of 213 NSCLC treated with immunotherapy were identified. Median age was 68 years (range 45-84) and patient were predominantly male (n=203). Most patients had an adenocarcinoma, 43% had a high PDL-1 expression (>50%) and 37% were treated with palliative intent with pembrolizumab monotherapy. Of the 169 without DM at baseline 10 (5.9%) developed glucose >11.1 in first 6 months of treatment; 5 received steroids, 2 had an infection, in 2 no clear cause found and settled spontaneously and only 1 ICPi induced DM was identified. Of the 43 with DM 23 (53%) developed glucose >11.1 in first 6 months of treatment. Whilst ICPi induced diabetes is rare, treatment with ICPi in diabetic patients often results in clinically relevant hyperglycemia, potentially resulting in poorer treatment outcome. Strict glucose monitoring and treatment of hyperglycaemia might improve this. Further survival analyses and prospective studies are needed to investigate the effect of hyperglycaemia in this frail population.

Background 95% of metastatic colorectal cancers (mCRCs) have normal mismatch repair proficient (pMMR) expression and a stable microsatellite phenotype (MSS). As a consequence, checkpoint inhibiting immunotherapy currently plays no role in these tumours. We recently found that RAS/RAF wild type (WT) mCRCs (50% of all CRCs) that first responded to cetuximab and then acquired resistance had converted from an immune-excluded or immune-desert phenotype before treatment to an inflamed phenotype at progression. This progression was characterized by increased CD8+ T cell infiltrates and upregulation of PDL1 and LAG3 immune checkpoints. To assess if the cetuximab induced immune infiltrates can be exploited for therapeutic benefit, the iSCORE trial will treat 25 patients with combined anti-PD1 (nivolumab) and anti-LAG3 (relatlimab) immunotherapy starting ideally within 4 weeks after progression on immunogenic FOLFIRI chemotherapy and cetuximab. Trial design iSCORE is designed to evaluate the efficacy of nivolumab and relatlimab in patients with RAS/RAF WT mCRC who have had radiological response to first line FOLFIRI and cetuximab, but then progressed. Eligible patients will receive nivolumab 480mg and relatlimab 160mg every 4 weeks. The primary endpoint is disease control rate (DCR) at 6 months from treatment initiation. With an A’Hern single stage design for efficacy, 5% significance and a power of 80%, 25 patients would need to be treated and a minimum of 6 would need to be progression free at 6 months in order to support an increase of the DCR at 6 months from <10% to 30% or more. Secondary endpoints include DCR at 12 and 24 months, duration of disease control, best objective response rate at 6, 12 and 24 months, progression free survival and overall survival. Exploratory objectives include investigating dynamic changes in the gut microbiota/metabonome, immune infiltrates, immune checkpoints and molecular tumour characteristics induced by LAG3 and PDL1 blockade. This will be achieved through sequential collection of stool and tumour biopsies and baseline tumour characteristics will be correlated with tumour response and survival. iSCORE is a single-centre phase II trial. Recruitment opened in March 2019 and 25 patients will be recruited in 36 months. Clinical trial identification NCT03867799. Legal entity responsible for the study The Royal Marsden NHS Foundation Trust. Funding The Royal Marsden NHS Foundation Trust, Bristol-Myers Squibb. Disclosure D. Cunningham: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck. 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 (self): Eli-Lilly. M. Gerlinger: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KG. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Servier; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.

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.

Immunotherapy treatment with checkpoint inhibitors (CPI) (CTLA-4 and PD-1 inhibitors) significantly improves survival in a number of cancers. Treatment can be limited by immune-mediated adverse effects including endocrinopathies such as hypophysitis, adrenalitis, thyroiditis and diabetes mellitus. If endocrinopathies (particularly hypocortisolemia) are not recognized early, they can be fatal. The diagnosis and management of endocrinopathies can be complicated by simultaneous multi-organ immune adverse effects. Here, we present Endocrine Emergency Guidance for the acute management of the endocrine complications of checkpoint inhibitor therapy, the first specialty-specific guidance with Endocrinology, Oncology and Acute Medicine input and endorsed by the Society for Endocrinology Clinical Committee. We present algorithms for management: endocrine assessment and management of patients in the first 24 hours who present life-threateningly unwell (CTCAE grade 3–4) and the appropriate management of mild-moderately unwell patients (CTCAE grade 1–2) presenting with features compatible with an endocrinopathy. Other important considerations in relation to hypohysitis and the maintenance of glucocorticoid therapy are discussed.

Important side effects and potential clinical hazards have emerged from long-term follow up in some drug classes used in type 2 diabetes treatment. Systematic phase 4 post-marketing data in early use of newer diabetes drugs may have a role in informing drug choice in practice and assist in pharmacoeconomic assessments of these drug choices.We carried out a comparison of the prevalence of drug withdrawals derived from both liraglutide registration trial data, and a systematic, prospective case-note review of all new liraglutide prescriptions (n=176) from a specialist diabetes clinic over the first 12 months of drug introduction.Trial data used for the marketing authorisation application for liraglutide reported 7.0% withdrawal due to adverse events. Equal numbers of patients experienced mild, moderate and severe side effects. By contrast, data derived from a 'real world' clinical group describe 14.8% withdrawal due to adverse events, with withdrawal typically occurring early, by three months. Adverse events were more frequently responsible for treatment withdrawal at lower, compared to higher, doses of liraglutide therapy.Systematic observations of withdrawals in early use of new drugs in current clinical practice are higher than reported in registration trial data. These data highlight that post-marketing surveillance should inform guideline recommendations and pharmacoeconomic evaluations. Copyright (C) 2012 John Wiley & Sons.

Mason and colleagues report that sexual precocity occurred in a 4 year old boy with inadvertent transfer of transdermal testosterone gel.1 We report contamination of blood samples during venepuncture. A patient receiving testosterone replacement treatment had a serum …