Summary Background Patients with advanced oesophageal cancer have a median survival of 3–6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion. Methods This was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I–III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (>11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov , NCT01915693 , and is completed. Findings 220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40–1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4–27·7) with usual care and 18·9 weeks (14·...

Background:Achieving earlier stage diagnosis is one option for improving lung cancer outcomes in the United Kingdom. Patients with lung cancer typically present with symptoms to general practitioners several times before referral or investigation.Methods:We undertook a mixed methods feasibility individually randomised controlled trial (the ELCID trial) to assess the feasibility and inform the design of a definitive, fully powered, UK-wide, Phase III trial of lowering the threshold for urgent investigation of suspected lung cancer. Patients over 60, with a smoking history, presenting with new chest symptoms to primary care, were eligible to be randomised to intervention (urgent chest X-ray) or usual care.Results:The trial design and materials were acceptable to GPs and patients. We randomised 255 patients from 22 practices, although the proportion of eligible patients who participated was lower than expected. Survey responses (89%), and the fidelity of the intervention (82% patients X-rayed within 3 weeks) were good. There was slightly higher anxiety and depression in the control arm in participants aged >75. Three patients (1.2%) were diagnosed with lung cancer.Conclusions:We have demonstrated the feasibility of individually randomising patients at higher risk of lung cancer, to a trial offering urgent investigation or usual care.

8507 Background: All patients with malignant pleural mesothelioma (MPM) eventually relapse following standard chemotherapy. However, there is no standard treatment option in this setting. Vinorelbine, exhibits useful clinical activity but has not been formally evaluated in a randomised clinical trial, despite its widespread off-label use worldwide. BRCA1 regulates spindle assembly checkpoint in MPM and predicts vinorelbine sensitivity in preclinical models [1,2], suggesting that BRCA1 negative patients may be chemoresistant. Methods: VIM, a Cancer Research UK funded, investigator-initiated randomised controlled phase 2 multi-centre UK trial, enrolled patients with MPM who had progressed after first-line chemotherapy. Pts were randomised 2:1 to either vinorelbine (60mg/m2 weekly Q21d escalating to 80mg/m2 from cycle 2) + active supportive care (ASC) versus ASC until disease progression, unacceptable toxicity or withdrawal of consent. The primary outcome was progression free survival (PFS) defined as the time from randomisation to any progression (based on Modified RECIST criteria for assessment of response in malignant pleural mesothelioma) or death. The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints were overall survival (OS), tolerability and safety. Results: Between May 2016 and Oct 2018, 154 patients were recruited from 10 UK sites and randomised to vinorelbine + ASC (n=98) or ASC alone (n=56). In the Intention-to-treat analysis, after 129 events, median PFS was 4.2 months (m) for vinorelbine + ASC compared to 2.8m for ASC alone (Hazard Ratio (HR) 0.59; 95% CI: 0.41 to 0.85; one-sided p = 0.0017). 108 deaths were reported. Median OS was 9.3m for vinorelbine + ASC compared to 9.1m for ASC alone (HR=0.79; 95% CI: 0.53 to 1.17; two-sided p = 0.24). Toxicity data and subgroup analyses including the impact of BRCA1 deficiency will be presented. Conclusion: The trial met its primary endpoint. Vinorelbine demonstrates useful clinical efficacy in relapsed MPM, supporting its off-label use, as a treatment option for patients with relapsed MPM.[1] Busacca et al, J Pathol 2012, 227(2), 200. [2] Busacca et al, Mol Cancer Res, 2021, 20(2) 379. Clinical trial information: NCT02139904.

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e21649 Background: Impaired DNA damage response (DDR) is a common feature of cancer, however therapeutic exploitation has been limited to cancers harbouring somatic inactivation of BRCA1/2 which causes homologous recombination deficiency (HRD). We hypothesized that patients (pts) with metastatic non-small cell lung cancer responding to platinum doublet based chemotherapy, might enrich for impaired DDR encompassing HRD, rendering these tumours more sensitive to inhibition of poly-ADP ribose polymerase (PARP) inhibition by olaparib. Methods: PIN was a multicentre double-blind placebo controlled randomised phase II screening trial (alpha and beta = 0.2). Chemonaive pts had advanced (stage IIB/IV) squamous (Sq) or non-sq (NS) NSCLC, ECOG performance status 0-1, no EGFR nor ALK mutation. Prior immunotherapy with a PD1/ PDL1 inhibitor was allowed. If tumour shrinkage was observed after 3 cycles of platinum chemotherapy, pts were randomised 1:1 to olaparib (O, 300mg po bd q21) or placebo (P), which was continued until disease progression or withdrawal. Primary end point was progression free survival (PFS), with a one-sided test for significance. Secondary endpoints were overall survival (OS), response (RECIST v1.1) and safety (CTCAE4.0). Results: 70 pts were randomised to O (32) or P (38) between Aug 2014 and Nov 2017. There was no difference in median dose intensity (% (IQR), O vs P) was 86.4 (64.3-95.7) vs 93.3 (80.2-97.6). Pts receiving O had a longer, but not statistically significant median PFS (weeks (IQR) was O 16.6 (7.1-21.7) vs P 12 (5.6-18.7)); and hazard ratio (HR) was 0.83 (80% CI 0.6-1.15, p = 0.23), using intention to treat (ITT) unadjusted analysis. However, the ITT Cox model, adjusted for smoking history and histology, showed a significantly longer PFS for pts receiving O (HR 0.73 (80% CI 0.52-1.02, p = 0.11)). Pts receiving O also had greater, but not statistically significant OS: median (weeks (IQR) was O 59.4 (38.7-67.9) vs P 31.3 (22.4-58.6)). OS HR was 0.68 (95% CI 0.37-1.26; two-sided p = 0.22). 3 patients were completely withdrawn prior to progression. No complete responses were observed and treatment was well tolerated. Conclusions: Design parameters justifying a Phase III trial (p < 0.2) were met in the adjusted, but not unadjusted PFS analysis, with a trend towards longer PFS and OS in the O arm. We speculate that this signal may be driven by a DDR deficient molecular subgroup. Translational studies are warranted to investigate these possibilities. Clinical trial information: NCT01788332.