Mesothelioma and Radical Surgery 2 (MARS 2): protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma.

INTRODUCTION: Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left. METHODS AND ANALYSIS: The MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery-(extended) pleurectomy decortication-versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment. ETHICS AND DISSEMINATION: Research ethics approval was granted by London - Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ISRCTN-ISRCTN44351742 and ClinicalTrials.gov-NCT02040272

Development of novel therapeutic strategies in relapsed advanced/metastatic non-small cell lung cancer

Recent advances in the treatment of advanced NSCLC include introduction of targeted therapies and immune-checkpoint inhibitors, leading to improvements in survival outcomes. However, significant new challenges and questions have arisen, including availability of adequate material for tissue molecular testing, overcoming resistance to first-line TKIs and immunotherapy agents, and the emerging role of ctDNA genotyping. This thesis describes the conduct of two national real-world studies of outcomes in patients with advanced adenocarcinoma NSCLC treated with pembrolizumab in the treatment-naive setting and combination docetaxel/nintedanib in the relapsed setting, demonstrating their safety and effectiveness during the early days of uptake in UK patients, while also benchmarking outcomes in a target population for a phase Ib/II clinical trial to determine the safety and efficacy of a novel therapeutic combination of nab-paclitaxel with nintedanib, the set-up of which is also described. This thesis also describes a single-centre retrospective study validating the adequacy of rebiopsy tissue for genotyping in relapsed NSCLC, followed by a study of optimal methods of tissue acquisition in the context of CRUK SMP2 programme, both providing valuable data to guide clinicians at a time when evidence was building for the need for repeated molecular genotyping, and subsequently also for the benefits of broader tissue NGS profiling. Finally, results of a prospective feasibility study of implementation of a national clinical EGFR ctDNA testing service in the NHS are presented, followed by a study evaluating the real-world clinical utility of ctDNA-based NGS demonstrating its complementary role when used with current standard-of-care molecular profiling technologies, by increasing the proportion of patients with actionable genomic variants in rapid and minimally-invasive manner. The work performed towards the thesis has enabled me to develop knowledge, skills and confidence to continue to contribute to the implementation and advancement of personalised cancer medicine and towards improving patient outcomes

Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer

Small cell transformation is a rare but well recognised mechanism of acquired resistance to EGFR-TKI therapy in EGFR-mutated NSCLC, but optimal drug therapy thereof is unknown. Nivolumab has demonstrated activity in relapsed de novo small cell lung cancer in early phase trials. Here, we report a case of transformed EGFR-mutant SCLC treated with nivolumab with no benefit