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

Abstract

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.