The Christie NHS Foundation Trust in Withington, Manchester, manages the Christie Hospital, one of the largest cancer treatment centres of its type in Europe. The Christie became a NHS Foundation Trust in 2007 and is also an international leader in cancer research and development, home to the Paterson Institute for Cancer Research.
Background Extrapolation of overall survival in health technology assessment (HTA) is a key area of uncertainty, as equally well-fitting models can generate divergent lifetime projections. This can lead to significant implications for decision-making. Subject experts are often consulted on the plausibility of survival projections, but input is rarely obtained in a robust manner. Objective This case study applies guidance from the National Institute for Health and Care Excellence Decision Support Unit Technical Support Document (TSD) on using structured expert elicitation for long-term survival estimation (TSD 26). This study focuses on its feasibility of implementation from the perspective of a company preparing a HTA submission. Methods The REVEL trial, evaluating ramucirumab plus docetaxel for stage IV non-small cell lung cancer, was selected as a case study. The elicitation was based on the Sheffield Elicitation Framework (SHELF) and undertaken in accordance with TSD 26. Results Five experts from four countries attended across three virtual workshops. Experts provided quantitative judgements on overall survival at 4 years for the intervention and comparator from the REVEL trial. Qualitative discussion of the change in hazard and scenario testing demonstrated the internal consistency of experts' judgments and provided valuable context for expert judgements. Group discussion in separate workshops posed challenges when the facilitation team had to relay the views of absent experts. Conclusions This case study demonstrates that it is feasible to follow the recommendations provided in TSD 26 when conducting elicitation for long-term survival outcomes and highlights the critical role of discussing the hazard function in group discussions.
PURPOSE:ctDNA dynamic levels may identify patients who will respond to therapy. We assessed ctDNA baseline levels and on-treatment dynamics in patients with advanced breast cancer on the plasmaMATCH trial with mutation-targeted therapies (cohorts A-D) and triple-negative breast cancer on olaparib and ceralasertib combination (cohort E). EXPERIMENTAL DESIGN:Blood samples were collected at baseline [cycle 1 day 1 (C1D1)] and before treatment on cycle 2 day 1 (C2D1). Samples were sequenced using error-corrected targeted panels (Guardant360/GuardantOMNI). Circulating DNA ratio was calculated as the ratio of C2D1/C1D1 circulating DNA ratio, and baseline ctDNA levels were associated with progression-free survival (PFS) and confirmed objective response rates (ORR). RESULTS:A total of 167 patients had assessable C1D1-C2D1 ctDNA results. There was a strong association between baseline ctDNA levels and response in cohort E; low baseline levels were associated with longer PFS (HR, 0.33; P = 0.001) and higher ORR (40% vs. 9.7%; P = 0.02). In cohorts A to D, there was a weaker association with PFS (HR, 0.60; P = 0.03) and ORR (15.2% vs. 5.7%; P = 0.17). Associations of baseline ctDNA level and ORR were validated in the independent PEARL study. For on-treatment dynamics, suppression of ctDNA below median was predictive in cohorts A to D (HR, 0.47; P = 0.001) but not in cohort E (HR, 1.02; P = 0.94). Undetectable ctDNA levels at C2D1 were associated with good outcomes in both cohorts: in cohort E with improved PFS (HR, 0.25; P = 0.01) and improved ORR (86% vs. 11%; P = 0.01). Six of seven patients with undetectable on-treatment ctDNA were BRCA1/BRCA2/PALB2 wild type. CONCLUSIONS:Baseline low ctDNA levels predict response to targeted therapy, potentially suggesting shared mechanisms between high ctDNA release and resistance to therapy. Both baseline ctDNA levels and on-treatment dynamics are a promising surrogate endpoint for drug development, with clearance of ctDNA being a robust cross-therapy surrogate for outcomes.
Curative-intent multimodality treatment-combining local treatments such as surgery or radiotherapy with systemic therapy-is the cornerstone of care in stage II-III non-small cell lung cancer (NSCLC). Since 2017, the systemic therapy backbones with multimodality treatment have undergone a dramatic transformation, driven by a series of pivotal, practice-changing clinical trials. Immunotherapy and targeted therapies, previously confined to the advanced/metastatic setting, are now firmly embedded in curative-intent regimens. Maintenance immunotherapy following chemoradiation in unresectable stage III disease, adjuvant tyrosine kinase inhibitors in resected epidermal growth factor receptor/anaplastic lymphoma kinase-positive tumours, neoadjuvant and perioperative chemoimmunotherapy in resectable stage II/III NSCLC and adjuvant chemoimmunotherapy following resection have all become new standards of care.This state-of-the-art review synthesises the key evidence underpinning these developments, highlights their clinical implications and identifies challenges to implementation-particularly the need for redefined clinical pathways, accurate pretreatment staging, timely biomarker testing and coordinated multidisciplinary decision-making. A novel treatment algorithm is proposed to support clinicians in navigating these complex treatment choices.We conclude that immunotherapy and targeted agents have irrevocably altered curative-intent NSCLC care, establishing multiple new standards that sometimes overlap and compete. In the surgical multimodality treatment pathway, neoadjuvant and perioperative chemoimmunotherapy offers the opportunity to increase the uptake of systemic therapy in comparison to adjuvant therapy and is considered by these authors to represent the optimal treatment path for most patients.In this unprecedented era of therapeutic expansion, the greatest challenge is no longer the absence of effective treatments, but the complexity of selecting, sequencing and delivering them, as well as patient optimisation. Lung cancer services must evolve through proactive pathway redesign, integrated diagnostics and new models of multidisciplinary care. High-quality, biomarker-driven and patient-centred care is now achievable for many patients with stage II-III NSCLC-but it will require system-level adaptation to deliver it.
