Applications of liquid biopsy in the Pharmacological Audit Trail for anticancer drug development.

Anticancer drug development is a costly and protracted activity, and failure at late phases of clinical testing is common. We have previously proposed the Pharmacological Audit Trail (PhAT) intended to improve the efficiency of drug development, with a focus on the use of tumour tissue-based biomarkers. Blood-based 'liquid biopsy' approaches, such as targeted or whole-genome sequencing studies of plasma circulating cell-free tumour DNA (ctDNA) and circulating tumour cells (CTCs), are of increasing relevance to this drug development paradigm. Liquid biopsy assays can provide quantitative and qualitative data on prognostic, predictive, pharmacodynamic and clinical response biomarkers, and can also enable the characterization of disease evolution and resistance mechanisms. In this Perspective, we examine the promise of integrating liquid biopsy analyses into the PhAT, focusing on the current evidence, advances, limitations and challenges. We emphasize the continued importance of analytical validation and clinical qualification of circulating tumour biomarkers through prospective clinical trials.

A Wolf in Sheep's Clothing: Systemic Immune Activation Post Immunotherapy.

Introduction: Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH). Methods: All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection. Results: Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH. Conclusion: SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.

Research Related Tumour Biopsies in Early-Phase Trials with Simultaneous Molecular Characterisation - a Single Unit Experience.

Early-phase cancer clinical trials are becoming increasingly accessible for patients with advanced cancer who have exhausted standard treatment options and later phase trial options. Many of these trials mandate research tissue biopsies. Research biopsies have been perceived as ethically fraught due to the perception of potential coercion of vulnerable human subjects. We performed an audit of two years of practice to assess the safety of ultrasound (US)-guided research biopsies, and to look at the yield of a simultaneous tumour next-generation sequencing (NGS) and immunohistochemistry (IHC) molecular characterisation programme. We show that in our institution, US-guided research biopsies were safe, produced adequate tumour content and in a selected subset who underwent in-house NGS sequencing, showed a high rate of actionable mutations with 30% having a Tier 1 variant. Nevertheless, these research biopsies may only provide direct benefit for a minority of patients and we conclude with a reflection on the importance of obtaining truly informed consent.