To Identify if Hair and Buccal Mucosa Samples Can Provide a Non-invasive, Practical, Accurate and Clinically Relevant Method to Determine the Internal Clock Time and to Monitor Individual Circadian Rhythms in Patients With Advanced Lung Cancer Receiving Immunotherapy-based Treatment.

Lung cancer remains a significant cause of death particularly in North Wales. A relatively new treatment, immune checkpoint inhibitors (ICI), which are a type of immunotherapy, have revolutionised cancer care over recent years. However, they are not always effective. Recent studies suggest the effectiveness of ICI is influenced by the time of day it is given, with morning administration generally resulting in better outcomes.

Numerous studies have found that ICI given in the morning yielded a significantly greater progression-free survival (PFS) and overall survival (OS) in patients with Non-Small Cell Lung Cancer (NSCLC). There are however discrepancies in the cut-off times and proportions of ICI infusions for the definition of 'morning administration' among these studies.

Mechanistically, this is proposed to be due to the modulation of the immune system by the circadian timing system, which is aligning human behaviour and physiology with the 24-hour cycles of the environment. The internal body clock controls a lot of important processes within cells, organs and systems. Circadian rhythm plays a key role in the immune system and tumour surveillance. Therefore, clock disruption has been linked to a variety of human illnesses including cancer. There is, however, significant inter-individual variation between people. The natural inclination to wake up early or sleep in is often referred to as 'chronotype'. For example, some people are known as early birds (or larks) and some as night owls. The chronotype may influence how effective immunotherapy is when given at fixed time-of-day to different people.

It is not trivial to accurately determine chronotype. The gold standard to determine central circadian phase is determining the dim light melatonin onset (DLMO). The hormone melatonin's release from the pineal gland is under direct control of the central clock in the brain and can be measured by frequent sampling of salivary levels in a darkened room around the time of expected DLMO, which is highly resource intensive. Further methods are used, i.e., wearables monitoring rest-activity cycles, body temperature or heart rate as well as more subjective questionnaires. However, these methods may not be accurate in cancer patients' where circadian disruption is common. Therefore, an accurate, minimally invasive test to determine chronotype is needed. A new tool has been developed by Warwick University called TimeTeller, which may be able to accurately determine chronotype based on a single sample of hair-follicles or a cheek swab.

This study will involve patients with NSCLC receiving immune checkpoint inhibitors, alone or in combination with cytotoxic platinum-based chemotherapy as indicated, to include pembrolizumab, atezolizumab and nivolumab as, adjuvant, neoadjuvant or palliative treatment. Hair or cheek swab samples will be taken on the first day of the first cycle (before receiving the first ICI administration) and again approximately 4-6 weeks later, equivalent to day 1 of cycle two for those receiving pembrolizumab alone (administered six weekly), day 1 of cycle three for those receiving pembrolizumab in combination with chemotherapy (administered three weekly), and on day 1 of cycle two for those receiving atezolizumab or nivolumab (administered four weekly).