ITTACA (Immunotherapy Time Teller for Advanced Lung Cancer)

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).

The individual chronotype will be determined from this using the TimeTeller algorithm. To compare chronotype as determined by TimeTeller, to chronotype determined by traditional methods, participants will also undergo actigraphy monitoring and complete several questionnaires on day 1, including the Morningness-Eveningness, uMCTQ and BACS questionnaires. Actigraphy data will be obtained via participants wearing a smart watch one week prior to the first cycle and six weeks which will monitor heart rate and rest activity cycles.

At baseline we will also assess the WHO performance status. This widely used scale assesses functional status on a 5-point scale, from 0 being asymptomatic, fully active and able to carry on all pre-disease activities without restriction, progressively worsening as the scale increases representing functional decline.

Therefore, this study will assess if TimeTeller is able to robustly identify the molecular clock in patients with treatment for advanced NSCLC from analysis of sparse, minimally invasive samples. Currently, the cancer unit in Alaw, Ysbyty Gwynedd, Bangor administers immunotherapy at a regimented middle of the daytime-point, because of pharmacy preparation constraints. Our scrutiny of published studies showed that, globally, about three quarters of ICI administrations occur between 10h30 and 15h30 local time. This project will take advantage of this consistent and uniform scheduling of ICI and explore the importance of the variability in the patients' biological clock as a secondary endpoint. It can assess if the individual patient's chronotype has any impact on ICI effectiveness and side-effect profile. Additionally, through the use of wearable devices that measure continuous data such as activity and questionnaires as further independent clock markers will be assessed, along and the one-year survival will be recorded. This intermediate outcome is considered the most relevant surrogate of OS on immunotherapy. It is hoped this study will pave the way for future prospective studies.

This study does not involve additional hospital visits, specific equipment at home, digital skills or lifestyle changes, and is not expected to be impacted by sex or ethnic heritage. If successful, the results of this trial could improve clinical outcomes in NSCLC with little additional cost in terms of patient time or finance.

The findings of this study will lay the groundwork for prospective interventional trials with a strong translational and personalised aspect, harnessing the most up-to-date algorithms in circadian-based treatment, whose benefits with conventional drugs have been recently appraised by an independent group. Moreover, our results, if successful, could directly impact local routine care and service policy for ICI ToD administration in the day unit, prioritising morning administration for all future patients.

Finally, this observational study is conceived as the first stage of a stepwise approach to improving outcomes on ICI through an integrative and comprehensive evaluation of the tumour and the host, as well as of their bidirectional interactions, paving the path for translational and interventional future trials.