DOI: 10.25934/pr00008926
title: The putative differential impact of opioids exposure in patients with advanced non-small cell lung cancer (NSCLC) treated with immunotherapy or chemotherapy: a post-hoc analysis of the randomized phase 2 POPLAR and phase 3 OAK trials.

description: Lung cancer is by far the leading cause of cancer death among both men and women, representing almost 25% of all cancer deaths. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. Overall, the chance that a man will develop lung cancer in his lifetime is about 1 in 15; for a woman, the risk is about 1 in 17.
In advanced stage NSCLC, the treatment scenario radically changed in the last few years, with the advent of immune checkpoint inhibitors (ICIs), treatments that help the body recognize and attack cancer cells, which improved the prognosis of a significant portion of patients with this disease. These agents are monoclonal antibodies that block regulatory immune axes such as the programmed death-1 / programmed death – ligand 1 (PD-1 / PD-L1), which is the most important for the treatment of NSCLC. PD-1 is a receptor expressed on the surface of multiple immune cell types, including T cells, B cells, and NK cells. One of its ligands, PD-L1, is expressed in different cell types including tumor cells, and is able to inhibit previously activated T cells. Cancer cells are able to exploit these regulatory axes in order to facilitate tumor evasion from immune system recognition and inhibit anti-cancer immune responses, mainly through the inhibition of T-cell function. Immunotherapy using ICIs overcomes this tumor-mediated immune inhibition by blocking these axes, leading to a proinflammatory tumor microenvironment which potentially increases tumor response.  However, only a subset of patients derives long-term benefit to these therapies, also due to the development of multiple mechanisms of immune escape, meaning the ability to overcome ICI-induced antitumor immune-response.
Patients with advanced NSCLC often present with poor clinical conditions and may require the simultaneous use of multiple medicines, including those medications chronically taken for other comorbidities before the ICI therapy starting date. Pain is a prevalent symptom in patients with NSCLC, and systemic opioids taken for pain management can be listed among the concomitant medications in up to > 60% cases.  Opioids are molecules that bind to the opioid receptors, which can be considered the pain receptors on nerve fibres, to produce morphine-like effects. From the medical perspective, opioids are used for both acute and chronic pain management, including cancer pain.  
Recently, the potential interfering effect of concomitant systemic opioids on ICIs efficacy has gained particular attention, with increasing evidence supporting the hypothesis of their disrupting role on immune responses. Gut-microbiome perturbations are among the possible mechanisms linking decreased anti-tumour immune-response and opioid therapy. The gut microbiome (gut-flora) represents the whole of the microorganisms that live in the digestive tracts, which exists in a continuous balance with the host and has been demonstrated to impact the overall health status of patients including the immune system function. Disruptions of this balance are able to affect protection from both local and systemic infections, development of the immune system during early life and autoimmunity, and anti-tumor immunity. From this perspective, several studies indicate that chronic exposure to morphine could significantly alter the composition and localization of commensal bacteria, leading to opioid-induced dysbiosis (OID), with possible effect on systemic immune response. 
All this evidence led us to hypothesize that baseline opioids exposure could be linked to a greater negative prognostic effect in patients treated with ICI immunotherapy in comparison to patients treated with standard cytotoxic chemotherapy.
POPLAR is a multicentre, randomised, open-label, all-comer phase 2 trial, that enrolled previously treated patients with advanced NSCLC to receive either atezolizumab () or docetaxel (chemotherapy). 

Usually, a phase 2 study preliminary explores drugs’ efficacy with a smaller sample size of patients then phase 3 studies, which are larger confirmatory trials that clearly establish the efficacy and safety profiles of investigational agents. In the phase 2 POPLAR trial, patients were enrolled and treated at multiple oncological institutions across the globe. Study participants were not selected on the basis of any specific tumor marker and were assigned to receive either the experimental (atezolizumab, a monoclonal antibody blocking the PD-L1 protein) or the control (docetaxel, a standard chemotherapy) treatment on a random basis, following an automated process called randomization, which ensure to have balanced cohorts to compare. The POPLAR study preliminary showed a survival benefit for immunotherapy with PD-L1 inhibition (atezolizumab) over chemotherapy (docetaxel). 
The OAK trial is a larger but similar phase 3 trial, in which patients with advanced NSCLC from several institutions across the globe were enrolled and randomised to receive either atezolizumab or docetaxel, confirming the survival benefit for immunotherapy with atezolizumab over chemotherapy with docetaxel. 
Our aim is to access and merge the POPLAR and OAK study datasets in order to analyse patients’ clinical outcomes across both the atezolizumab and docetaxel cohorts according to the opioid-exposure at baseline (any systemic opioids taken within 30 days prior to treatment initiation). We will be able to evaluate the potentially different prognostic effect of opioid exposure between two prospectively randomized cohorts. The prospective nature of the data, which means collected from the time of patients’ ennoblement onwards, will allow us to have a reliable set of information to work on, while the randomization process, which means that patients were allocated to the atezolizumab or the docetaxel arm following automated randomization, will ensure a balanced distribution of patients’ characteristics between the study groups. All that, will allow us to eventually confirm whether or not opioids exert a differential effect in patients with NSCLC depending on the treatment strategy.