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.

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.

肺癌迄今仍是男女人群中最主要的癌症致死病因，占所有癌症死亡病例的近25%。非小细胞肺癌（non-small cell lung cancer, NSCLC）是最常见的肺癌类型，占全部肺癌确诊病例的84%。总体而言，男性终身罹患肺癌的风险约为1/15；女性则约为1/17。在过去数年间，晚期非小细胞肺癌的治疗格局发生了根本性改变，随着免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）的问世——这类药物可帮助机体识别并攻击癌细胞——显著改善了该疾病相当比例患者的预后。此类药物为单克隆抗体（monoclonal antibodies），可阻断程序性死亡蛋白1/程序性死亡蛋白配体1（programmed death-1 / programmed death-ligand 1, PD-1 / PD-L1）等免疫调节通路，而该通路是晚期NSCLC治疗中最为关键的靶点。PD-1是表达于多种免疫细胞表面的受体，包括T细胞、B细胞及自然杀伤细胞（natural killer cells, NK细胞）。其配体之一PD-L1可在包括肿瘤细胞在内的多种细胞表面表达，能够抑制已活化的T细胞功能。癌细胞可利用此类免疫调节通路，逃避免疫系统的识别，并抑制抗肿瘤免疫应答，其中主要通过阻断T细胞功能实现。免疫检查点抑制剂类免疫治疗可通过阻断上述通路，克服肿瘤介导的免疫抑制，构建促炎性肿瘤微环境，进而潜在提升肿瘤应答率。然而，仅部分患者可从此类治疗中获得长期获益，这部分归因于多种免疫逃逸机制的产生，即肿瘤克服免疫检查点抑制剂诱导的抗肿瘤免疫应答的能力。晚期非小细胞肺癌患者常伴随较差的临床状态，在启动免疫检查点抑制剂治疗前，可能需要同时服用多种药物，包括因其他合并症长期服用的药物。疼痛是NSCLC患者的常见症状，用于疼痛管理的全身性阿片类药物在合并用药中的占比可高达60%以上。阿片类药物可与阿片受体结合——该受体可视为神经纤维上的疼痛受体——从而产生类似吗啡的效应。从医学角度而言，阿片类药物可用于急性与慢性疼痛管理，包括癌痛。近年来，合并使用的全身性阿片类药物对免疫检查点抑制剂疗效的潜在干扰效应受到广泛关注，越来越多的证据支持其可破坏免疫应答的假说。肠道微生物组（gut-flora，肠道菌群）指定居于消化道内的全部微生物，其与宿主处于持续动态平衡状态，现已证实其可影响患者的整体健康状态，包括免疫系统功能。这种平衡被打破后，可影响机体对局部与全身性感染的防御能力、早期生命阶段免疫系统的发育与自身免疫性疾病的发生，以及抗肿瘤免疫功能。基于此，多项研究表明，长期暴露于吗啡可显著改变共生菌的组成与定位，引发阿片类药物诱导的菌群失调（opioid-induced dysbiosis, OID），进而可能影响全身性免疫应答。基于上述证据，我们提出假说：与接受标准细胞毒性化疗（cytotoxic chemotherapy）的患者相比，基线时暴露于阿片类药物的患者在接受免疫检查点抑制剂免疫治疗时，预后更差。POPLAR研究是一项多中心、随机、开放标签、全人群II期临床试验，纳入既往接受过治疗的晚期非小细胞肺癌患者，随机分配接受阿替利珠单抗（atezolizumab）或多西他赛（docetaxel，化疗）治疗。通常而言，II期研究以相对较小的样本量初步探索药物疗效，后续的III期研究则为更大规模的确证性试验，可明确阐明试验性药物的疗效与安全性特征。在II期POPLAR试验中，患者于全球多家肿瘤学机构入组并接受治疗。研究参与者未基于特定肿瘤标志物进行筛选，通过自动化随机化流程（即随机分组）被随机分配至试验组（阿替利珠单抗，一种阻断PD-L1蛋白的单克隆抗体）或对照组（多西他赛，标准化疗药物），以确保两组队列的基线特征均衡，便于疗效对比。POPLAR研究的初步结果显示，相较于化疗（多西他赛），PD-L1抑制性免疫治疗（阿替利珠单抗）可带来生存获益。OAK试验是一项规模更大、设计相似的III期临床试验，纳入全球多家机构的晚期非小细胞肺癌患者，随机分配接受阿替利珠单抗或多西他赛治疗，证实了阿替利珠单抗免疫治疗相较于多西他赛化疗的生存获益。本研究旨在获取并合并POPLAR与OAK两项研究的数据集，以根据患者基线时的阿片类药物暴露情况（治疗启动前30天内服用的任何全身性阿片类药物），分析阿替利珠单抗与多西他赛两个队列中患者的临床结局。我们将评估阿片类药物暴露在两个前瞻性随机队列中可能存在的不同预后效应。本研究的数据为前瞻性收集，即从患者入组时起开始采集，可为我们提供可靠的分析数据集；同时，随机分组流程可确保研究组间患者特征的均衡分布。综上，本研究最终可明确阿片类药物是否会根据治疗策略的不同，对非小细胞肺癌患者产生差异化的影响。