DOI: 10.25934/pr00009018
title: Differential effect of systemic antibiotics and proton pump inhibitors on clinical outcomes from immunotherapy or placebo as sequential therapy in patients with locally advanced, unresectable non-small cell lung cancer (stage III) who have not progressed following chemoradiation therapy: A post-hoc analysis of the PACIFIC trial.

description: Lung cancer is the most commonly diagnosed cancer and represents the leading cancer-related death worldwide among both men and women. Symptoms of lung cancer include a cough that will not go away, chest pain and fatigue and treatment is often multidisciplinary, including surgery, radiation therapy, immunotherapy, chemotherapy and targeted therapy. 
Non-small-cell lung cancer (NSCLC) is one of the two primary types of lung cancer and the most common kind, accounting for 84% of all cases, differently from the other type, called small cell lung cancer (SCLC), which is less common (16% of the cases), but more aggressive from the clinical point of view, being able to spreads more rapidly throughout the body, compared to NSCLC. 
Among NSCLC, approximately 30% of patients present with locally advanced Stage III disease at first diagnosis, which often implies that the tumour has spread to the lymph nodes and cannot be surgically resected (e.g. total surgical removing of the tumour within the lung).
The standard treatment for stage III NSCLC that cannot be treated with radical surgery is chemotherapy combined with radiation therapy, administered with curative intent, which means a treatment delivered to eradicate the tumour permanently. The chemotherapy used is defined as “platinum-based” chemotherapy, as it contains a platinum derivate as the most important drug. Platinum derivates directly kill tumour cells by damaging their DNA and are able to boost radiation therapy efficacy.
There are two ways to deliver chemotherapy with radiation therapy, concurrently (cCTRT), meaning at the same time, and sequentially, meaning chemotherapy first and then radiotherapy. Sequential radiotherapy has been always considered to be less effective, but with a better safety and adverse events profile (for instance like a reduced incidence of decreasing values of the white blood cells) 
A meta-analysis of concurrent versus sequential chemoradiotherapy showed better outcomes with concurrent therapy, but still among patients who have received concurrent chemoradiation therapy (cCTRT), the median progression-free survival (PFS) is approximately 8 months and the 5-year overall survival (OS) is only 15%. 
Following the publication of the efficacy results from the landmark PACIFIC trial, immune checkpoint blockade with durvalumab as a sequential/consolidation therapy in patients who have not progressed following cCTRT, became the new standard of care in this setting, as durvalumab confirmed significant improvements in OS and PFS compared to placebo, with a manageable safety profile. 
Immune checkpoint blockade (or Immune checkpoint Inhibitors – ICI) refers to a type of drugs that blocks proteins called checkpoints. Checkpoints are expressed by some types of immune system cells, such ass T-cells, and some cancer cells and help keep the immune responses from being strong enough to kill cancer cells. By blocking the checkpoint proteins, ICI are able to re-invigorate the response of our immune system against the tumour. 
Despite this, there is still a need for additional information that could help improving the decision-making process when planning a therapeutic strategy in this setting.
Patients with cancer may have several comorbidities and being on non-oncology medications, which in turns may affect clinical effectiveness of ICI. The detrimental role of systemic antibiotics taken prior to ICI initiation (pATB, meaning prior antibiotic therapy) and proton pump inhibitors (PPIs, drugs that are able to reduce the amount of acid made by the glands in the lining of your stomach) has been the focus of intense research, leading to convincing clinical and mechanistic evidence supporting pATB/PPI associated intestinal dysbiosis (i.e. the perturbation of the gut microbiota induced by antibiotics (ATB) and PPI) as a potential negative factor for chemotherapy-free ICI-based regimens in the context of advanced stage NSCLC, independently of the underlying prescription's indication. 
Intestinal dysbiosis refers to a condition of alteration of the normal gut microbiota (or gut microbiome, or gut flora), which consists of whole combination of microorganisms, including bacteria, that live in the digestive system. Several reports highlight how a proper balance of the gut-microbiota is very important for the healthy functioning of the immune system and that multiple drugs taken for a variety of reason (such as antibiotics and PPI), can affect this balance.
Neutropenia is a condition often caused by chemotherapy, where you have a low number of white blood cells called neutrophils in your blood, and is associated with a weakened immune function, making it harder for your body to fight infection. Considering that neutropenia and infections during definitive chemoradiation in stage III NSCLC were historically reported in up to >50% and >20%, respectively, patients achieving partial response/stable disease to cCTRT have significant risks of being in need of systemic antibiotics, leaving unanswered questions about the possible impact on clinical outcomes of pATB and PPIs given prior to sequential/consolidation ICI.
PACIFIC is a Phase III, double-blind, placebo-controlled, multi-centre study which randomized patients with NSCLC who present with Stage III disease not amenable to surgical resection and who have not progressed following curative, platinum-based, cCTRT, to receive either Durvalumab or Placebo, as sequential maintenance therapy for up to 12 months.
Our aim is to access to the PACIFIC study dataset and analyse patients’ clinical outcomes across both the cohorts according to the exposure to PPIs and systemic antibiotics. The overarching goal of this analysis is to provide for the first-time important and practice informing evidence about the safe use of systemic antibiotics and PPIs in the era of immunotherapy for advanced Stage III NSCLC.