DOI: 10.25934/pr00011041
title: Differential effect of systemic antibiotics and proton pump inhibitors on clinical outcomes from adjuvant immunotherapy or best supportive in patients with resected early stage NSCLC (stage III): A post-hoc analysis of the Impower010 trial.

description: Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for approximately 25% of all cancer-related mortality. The most common form is non-small cell lung cancer (NSCLC), which makes up about 84% of all lung cancer cases. Among those diagnosed with NSCLC, around 30% have early-stage disease that is considered resectable, meaning it can potentially be removed completely with surgery. For these patients, surgery is the main treatment with the goal of curing the disease. However, even when the tumor is entirely removed, there is still a high risk that the cancer will come back—especially in patients with stage II and stage IIIA disease, which are more advanced early stages where the cancer may have spread to nearby lymph nodes but not to distant organs.

To lower this risk of recurrence, patients often receive adjuvant chemotherapy, which is additional treatment given after surgery to kill any remaining cancer cells. This typically involves platinum-based chemotherapy, a type of drug that contains platinum compounds and works by damaging the DNA of cancer cells so they can’t grow or divide. While this approach has been shown to improve survival, the benefit is limited, and many patients still experience relapse.

Recently, the introduction of immune checkpoint inhibitors (ICIs) has changed the treatment landscape for lung cancer. These are a type of immunotherapy, meaning they help the body’s own immune system recognize and attack cancer cells. One important advance has been using ICIs in the adjuvant setting—after surgery and chemotherapy—to further reduce the chance of the cancer coming back.

A key study in this area is the IMpower010 trial, which investigated whether immunotherapy could help patients with resected early-stage NSCLC. In this phase III study, patients who had surgery and completed chemotherapy were randomly assigned to receive either atezolizumab (a type of ICI that blocks a protein called  Programmed Death-Ligand 1 (PD-L1), which helps cancer cells hide from the immune system) or best supportive care. The results showed that atezolizumab significantly improved disease-free survival—the length of time patients lived without their cancer returning—especially in those whose tumors expressed PD-L1 in at least 1% of their cancer cells. Based on these results, atezolizumab was approved as an adjuvant treatment for certain patients with resected NSCLC, offering a new option to help prevent relapse.

Despite these advances, several factors can influence how well ICIs work. People with cancer often take other medications for unrelated health issues, and some of these drugs might affect the immune system in ways that could interfere with immunotherapy. Two commonly used types of drugs that have raised concern are systemic antibiotics (which treat bacterial infections throughout the body) and proton pump inhibitors (PPIs), which reduce stomach acid and are often used to treat conditions like gastroesophageal reflux disease (GERD), a chronic form of acid reflux.

Both antibiotics and PPIs can disrupt the gut microbiome—the community of bacteria and other microorganisms in the digestive tract—which is increasingly recognized as playing a key role in how the immune system responds, including to ICIs. In advanced NSCLC, studies have shown that patients who received antibiotics before starting immunotherapy tended to have worse outcomes, likely due to these microbiome changes. Similar concerns have been raised for PPIs. However, it is still unclear whether such effects also occur in the adjuvant setting, where the goal is to prevent recurrence rather than treat an active tumor.

This study aims to explore this question by analyzing data from the IMpower010 trial to determine whether taking antibiotics or PPIs before starting adjuvant atezolizumab affects treatment outcomes. Specifically, we will look at whether patients who used these medications shortly before starting immunotherapy had worse disease-free and overall survival compared to those who did not. Because the IMpower010 trial included a control group that did not receive immunotherapy, we can also assess whether any negative effects of these medications are specific to patients treated with atezolizumab, or if they impact outcomes more generally.

By examining these associations, this research hopes to clarify whether commonly used drugs like antibiotics and PPIs could unintentionally reduce the effectiveness of adjuvant immunotherapy. If a significant link is found, the findings could help guide future treatment recommendations and ultimately improve outcomes for patients with resected early-stage NSCLC.