Impact of concomitant fibrates on immunotherapy outcomes for advanced non-small cell lung cancer

• Type of Material: Article
• Authors: William Stokes, Emory University; Madhusmita Behera, Emory University; Renjian Jiang, Emory University; David Gutman, Emory University; Zhonglu Huang, Emory University; Abigail Burns, Atlanta Veterans Affairs Health Care System; Nikhil Sebastian, Emory University; Vidula Sukhatme, Emory University; Michael Lowe, Emory University; Suresh Ramalingam, Emory University; Vikas Sukhatme, Emory University; Drew Moghanaki, University of California Los Angeles
• Language: English
• Date: 2022-05-24
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/cam4.4847
• Title of Journal or Parent Work: CANCER MEDICINE
• Volume: 12
• Issue: 1
• Start Page: 358
• End Page: 367
• Keywords: NIVOLUMAB; peroxisome proliferator-activated receptor (PPAR) agonists; Oncology; 1ST-LINE TREATMENT; THERAPY; immune checkpoint inhibitors; Science & Technology; fibrates; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Background: Peroxisome proliferator-activated receptor agonists such as fibrates restore oxidative metabolism in cytotoxic T-lymphocytes, thereby enhancing response to immune checkpoint inhibitors (ICI) in preclinical models. However, there is no evidence in humans on the clinical impact of fibrates as an adjunct to ICI. Methods: In this cohort study of Veterans with non-small cell lung cancer (NSCLC) receiving ICI, fibrate exposure was defined as a prescription filled within 90 days of an ICI infusion. Overall survival (OS), measured from the start of ICI, was compared between exposed and unexposed Veterans. Cox multivariable analysis (MVA) was used to identify factors associated with OS. A sensitivity analysis of Veterans with stage IV NSCLC who received docetaxel without ICI was similarly performed. Results: The ICI cohort included 3593 Veterans, of whom 301 (8.5%) coincidentally received a fibrate. Veterans receiving fibrates were more likely to be older, white, male, and married, and to have greater comorbidity burden, but less likely to receive chemotherapy. Coincidental fibrates were associated with improved OS both on MVA (HR 0.86, 95%CI 0.75–0.99) and in a matched subset (HR 0.75, 95%CI 0.63–0.90). In contrast, among the cohort of 968 Veterans treated with chemotherapy, fibrates did not have a significant impact on OS by MVA (HR 0.99, 95%CI 0.79–1.25) or in a matched subset (HR 1.02, 95%CI CI 0.75–1.39). Conclusions: Concomitant fibrates are associated with improved OS among NSCLC patients receiving ICI but not among those receiving chemotherapy. This hypothesis-generating observation supports a potential role for fibrates as an adjunct to immunotherapy.