Naloxegol, an Oral Peripherally Acting Opioid Receptor Antagonist, Administered Concurrently with First-Line Systemic Therapy for Advanced Lung Adenocarcinoma (Alliance A221504): A Feasibility and Safety Study

<b>Background</b>: Mu opioid receptors (MORs) in peripheral tissues mediate adverse effects of opioids that impair health-related quality of life (HRQoL) and may stimulate cancer progression via mitogenic signaling. Naloxegol, a peripherally acting MOR antagonist (PAMORA), is approved for opioid-induced constipation. Safety and efficacy of naloxegol have not been evaluated concurrently with systemic cancer therapy. <b>Methods</b>: We conducted a randomized, double-blind, placebo-controlled trial of naloxegol in patients with advanced lung adenocarcinoma starting first-line systemic therapy. <b>Results</b>: Only 50 patients were enrolled; the trial was terminated early due to slow accrual. Two of the three components of the feasibility primary endpoint were not met (accrual and PRO completion). At 6 months, FACT-L emotional well-being was better with naloxegol (<i>p</i> = 0.0113). There were trends towards better Trial Outcome Index (<i>p</i> = 0.0505) and physical well-being (<i>p</i> = 0.0628) with naloxegol. Bowel function favored naloxegol for constipation (<i>p</i> = 0.0223), rectal pain during defecation (<i>p</i> = 0.0075), and abdominal pain from constipation (<i>p</i> = 0.0113). Adverse event frequency and severity, PRO-CTCAE, urinary hesitancy, pain scores, and progression-free and overall survival were comparable between naloxegol and placebo. <b>Conclusions</b>: Naloxegol appears to be safe and tolerable, with a signal of improved HRQoL and previously unappreciated benefit for emotional well-being, without adverse clinical outcomes. Our findings should be confirmed in larger studies. ClinicalTrials.gov ID: NCT03087708.