# 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

## TL;DR

This study tested if naloxegol, a drug used to treat opioid-induced constipation, is safe and beneficial for lung cancer patients receiving standard treatment.

## Contribution

The study explores the safety and potential quality-of-life benefits of naloxegol in cancer patients, a novel use for the drug.

## Key findings

- Naloxegol improved emotional well-being and bowel function without causing adverse clinical outcomes.
- Patients on naloxegol had better outcomes for constipation-related symptoms and pain.
- The trial was closed early due to slow recruitment, limiting statistical power.

## Abstract

Opioids relieve cancer-related pain by acting on receptors in the brain. Opioids acting on receptors in peripheral tissues mediate adverse effects, e.g., constipation. Research on cells and animals suggests that opioid receptors on cancer cells and blood vessels may stimulate cancer progression. Medications (including naloxegol) that only block opioid receptors in peripheral tissues are approved to treat opioid-induced constipation. To examine the feasibility, safety, and benefits of naloxegol in patients with cancer, we conducted a trial of naloxegol vs. placebo in patients with advanced lung adenocarcinoma starting systemic therapy. Feasibility included the accrual rate, ≥grade 3 adverse events, and completion of patient-reported outcome questionnaires. The trial was closed early due to slow accrual, limiting the ability to assess endpoints. There was no undesirable impact on adverse events, patient-reported symptoms, pain, or clinical outcomes. Patients receiving naloxegol experienced better emotional well-being, constipation, and pain related to constipation, which needs confirmation in larger studies.

Background: 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. Methods: We conducted a randomized, double-blind, placebo-controlled trial of naloxegol in patients with advanced lung adenocarcinoma starting first-line systemic therapy. Results: 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 (p = 0.0113). There were trends towards better Trial Outcome Index (p = 0.0505) and physical well-being (p = 0.0628) with naloxegol. Bowel function favored naloxegol for constipation (p = 0.0223), rectal pain during defecation (p = 0.0075), and abdominal pain from constipation (p = 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. Conclusions: 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.