Data from Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial

Abstract

<div>AbstractPurpose:<p><i>RUNX3</i> is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced <i>RUNX3</i> in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR–tyrosine kinase inhibitors (TKI) for patients with stage IV lung cancer carrying <i>EGFR</i> mutations.</p>Patients and Methods:<p>We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased <i>RUNX3</i> levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had <i>EGFR</i> mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, <i>n</i> = 55) or placebo (<i>n</i> = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively.</p>Results:<p>After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months [95% confidence interval (CI), 10.4–18.3], while the placebo group had a PFS of 10.9 months (9.0–13.2; <i>P</i> = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; <i>P</i> = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (<i>P</i> = 0.01) and never-smokers (<i>P</i> = 0.03) treated with nicotinamide.</p>Conclusions:<p>The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked (ClinicalTrials.gov Identifier: NCT02416739).</p></div>