Purpose: RUNX3 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 RUNX3 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 EGFR mutations. Patients and Methods: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR 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, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Results: 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; P = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; P = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (P = 0.01) and never-smokers (P = 0.03) treated with nicotinamide. Conclusions: 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).

中文翻译：

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烟酰胺联合 EGFR-TKIs 治疗伴有 EGFR 突变的 IV 期肺腺癌：随机双盲（IIb 期）试验

目的：RUNX3是一种抑癌基因，在大约70%的肺腺癌中失活。烟酰胺是一种沉默调节蛋白抑制剂，已被证明具有重新激活癌细胞中表观遗传沉默的 RUNX3 的潜力。这项研究评估了烟酰胺与第一代 EGFR 酪氨酸激酶抑制剂 (TKI) 联合治疗携带 EGFR 突变的 IV 期肺癌患者的治疗效果。患者和方法：我们评估了烟酰胺对致癌物诱发的小鼠肺腺癌的影响，并观察到烟酰胺增加了 RUNX3 水平并抑制了肺癌生长。随后，连续招募了 110 名具有 EGFR 突变的 IV 期肺癌患者：70 名女性（63.6%）和 84 名从不吸烟者（76.4%）。患者被随机分配接受烟酰胺（1 克/天，n = 55）或安慰剂（n = 55）。主要和次要终点分别是无进展生存期（PFS）和总生存期（OS）。结果：中位随访 54.3 个月后，烟酰胺组的中位 PFS 为 12.7 个月 [95% 置信区间 (CI)，10.4–18.3]，而安慰剂组的中位 PFS 为 10.9 个月（9.0–13.2） P = 0.2）。两组的中位 OS 相似（烟酰胺组为 31.0 个月，安慰剂组为 29.4 个月；P = 0.2）。值得注意的是，亚组分析显示，接受烟酰胺治疗的女性（P = 0.01）和从不吸烟者（P = 0.03）的死亡风险显着降低。结论：在 EGFR-TKIs 中添加烟酰胺显示出 PFS 和 OS 的潜在改善，对女性患者和从不吸烟的患者具有显着的生存益处（ClinicalTrials.gov 标识符：NCT02416739）。