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Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A
Hyung-Joo Oh1, Suk-Chul Bae2, In-Jae Oh1
1Department of Internal Medicine, Chonnam National University Medical School, and CNU Hwasun Hospital, Hwasun, Jeonnam, South Korea.
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).
Insights
Nicotinamide combined with EGFR-TKIs showed potential benefits for stage IV lung cancer patients. Survival improvements were notable in female patients and never-smokers, suggesting a targeted therapeutic approach.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- RUNX3, a tumor suppressor gene, is inactivated in ~70% of lung adenocarcinomas.
- Nicotinamide, a sirtuin inhibitor, can re-activate epigenetically silenced RUNX3.
- EGFR-tyrosine kinase inhibitors (TKIs) are a standard treatment for EGFR-mutated lung cancer.
Purpose of the Study:
- To assess the therapeutic benefits of combining nicotinamide with first-generation EGFR-TKIs.
- To evaluate the impact of nicotinamide on progression-free survival (PFS) and overall survival (OS) in patients with stage IV lung cancer and EGFR mutations.
Main Methods:
- Mice models showed nicotinamide increased RUNX3 and inhibited lung cancer growth.
- 110 patients with stage IV EGFR-mutated lung cancer were randomized to nicotinamide (1g/day) or placebo.
- Primary endpoint was PFS; secondary endpoint was OS, with a median follow-up of 54.3 months.
Main Results:
- Median PFS was 12.7 months with nicotinamide vs. 10.9 months with placebo (P=0.2).
- Median OS was 31.0 months with nicotinamide vs. 29.4 months with placebo (P=0.2).
- Subgroup analyses revealed significantly reduced mortality risk for females (P=0.01) and never-smokers (P=0.03) with nicotinamide.
Conclusions:
- Combining nicotinamide with EGFR-TKIs showed potential for improved PFS and OS in stage IV lung cancer.
- Significant survival benefits were observed in female patients and never-smokers treated with nicotinamide.
- Nicotinamide may represent a valuable addition to EGFR-TKI therapy for specific lung cancer patient subgroups.
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