Despite advances in first-line treatment, long-term prognosis for advanced non–small cell lung cancer (NSCLC) remains poor. Patients resistant to immune checkpoint inhibitors (ICIs) have limited treatment options.
THIO (6-thio-2’-deoxyguanosine) is a telomere-targeting agent that selectively kills telomerase-positive cancer cells, which comprise 78% to 83% of NSCLC cases. By inducing telomere dysfunction, chromatin uncapping, and DNA damage, THIO enhances tumor susceptibility to ICIs.
A phase 2 dose-optimization study (NCT05208944) was conducted to evaluate THIO plus cemiplimab in ICI-resistant NSCLC patients, and the results were reported at the 2025 European Lung Cancer Congress.1
Patients received THIO 360 mg, 180 mg, or 60 mg, followed by cemiplimab 350 mg intravenously for up to 1 year, and researchers assessed telomere dysfunction–induced foci (TIFs) in circulating tumor cells (CTCs) in 12 patients (baseline and posttreatment) using flow cytometry (TRF1 and γH2AX labeling).
As of January 15, 2025, estimated overall survival was reportedly 16.9 months (95% confidence interval [CI], 12.5 months; 99% CI, 10.8 months). Induction of TIFs in CTCs confirmed on-target activity, with a potential link between TIF positivity and improved clinical outcomes.
Grade ≥3 adverse events were reported in 9.8% of patients at 180 mg, with an alanine aminotransferase increase in 11.4% of all patients.
The researchers who reported their findings in a poster presented by Maia Biotechnology wrote that initial interleukin-6 elevation may correlate with immune response to THIO plus cemiplimab, suggesting a predictive biomarker for treatment efficacy.
The combination of THIO plus cemiplimab shows durable clinical activity in ICI-resistant and chemotherapy-refractory NSCLC patients, the researchers wrote. The 180-mg THIO dose demonstrated better safety and efficacy, supporting its potential for long-term administration and prolonged survival benefits.
Reference
- Jakowski T, Csoszi T, Urban L, et al. Phase 2 study of telomere-targeting agent THIO sequenced by cemiplimab in immune checkpoint inhibitor-resistant advanced NSCLC: interleukin-6 as a potential predictive biomarker. Presented at: 2025 European Lung Cancer Congress. March 26-29, 2025; Paris, France. Poster 997.