1492 Telomere-targeting agent THIO in sequence with cemiplimab demonstrates long-term therapeutic benefits beyond treatment cessation – A phase 2 THIO-101 trial in advanced ICI resistant NSCLC patients

<h3>Background</h3> Despite recent advances in first-line treatments for advanced NSCLC, long-term outlook for patients (pts) remains poor, with only 28% surviving beyond 5 years and limited treatment options for those resistant to immune checkpoint inhibitors (ICI). Biomarkers assessing telomere damage in cancer cells are becoming increasingly important for accurately determining efficacy following treatment. THIO is a newly developed treatment targeting telomerase-positive cancer cells, with a mechanism of action including chromatin uncapping and elimination of cancer cells. In animal models, THIO followed by ICI overcame ICI resistance. We describe updated efficacy and new biomarker findings from a phase 2 study of THIO in advanced NSCLC. <h3>Methods</h3> NCT05208944 is a phase 2 study of pts with advanced NSCLC relapsing after 1–4 prior treatments, including ICI. After completion of the safety stage using THIO 360 mg IV then cemiplimab, pts were randomized to receive de-escalating doses of THIO then an ICI (cemiplimab) 350 mg. THIO 180 mg was selected for further investigation by the Safety Review Committee. Telomere dysfunction-induced foci (TIF)-positive CTCs were characterized as gammaH2AX⁺/TRF1⁺. <h3>Results</h3> At data cut-off (01Aug2024), 69 pts had received ≥1 dose of THIO and were efficacy evaluable across all doses. At the 180mg dose in the 3^rd-line setting DCR of 88% greatly exceeded the threshold required for Stage 2 expansion and ORR was 38%, median survival follow-up was 10.6 months and OS% at 6 months was 75%. THIO combined with cemiplimab had a generally acceptable safety profile. Treatment with THIO at 180mg dose induced a 1.73-fold increase in telomere dysfunction (TIFs) in CTCs. <h3>Conclusions</h3> In the 3^rd-line setting OS% at 6 months was 75%, median PFS and OS were on track to substantially surpass current treatment options, with patients maintaining long-term therapeutic benefits beyond treatment cessation. Patients reached median survival follow-up of 10.6 months compared to currently expected OS of 5.8 months. Additionally, TIF formation in CTCs was shown to be a good biomarker of on-target activity. <h3>Trial Registration</h3> NCT05208944 is a phase 2 study of pts with advanced NSCLC relapsing after 1–4 prior treatments, including ICI. <h3>Ethics Approval</h3> Ethics approval for this study was obtained from the following ethics committees: Bellberry Human Research Ethics Committee (Australia) on 01-Mar-2022 (Approval No: CT-2021-CTN-04933-1), Medical Research Council Ethics Committee (Hungary) on 20-Jul-2022 (EudraCT No: 2021-005136-34), (Poland) on 22-Nov-2022 (EudraCT No: 2021-005136-34), Ethics Committee in Bulgaria) on 06-Oct-2022 (EudraCT No: 2021-005136-34), and United States on 27-Jul-2023 (IND No: IND-163503). All participants provided informed consent prior to their inclusion in the study. The trial adhered to the Declaration of Helsinki and local regulations for ethical research involving human subjects.