A phase 2, multicenter, open-label, dose-optimization study evaluating telomere-targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC: Updated results.
Authors: Jankowski Tomasz , Csőszi Tibor , Urban Laszlo , Nagy Tunde , Chilingirova Nataliya , Cholakova Maria , Joshi Rohit , Moore Melissa M. , Ramlau Rodryg , Soter Szabolcs , Kotlarski Marek , Koynov Krassimir Dimitrov , Mruk Andrzej , Seidl Brenton , Minchev Velko , Muller Veronika , Vitoc Vlad , Gryaznov Sergei , Tudos Oleg , Zaporojan Victor 
Published: June 2024

8601 Background: Despite recent approvals for the first-line (1L) treatment of advanced non-small-cell lung cancer (NSCLC), long-term prognosis remains poor with a 5-year survival rate of 28% and limited options exist in patients (pts) refractory or resistant to immune checkpoint inhibitors (ICI). THIO (6-thio-2’-deoxyguanosine) is a small molecule, first-in-class direct cancer telomere-targeting agent that selectively targets telomerase positive (TERT+) cancer cells. It is incorporated de novo in synthesized telomeres leading to chromatin uncapping, generation of DNA damage signals, and rapid apoptosis. In advanced cancer animal models, THIO followed by an ICI demonstrated the ability to overcome ICI resistance. Methods: Here we describe a phase 2 dose-optimization study (NCT05208944) for adults with advanced NSCLC who progressed or relapsed after 1–4 prior treatment (tx) lines including 1L ICI alone or in combination with platinum chemotherapy. Following a safety lead-in of 10 pts who received THIO 360 mg IV [120 mg QD, D1–3] followed by 350 mg IV cemiplimab on D5 Q3W, the study proceeded to a 2-stage design with pts randomized to 1 of 3 arms: THIO 60 mg, 180 mg, or 360 mg, all followed by cemiplimab Q3W. In Stage 1 if at least 8 of 19 pts/arm achieved disease control, an additional 22 pts could be enrolled in that arm (up to 41 pts/arm). Study endpoints include safety (DLTs and AEs/SAEs) and efficacy (ORR, DCR, DOR, PFS, and OS). Results: Recruitment into the 360 mg arm was paused after 4 pts following 1 instance of G4 ALT Increase and AST Increase (without clinical presentation). At the end of Stage 1 cut-off (13-Nov-2023), the DCR greatly exceeded the threshold required for Stage 2 expansion in both arms: 60 mg 14/16 (88%); 180 mg 11/13 (85%). The 180 mg dose was selected for further investigation by the trial’s Safety Review Committee based on superior efficacy (31% PR rate; 54% reduction in tumor burden). As of 8-Jan-2024, 56 pts received ≥1 dose of THIO in the 60 and 180 mg arms (24 and 32 pts, respectively). Prior lines of tx at study entry were: 60 mg (1L 75%, 2L 21%, 3L 4%); 180 mg (1L 66%, 2L 31%, 4L 3%). Most pts received platinum chemotherapy prior to study entry (60 mg 88%; 180 mg 78%). Across all pts treated n=70, most AEs were G1/2. The most frequent related AEs were AST increase (23%), ALT increase (20%), and nausea (11%). All instances of LFT elevations were without clinical symptoms and resolved to baseline. Conclusions: THIOfollowed by cemiplimab was generally well tolerated in this difficult-to-treat population (all pts progressing following ICI tx and the majority following platinum chemotherapy). Based on safety and promising efficacy, the 180 mg dose was selected for further development. Enrollment is ongoing and is expected to be completed in Feb-2024. Updated primary endpoint data, including preliminary durability data, will be presented. Clinical trial information: NCT05208944 .