Phase 2 study of PFS in third-line immune checkpoint inhibitor–resistant advanced NSCLC treated with the telomere-targeting agent ateganosine (THIO; 6-thio-2'-deoxyguanosine) sequenced with ICI.

Abstract

e20610 Background: Despite advancements in third line treatments, long-term survival for advanced non-small cell lung cancer (NSCLC) remains suboptimal, with median survival follow-up of only 5.8 months 1 . Among patients treated with prior platinum chemotherapy and immune checkpoint inhibitors (ICIs), the median survival was reported to be 6.47 months 2 . Treatment options for ICI-resistant patients are limited. Ateganosine, a telomere-targeting agent that modifies telomeres in cancer cells, demonstrates improved progression-free survival (PFS) independent of PD-L1 expression. Methods: NCT05208944 is a phase 2, multicenter, open-label study that enrolled 79 patients with advanced NSCLC who relapsed after 1 - 4 prior treatments, including ICIs. At data cut off (Jan 15, 2026), in the third line therapy 22 patients treated with THIO (60, 180, or 360 mg) were evaluated for (PFS) and their prior PD-L1 expression at the time of study enrollment (C1D1). Results: In the third line therapy 17 out of 22 patients (77%) surpassed the benchmark value, and in the 180 mg dose group (n = 10) it reached 24.1 weeks compared to 2.5 months for the benchmark 3,4 . Exploratory biomarker analyses showed that baseline LDH levels were prognostic for outcomes. Across all patients, elevated LDH was associated with shorter PFS (log-rank p = 0.03, 2-sided) and OS (log-rank p = 0.01, 2-sided), with patients with no available LDH values excluded. In the third-line population, elevated LDH remained prognostic for OS (log-rank p = 0.04, 2-sided). THIO followed by cemiplimab was generally well tolerated in this difficult-to-treat population. The response to THIO and cemiplimab, demonstrated by partial response (PR) and stable disease (SD) was independent of baseline PD-L1 status. This indicates that THIO can be effective across patients regardless of their PD-L1 status. Conclusions: Ateganosine demonstrates clinically meaningful PFS improvement in third line patients with advanced NSCLC, independent of PD-L1 status. The improved PFS observed in patients treated with THIO in sequential combination with an immune checkpoint inhibitor (ICI), compared to standard chemotherapy, supports its potential to expand treatment options for ICI-resistant advanced NSCLC. Baseline LDH levels provide prognostic information across populations and may help identify patients most likely to benefit from therapy. Clinical trial information: NCT05208944 .