THIO Plus Cemiplimab Demonstrates Promising Activity in ICI-Resistant Advanced NSCLC
核心洞察
The combination of THIO (ateganosine) plus cemiplimab showed clinical activity with a 77% disease control rate in patients with advanced NSCLC resistant to immune checkpoint inhibitors.
Median overall survival reached 17.8 months in the third-line setting, with partial responses observed in 10 patients across second- and third-line treatments.
The treatment was generally well tolerated with most adverse events being grades 1-2, and biomarker analyses suggested response occurred independent of PD-L1 (搜索) status.
The combination of THIO (ateganosine, 6-thio-2'-deoxyguanosine) plus cemiplimab (Libtayo) demonstrated clinical activity and acceptable safety in patients with advanced non-small cell lung cancer (NSCLC) resistant to immune checkpoint inhibitors (ICIs), according to findings from the phase 2 dose-optimization THIO-101 study presented at the 2025 ASCO Annual Meeting.
Seventy-nine patients received at least one THIO dose at 60 mg (n = 24), 180 mg (n = 41), or 360 mg (n = 14) levels. Results showed partial responses in 10 patients across all dose levels, including 6 in the second-line setting and 4 in the third-line setting. The overall disease control rate reached 77%.
Survival Outcomes Show Promise
The estimated median overall survival in the third-line setting (n = 22) across all dose levels was 17.8 months, with a 95% confidence interval lower bound of 12.5 months. Follow-up for survival exceeded 12 months for 36 patients. Notably, 63% of patients crossed the 5.8-month OS threshold, and 77% of patients crossed the 2.5-month progression-free survival threshold.
"The combination of THIO plus cemiplimab has durable activity in this hard-to-treat patient population [of checkpoint inhibitor–resistant and chemotherapy-resistant progressors]," wrote lead study author Tomasz Jankowski, MD, PhD, of Poland's Medical University in Lublin, and coinvestigators. "THIO can be effective across patients regardless of their PD-L1 (搜索) status."
Mechanism and Rationale
THIO is described as a small molecule, first-in-class direct cancer telomere-targeting agent that selectively kills telomerase (搜索) (TERT (搜索))-positive cancer cells. More than 80% of all cancers, including an estimated 78% to 83% of all NSCLC cases, are telomerase positive. The drug is incorporated into de novo synthesized telomeres, leading to chromatin uncapping, generation of DNA damage signals, and rapid apoptosis.
Preclinical data showed that sequential treatment with THIO and ICIs overcame tumor resistance to immunotherapy, demonstrating potent and durable clinical activity. Preliminary data indicate that at low doses, THIO induces sensitivity to ICIs when given prior to immunotherapy in tumors that are otherwise resistant to this class of agents.
Study Design and Patient Population
The THIO-101 trial enrolled adult patients with advanced NSCLC who progressed or relapsed following 1 to 4 lines of prior therapy, including at least one frontline ICI alone or in combination with platinum-based chemotherapy. The trial used a 3+3, Simon 2-stage design with a safety lead-in phase followed by dose-finding.
At the data cutoff date of May 15, 2025, all 79 patients had previously progressed on at least one prior line of ICI with or without chemotherapy in the advanced setting, with 34% having received 2 prior lines of treatment. The median age was 67 years (range, 45-85), 35% were female, and 73% had an ECOG performance status of 1.
Safety Profile and Biomarker Findings
Most treatment-emergent adverse events were grades 1 and 2 in severity and were similar across dose levels. The most common adverse events included increased aspartate aminotransferase levels (26.6%), increased alanine aminotransferase levels (22.8%), and nausea (12.7%). Grade 3 or higher increased ALT and AST levels each occurred in 9 patients (11.4%).
One case of grade 4 liver function test level elevation occurred at the 360-mg dose in part B, leading to paused enrollment on that arm. No dose-limiting toxicities were reported in the safety lead-in phase.
Biomarker analyses confirmed that response to THIO plus cemiplimab occurred independent of baseline PD-L1 (搜索) status. Additionally, researchers assessed telomere dysfunction-induced foci (TIFs) in circulating tumor cells in 12 patients, with induction of TIFs confirming on-target activity and showing a potential link between TIF positivity and improved clinical outcomes.
Predictive Biomarker Discovery
Initial interleukin-6 elevation may correlate with immune response to THIO plus cemiplimab, suggesting a predictive biomarker for treatment efficacy, according to findings presented at the 2025 European Lung Cancer Congress. The 180-mg THIO dose demonstrated better safety and efficacy, supporting its potential for long-term administration and prolonged survival benefits.
Future Development Plans
An expansion cohort is planned based on part B data for the third-line setting. Up to 48 patients will be enrolled in part C starting in the first half of 2025, featuring two arms: THIO alone and THIO plus cemiplimab. Additionally, up to 100 patients will be enrolled in part D, with eligible patients needing to have had resistance to ICIs and chemotherapy.