THIO Plus Cemiplimab Associated with Prolonged OS in ICI-Resistant NSCLC

THIO with cemiplimab is active and well-tolerated in patients with advanced non–small cell lung cancer resistant to immune checkpoint inhibitors in second- and third-line settings.

The combination of THIO (ateganosine, 6-thio-2’-deoxyguanosine, 6-thio-dG) and cemiplimab (Libtayo) demonstrated clinical activity and was well tolerated in patients with advanced non–small cell lung cancer (NSCLC) resistant to immune checkpoint inhibitors (ICIs) in second- and third-line settings. These findings from the phase 2 dose-optimization THIO-101 study (NCT05208944) were presented at the 2025 American Society of Clincial Oncology Annual Meeting.1

Seventy-nine patients overall received at least 1 THIO dose at 60 mg (n = 24), 180 mg (n = 41), or 360 mg (n = 14).

Results showed that, across all THIO dose levels, partial responses (PRs) occurred in 10 patients, which included 6 in the second-line setting and 4 in the third-line setting. Through a second scan via investigator assessment, there were 4 PRs in each of the 2 settings. The disease control rate (DCR) overall was 77%.

The estimated median overall survival (OS) 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; the follow-up for survival was above 12 months for 36 patients. Sixty-three percent of patients crossed the 5.8-month OS threshold, and 77% of patients crossed the 2.5-month progression-free survival (PFS) threshold.

Regarding safety, most treatment-emergent adverse events (TEAEs) were grades 1 and 2 in severity and were similar across dose levels.

“The combination of THIO plus cemiplimab has durable activity in this hard-to-treat patient population [of checkpoint inhibitor–resistant and chemotherapy-resistant progressors],” lead study author Tomasz Jankowski, MD, PhD, of Poland’s Medical University in Lublin, and coinvestigators wrote in a poster presented during the meeting. “THIO can be effective across patients regardless of their PD-L1 status.”

Exploring the Trial Background and Rationale

Survival outcomes for patients with advanced NSCLC are approximately 28% at 5 years, and there are limited options for those who are refractory or resistant to ICIs. More than 80% of all cancers, including an estimated 78% to 83% of all NSCLC cases, are telomerase (TERT) positive.

THIO is described as a small molecule, first-in-class direct cancer telomere–targeting agent that selectively kills TERT-positive cancer cells. It is incorporated into de novo synthesized telomeres that lead 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.2 The authors also noted that preliminary data show that at low doses, THIO induces sensitivity to ICIs when given prior to immunotherapy in tumors that are otherwise resistant or don’t respond to this class of agents.1

Zeroing in on the THIO-101 Design

In the ASCO presentation of THIO-101, investigators presented data on adult patients with advanced NSCLC who progressed or relapsed following 1 to 4 lines of prior therapy, including at least 1 frontline ICI alone or in combination with platinum-based chemotherapy. The trial had a 3+3, Simon 2-stage design. The safety lead-in phase (part A) consisted of 10 patients treated with THIO intravenously (IV) at 360 mg intravenously (120 mg daily on days 1 to 3), followed by 350 mg of cemiplimab on day 5 every, 3 weeks. After part A, enrollment was opened in the dose-finding portion (part B).

In part B, 79 patients were assigned to receive 1 of the 3 THIO doses followed by cemiplimab every 3 weeks for up to 1 year. Disease status was assessed at day 1 of cycles 3 and 5, and every 9 to 12 weeks thereafter.

Enrollment was completed for parts A and B in February 2024. The primary end points were objective response rate, DCR, and safety; secondary end points were duration of response, PFS, and OS. Pharmacokinetics and pharmacodynamics served as exploratory end points.

Expanding on Patient Baseline Characteristics

At the data cutoff date of May 15, 2025, 79 patients with advanced NSCLC had received at least 1 dose of THIO. All patients had previously progressed on at least 1 prior line of ICI with or without chemotherapy in the advanced setting with documented disease progression at study entry, and 34% of patients had received 2 prior lines of treatment.

Regarding other baseline characteristics, the median age overall was 67 years (range, 45-85), 35% of patients were female, and 73% of patients had an ECOG performance status of 1. Sixty percent of patients had nonsquamous disease, 5% of patients had brain metastases, and 15% of patients had liver metastases.

Specifying the Safety Data and Next Steps

TEAEs overall comprised increased aspartate aminotransferase (AST) levels (26.6%); increased alanine aminotransferase (ALT) levels (22.8%); nausea (12.7%); neutropenia (5.1%); anemia, pyrexia, and decreased appetite (3.8% each); and increased blood alkaline phosphate levels, increased blood bilirubin levels, increased gamma-glutamyltransferase levels, leukopenia, asthenia, erythema, hypothyroidism, and infusion-related reaction (2.5% each).

Nine patients each (11.4%) experienced grade 3 or higher increased ALT levels and increased AST levels, which included 2 patients treated at the 360-mg dose, 4 patients treated at the 180-mg dose, and 3 patients treated at the 60-mg dose. All other grade 3 or higher TEAEs occurred in fewer than 5 patients.

No dose-limiting toxicities were reported in the safety lead-in phase of part A. However, there was 1 case of grade 4 liver function test level elevation at the 360-mg dose in part B, leading to paused enrollment on that arm.

Biomarker analyses showed that response to THIO plus cemiplimab occured independent of baseline PD-L1 status.

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. Part C will have 2 arms: THIO alone and THIO plus cemiplimab. Additionally, up to 100 patients will be enrolled in part D. Eligible patients need to have had resistance to ICIs and chemotherapy.

References

1. Jankowski T, Csõszi T, Urban L, et al. Phase 2 study of telomere-targeting agent THIO sequenced with cemiplimab in third-line immune checkpoint inhibitor–resistant advanced NSCLC: evaluation of overall survival (OS). J Clin Oncol. 2025;43(suppl_16):8585. doi:10.1200/JCO.2025.43.16_suppl.8585
2. Mender I, Gryaznov S, Dikmen ZG, et al. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine. Cancer Disc. 2015;5(1):82-95.doi:10.1158/2159-8290.CD-14-0609