The combination of 6-thio-2’-deoxyguanosine (THIO), a first-in-class telomere-targeted agent, and cemiplimab (Libtayo) has shown promising activity in patients with advanced non-small cell lung cancer (NSCLC) who have developed resistance to checkpoint inhibitors. These findings come from the phase 2 THIO-101 trial (NCT05208944), presented at the 2024 SITC Annual Meeting.
Efficacy in Heavily Pretreated Patients
The data, with a cutoff of September 16, 2024, revealed that among 69 evaluable patients who completed at least one post-baseline assessment, 9 experienced partial responses (PRs) per RECIST 1.1 criteria, and 7 achieved confirmed PRs via a second scan, as assessed by investigators. Notably, 19 patients had survival follow-up exceeding 12 months. In the second line of therapy, all 9 patients were ongoing follow-up, while 8 of 10 patients in the third line were also ongoing follow-up, with one patient receiving 25 cycles of therapy.
In the third-line setting (n = 20), the disease control rate (DCR) was 85%. With a median survival follow-up of 11.5 months, 70% of these patients surpassed the 5.8-month overall survival (OS) threshold, and 85% exceeded the 2.5-month progression-free survival (PFS) threshold.
Enhanced Response with Optimized Dosing
Patients treated with THIO at a dose of 180 mg plus cemiplimab in the third line of therapy (n = 8) experienced an objective response rate (ORR) of 38%. At a median survival follow-up of 11.4 months, the median PFS was 5.5 months, 75% of patients crossed the 5.8-month OS threshold, and 88% crossed the 2.5-month PFS threshold. The 6-month OS rate was 75%.
"This regimen demonstrated an ORR of 38% in the selected 180-mg dose, significantly surpassing the approximately 6% seen with standard therapies in a heavily pretreated population," said Victor Zaporojan, MD, senior medical director of MAIA Biotechnology, during the presentation. "The THIO and cemiplimab combination not only offers a durable and effective treatment for advanced NSCLC but also has the potential to redefine standard care with promising response rates and extended survival benefits."
Study Design and Patient Characteristics
The THIO-101 trial was an open-label, multicenter study that enrolled adult patients with advanced NSCLC who experienced disease progression or relapse following treatment with an immune checkpoint inhibitor in the first or second line of therapy. Eligible patients had stage III or IV disease, at least one measurable lesion per RECIST 1.1, a life expectancy of more than 12 weeks, an ECOG performance status of 0 or 1, and adequate organ function. Prior treatment with a PD-1/PD-L1 inhibitor with or without chemotherapy was permitted, but immune checkpoint inhibitor therapy was allowed in only one of the first two lines of prior therapy.
Part A of the study used a modified 3+3 design, where patients received THIO 120 mg on days 1-3 every 3 weeks (total of 360 mg per cycle) plus cemiplimab 350 mg on day 5. Subsequently, patients were randomly assigned to receive THIO 60 mg (n = 24), 180 mg (n = 41), or 360 mg (n = 14) on days 1-3 every 3 weeks in combination with cemiplimab 350 mg on day 5.
The co-primary endpoints were safety, ORR, and DCR. Secondary endpoints included duration of response, PFS, and OS. Exploratory endpoints included pharmacokinetics and pharmacodynamics.
At baseline, all patients had previously experienced disease progression following treatment with at least one prior immune checkpoint inhibitor with or without chemotherapy. The median age of the overall study population (n = 79) was 67 years (range, 45-85); most patients were male (65%), had an ECOG performance status of 1 (73%), and had nonsquamous histology (60%). Brain and liver metastases were present at rates of 5% and 15%, respectively. Patients underwent 1 (66%), 2 (28%), 3 (4%), or 4 (3%) prior lines of therapy; 34% of patients underwent at least two prior lines of therapy at study entry.
Biomarker Correlation
Additional findings indicated that patients treated with THIO plus cemiplimab showed induction of telomere dysfunction-induced foci (TIF) in circulating tumor cells, suggesting a potential link between TIF positivity and more favorable outcomes.
"Increased TIF levels correlate with improved outcomes and stable levels may indicate disease progression. TIF serves as a valuable biomarker for personalizing cancer therapies and refining treatment strategies, ultimately enhancing patient care outcomes," Zaporojan noted.
Safety Profile
Treatment with THIO plus cemiplimab was generally well-tolerated, with most adverse events (AEs) being grade 1 or 2. No dose-limiting toxicities were reported during the safety lead-in. In the overall population, common treatment-emergent AEs (TEAEs) included increased aspartate aminotransferase (AST; 26.6%), increased alanine aminotransferase (ALT; 22.8%), nausea (12.7%), and neutropenia (5.1%). Grade 3 or higher TEAEs included increased ALT (11.4%), increased AST (11.4%), and neutropenia (3.8%). Enrollment into the 360-mg arm was paused following an instance of grade 4 liver function test elevation.
The 180-mg dose level of THIO was selected as the best dose in November 2023. Part B of the study, evaluating THIO at this dose, completed enrollment in February 2024.
