THIO Plus Cemiplimab Displays Efficacy in Checkpoint Inhibitor–Resistant NSCLC

The small molecule, first-in-class telomere-targeted agent 6-thio-2’-deoxyguanosine (THIO; 6-thio-dG) in combination with cemiplimab (Libtayo) demonstrated durable activity in patients with advanced checkpoint inhibitor–resistant non–small cell lung cancer (NSCLC), according to findings from the phase 2 THIO-101 trial (NCT05208944) presented during the 2024 SITC Annual Meeting.¹

At the September 16, 2024, data cutoff, among evaluable patients who completed at least 1 post-baseline assessment (n = 69), 9 experienced partial responses (PRs) per RECIST 1.1 and 7 achieved confirmed PRs via a second scan per investigator assessment. Nineteen patients had survival follow-up exceeding 12 months; all 9 patients in the second line of therapy were ongoing follow-up, 8 of 10 patients in the third line were ongoing follow-up, and 1 patient had received 25 cycles of therapy.

Patients treated in the third-line setting (n = 20) achieved a disease control rate (DCR) of 85%. At a median survival follow-up of 11.5 months, 70% of these patients crossed the 5.8-month overall survival (OS) threshold and 85% crossed the 2.5-month progression-free survival (PFS) threshold.

Additionally, patients who received 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% [ORR] seen with standard therapies in a heavily pretreated population,” Victor Zaporojan, MD, the senior medical director of MAIA Biotechnology, said 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.”

THIO was granted orphan drug designation from the FDA in April 2022 for the treatment of patients with hepatocellular carcinoma.² In August 2022, the agent also received orphan drug designation from the FDA in small cell lung cancer.³

THIO-101 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.⁴ Eligible patients needed to have stage III or IV disease, have at least 1 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; immune checkpoint inhibitor therapy was allowed in the first or second line of prior therapy, but not both.

Part A of the study utilized a modified 3+3 design where patients received THIO 120 mg on days 1 through 3 every 3 weeks for a total of 360 mg per cycle plus cemiplimab 350 mg on day 5.1,4 Patients were then randomly assigned to received THIO 60 mg (n = 24), 180 mg (n = 41), or 360 mg (n = 14) on days 1 through 3 every 3 weeks in combination with cemiplimab 350 mg on day 5.

The coprimary end points were safety, ORR, and DCR. Duration of response, PFS, and OS represented secondary end points. Exploratory end points included pharmacokinetics and pharmacodynamics.¹

At baseline, all patients had previously experienced disease progression following treatment with at least 1 prior immune checkpoint inhibitor with or without chemotherapy in the advanced setting. 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 2 prior lines of therapy at study entry.

Additional findings from the study showed that patients treated with THIO plus cemiplimab displayed induction of telomer dysfunction-induced foci (TIF) in circulating tumor cells. Study authors noted that this suggested 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 commented.

In terms of safety, treatment with THIO plus cemiplimab was generally well tolerated and most adverse effects (AEs) were grade 1 or 2; no dose-limiting toxicities were reported during the safety lead in. In the overall population, any-grade treatment-emergent AEs (TEAEs) occurring in at least 2 patients 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.

In November 2023, the 180-mg dose level of THIO was selected as the best dose. Part B of the study is evaluating THIO at this dose and completed enrollment in February 2024.

References

1. Csoszi T, Jankowski T, Urban L, et al. Telomere-targeting agent THIO in sequential combination with cemiplimab demonstrates long term therapeutic benefits beyond treatment cessation. A phase 2 trial in advanced immune checkpoint inhibitor resistant non-small cell lung cancer patients. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 1492.
2. MAIA Biotechnology, Inc. announces FDA orphan drug designation for THIO for the treatment of hepatocellular carcinoma (HCC). News release. MAIA Biotechnology. April 26, 2022. Accessed November 8, 2024. https://ir.maiabiotech.com/news-events/press-releases/detail/35/maia-biotechnology-inc-announces-fda-orphan-drug
3. MAIA Biotechnology receives FDA orphan drug designation for THIO for the treatment of small-cell lung cancer (SCLC). News release. MAIA Biotechnology. August 2, 2022. Accessed November 8, 2024. https://ir.maiabiotech.com/news-events/press-releases/detail/41/maia-biotechnology-receives-fda-orphan-drug-designation-for
4. THIO sequenced with cemiplimab in advanced NSCLC. ClinicalTrials.gov. Updated August 31, 2023. Accessed November 8, 2024. https://clinicaltrials.gov/study/NCT05208944